Similarity Report

PAPER NAME ABSTRACT

draftfeb04.docx This article investigates the growing interest in nanoformulations that are derived from
80
phytochemicals for the purpose of treating lung cancer, with a specific focus on the
administration of targeted drugs. Phytochemicals such as curcumin, colchicinamide, and
79
taxol possess properties that can combat cancer by regulating the molecular pathways
WORD COUNT CHARACTER COUNT
involved in its progression. Phytochemicals have the challenges of poor solubility and limited
24717 Words 147685 Characters bioavailability, but phytochemicals can be employed into innovative medication delivery
58
technologies such as nanoparticles and liposomes. Phyto-nanoformulations, which play a
PAGE COUNT FILE SIZE crucial role in lung cancer therapy, enhance the absorption and effectiveness of drugs while
minimizing adverse effects and drug resistance. These findings imply a potential avenue for
63 Pages 1.5MB improving the treatment of lung cancer by precisely and effectively delivering therapies that
are based on phytochemicals.
SUBMISSION DATE REPORT DATE
1. INTRODUCTION
Feb 5, 2024 12:15 PM GMT+5:30 Feb 5, 2024 12:17 PM GMT+5:30
The most common cancer diagnosed globally was lung cancer, which had the lowest five-
60
year overall 15% survival rate and was responsible for a large part of 18.4% of cancer deaths
worldwide [1],[2]. The survival rate of lung cancer patients is only 15%, five years following
22% Overall Similarity their diagnosis since the disease usually progresses to an advanced stage in most cases[3][4].
2
Lung cancer is a significant public health issue, with a high global fatality rate. Tobacco use
The combined total of all matches, including overlapping sources, for each database.
is the key etiological factor for this LC, according to scientific studies[5], [6]. This is largely
15% Internet database 16% Publications database attributable to smoking, which contains several mutagenic substances that can result in
LC[7]. LC is caused by exposure to carcinogens like air pollution[8], asbestos[9], radon[10],
Crossref database Crossref Posted Content database 82
and genetic factors[11][12]. A two- to three-fold increased risk of LC and other malignancies
linked to quitting smoking exists in families with first-degree LC relatives[13]. According to
Excluded from Similarity Report past studies, an estimated 70% of air pollution and the emission of a variety of pollutants,
including SOx, NOx, CO2, and VOC (volatile organic compounds)[14], have been linked to
Submitted Works database Bibliographic material the growth of coal-based power plants[15], [16], [17].
Quoted material Cited material 1
Lung Cancer Cell Types
Small Matches (Less then 8 words)
1. Adenocarcinoma
It makes up 20-30% of pulmonary neoplasms. It starts more often in the periphery; it
originates from epithelial cells and less from glandular cells. It often appears in the
parenchymal scar tissue of previous pathological processes. Due to localization
adenocarcinoma has a later onset and clinical manifestations are less evident compared to
epidermoid carcinoma. It shows a high tendency to metastasize (second after SCLC)[18].
2. Non-small cell carcinoma
The incidence is estimated at about 15-20%. It can be of central or peripheral origin. The
tumor mass often has large dimensions at the time of diagnosis and is relatively limited.
Very often necrotic areas are found. Large nuclei, visible nucleoli, and abundant cytoplasm.
These elements, have no aspects of epidermoid, glandular, or neuroendocrine differentiation
and are organized in solid areas. According to the type of cell differentiation, two variants are
distinguished: Giant cell form: with an increased number of polynuclear cells, pleiomorphic
and others with different shapes. Clear cell form: rare, characterized by cells with clear,
foamy, and mucin-free cytoplasm[19].

Summary
 3. Small cell carcinoma (SCLC)
SCLC, accounts for about 25% of malignant lung tumors. (About 1 in 5 cases with
pulmonary Ca results in small cells.) It is a neoplasm of a higher malignant character and
with a pronounced ability to spread (metastasize) by hematogenous or lymphatic route. The
initial mass most often has centrohylar placement. The clinical onset is often signaled by
metastases. The frequency of this phenomenon is so high that in the face of a histologically
confirmed SCLC, one must consider the presence of metastasis[20]. The histological type of
SCLC is debatable: Frequent association with paraneoplastic syndromes suggests a cell
origin with neurosecretory function[21]. This hypothesis comes from immunohistochemical
studies, which often show features of neuroendocrine differentiation such as: Cytoplasmic
granulations and the presence of peptides and amines (serotonin, calcitonin, leukoencephalin,
gastrin, etc.)
3.1.Squamous cell carcinoma
40
Squamous cell carcinoma of the lung is a type of lung cancer that originates in the thin, flat
19
cells lining the airways. It is a subtype of non-small cell lung cancer (NSCLC) and accounts
71
for about 30% of all lung cancers.This type of cancer is strongly associated with smoking,
and other risk factors include age, family history, and exposure to second-hand smoke,
mineral and metal particles, or asbestos[22].
74
Squamous cell lung cancer often occurs in the central part of the lung or the main airway,
39
such as the left or right bronchus. It is more common in women than in men and is more
27
likely to occur in younger people than other types of lung cancer. The prognosis for
squamous cell lung cancer is often guarded, as it is usually diagnosed after the disease has
53
spread. The survival rate is significantly higher if the disease is detected and treated
early[23].
25
Considering that more than 40% of people do not smoke, lung cancer has been identified as
the main cause of cancer mortality[3], [24].
Lung cancer must be detected early to avoid the disease spreading to the metastatic stage.
Coughing, breathing problems, trouble sleeping, and systemic symptoms like anorexia and
8
weight loss are typical indicators of lung cancer[25]. Chest radiography, computational
tomography, and possibly positron emission tomography is used in most diagnostic
techniques[26].
8
The malignancy type, the disease stage at the time of the diagnosis, and the patient's physical
66
condition all plays a significant role in how lung cancer is treated[27]. Surgery is the main
form of treatment for non-malignant lung tumours, but it can only be used in a small
percentage of patients—between 10% and 20%—and is constrained by the size and location
of the tumours. Furthermore, surgery might not completely remove the tumour, especially in
cases of SCLC, which is known for its accelerated cell division due to its metastatic
nature[28]. The use of treatments for lung cancer, including chemotherapy, surgery,
immunotherapy, targeted therapies, radiation therapy, and photodynamic or laser therapy is
widespread[29], [30]. Although radiotherapy can specifically target tumour cells, it can also
harm normal lung cells. Additionally, there is no effective method to prevent the negative
effects of radiotherapy[31], which include fatigue[32], [33], vomiting[34], [35], bone marrow
issues[36], hair loss[37], and nausea[38].
LC is just one of the many ailments that have been treated for centuries with herbal
medicines[39]. The phytochemical compound’s (PC) like alkaloids, phenolic compounds,
92
terpenoids, saponins have proven efficacy in LC treatment. Studies have shown that they can
significantly lengthen the time that patients with lung cancer survive, lessen the
75
chemotherapy side effects, and enhance the quality of life[40], [41]. Many studies have
proven PC role in cancer treatment [42]. The main problem seen in PC are poor
bioavailability, solubility, and PC gets degraded by enzymes and get metabolise in the liver,
gastrointestinal tract, which reduces circulation time and circulating concentration [43].
Hence to overcome these problems nanotechnology is used.
83
The use of nanotechnologies to enhance the delivery of plant-based chemicals at site of
tumours and cancer cells to increase therapeutic efficacy [44], [45]. The localized drug
delivery improves overall bioavailability to the site of tumours in LC.
59
This article reviews the role of phytochemicals in the treatment of lung cancer, the scope of
preparation of phytochemical nano delivery system and physicochemical properties,
challenges, and futures.
2. Potential Molecular Pathways for treatment of Lung Cancer
Lung cancer arises from intricate signaling networks within cells, with various pathways
playing crucial roles. These pathways, including Ras, BRAF/MAPK, PI3K, LKB1/AMPK,
TP53, RB1, and MYC.
In healthy cells, these pathways operate in a balanced manner. However, lung cancer is
characterized by mutations and alterations that disrupt this balance, leading to uncontrolled
cell proliferation and impaired cell death mechanisms. For example, hyperactivation of Ras,
BRAF/MAPK, and PI3K pathways and silencing or weakening of LKB1/AMPK and TP53
pathways contribute to unchecked cell growth and tumor formation.
PATHWAYS
1. Ras Pathway:
Activated by extracellular signals, Ras proteins relay growth factor signals to the MAPK
cascade, triggering a series of phosphorylation events. This pathway regulates cell
proliferation, differentiation, and survival. Mutations in Ras are prevalent in various cancers,
leading to uncontrolled cell growth [7].
Despite the high prevalence of Ras mutations in lung cancer, there have been few effective
therapies that directly target this pathway. However, there are a number of new drugs that are
being developed that target different parts of the Ras pathway. These drugs are either in
clinical trials or are being approved for use in other cancers include:
MEK inhibitors: These drugs block the activity of MEK, a protein that is downstream of Ras
in the signaling pathway. MEK inhibitors that are approved for use in other cancers include
trametinib (Mekinist) and cobimetinib (Cotellic)[46].
35
KRAS G12C inhibitors: These drugs are designed to specifically target the KRAS G12C
35
mutation, which is the most common Ras mutation in lung cancer. The first KRAS G12C
 33
inhibitor, sotorasib (Lumakras), was recently approved by the FDA for the treatment of
patients with advanced lung cancer who have the KRAS G12C mutation[47].
2. BRAF/MAPK Pathway:
BRAF, a key component, activates the MAPK signaling pathway, promoting cellular
responses to growth signals. Mutations, especially in BRAF, result in constitutive activation,
contributing to abnormal cell division and tumor development across multiple cancer
types[8].
76
BRAF is a key component of the MAPK pathway. Mutations, particularly the V600E
42
mutation, result in constitutive activation of the pathway, promoting tumor growth and
progression in lung cancer[48].
Targeting mutated BRAF has been a promising approach in treating lung cancer. Drugs like
Dabrafenib and Vemurafenib selectively inhibit mutated BRAF, thereby suppressing
downstream MAPK signaling and inhibiting tumor growth. These inhibitors have shown
efficacy, particularly in lung cancers harboring BRAF V600E mutations[49].
3. PI3K Pathway:
42
Initiated by growth factors, the PI3K/Akt pathway regulates crucial cellular processes such as
growth, metabolism, and survival. Dysregulation, often due to mutations, is implicated in
cancer, diabetes, and cardiovascular diseases, influencing disease progression and therapeutic
responses [9].
These are the genes in the PI3K pathway that are frequently mutated or altered in lung
cancer, including:
PIK3CA: This gene encodes the p110α subunit of PI3K, which is a key enzyme in the
pathway. Mutations in PIK3CA are found in about 20-30% of lung cancers[50].
PTEN: This gene encodes a tumor suppressor protein that inhibits the PI3K pathway.
Mutations or deletions of PTEN are found in about 10-15% of lung cancers[51].
AKT1, AKT2, and AKT3: These genes encode AKT proteins, which are downstream
effectors of PI3K. Mutations in AKT genes are less common in lung cancer but can also
contribute to tumorigenesis[52].
70
Several drugs that target the PI3K pathway are being developed or investigated for the
treatment of lung cancer. These drugs work by inhibiting different components of the
pathway, thereby blocking cell growth and proliferation. Some of the most promising PI3K
pathway inhibitors for lung cancer include:
Alpelisib: This drug is a specific inhibitor of PI3Kα, which is encoded by the PIK3CA gene.
32 18
It has been approved by the FDA for the treatment of advanced breast cancer and is being
investigated in clinical trials for lung cancer[53].
27
Duvelisib: This drug is a dual inhibitor of PI3K and mTOR, another protein in the PI3K
49 18
pathway. It is approved by the FDA for the treatment of certain types of brain tumors and is
being investigated in clinical trials for lung cancer[54].
Umbralisib: This drug is a selective inhibitor of PI3Kδ, which is another subunit of PI3K. It
18
is being investigated in clinical trials for lung cancer and other types of cancer[55].
4. LKB1/AMPK Pathway:
34
LKB1 activates AMP-activated protein kinase (AMPK), a cellular energy sensor. This
pathway plays a pivotal role in maintaining energy homeostasis by regulating metabolism,
cell growth, and autophagy. Mutations in LKB1 are linked to various cancers and metabolic
disorders[10].
10
Mutations in the LKB1 gene are found in about 20-30% of non-small cell lung cancer
(NSCLC), the most common type of lung cancer. Other genes in the LKB1/AMPK pathway
that are frequently mutated in lung cancer include:
13
KEAP1: This gene encodes the protein Kelch-like ECH-associated protein 1, which normally
28
targets NRF2 (nuclear factor erythroid 2-related factor 2) for degradation. NRF2 is a
transcription factor that regulates the expression of antioxidant and detoxification genes.
Mutations in KEAP1 lead to the stabilization of NRF2, which can promote cancer cell
survival[56].
STK11: This gene encodes the protein LKB11, which is another AMPK kinase that can
activate AMPK in the absence of LKB1. Mutations in STK11 can also contribute to the
inactivation of the LKB1/AMPK pathway in lung cancer[57].
There are currently no drugs that directly target the LKB1/AMPK pathway that are approved
64
for the treatment of lung cancer. However, several drugs are being developed that target
different components of the pathway, and some of these drugs are in clinical trials. These
drugs include:
AMPK activators: These drugs directly activate AMPK, mimicking the effects of LKB1.
Some AMPK activators that are being studied in lung cancer include metformin, AICAR (5-
aminoimidazole-4-carboxamide ribonucleotide), and GSK621[58].
36
mTOR inhibitors: mTOR (mammalian target of rapamycin) is a downstream target of AMPK
that promotes cell growth and proliferation. mTOR inhibitors, such as everolimus and
10
rapamycin, are being studied in combination with other drugs for the treatment of lung
cancer[59].
48
PARP inhibitors: PARP (poly(ADP-ribose) polymerase) is an enzyme that is involved in
DNA repair. PARP inhibitors, such as olaparib and niraparib, can be effective in lung cancer
patients with mutations in BRCA genes, which are involved in DNA repair. PARP inhibitors
may also have activity against lung cancer cells with mutations in the LKB1/AMPK
pathway[60].
5. TP53 Pathway: TP53 loses its tumor suppression function – Mutant tp53 acquiring
oncogenic function
TP53, known as the "guardian of the genome," responds to cellular stress, orchestrating cell
cycle arrest, DNA repair, or apoptosis. This pathway is crucial for preventing the propagation
of damaged DNA, and mutations in TP53 are common in many types of cancer[11].
Several genes interact with TP53 to regulate its function and contribute to different aspects of
tumor suppression. Some of the key TP53 pathway genes involved in lung cancer include:
23
MDM2: This gene encodes an E3 ubiquitin ligase that targets p53 for degradation, thereby
inhibiting its tumor suppressor activity[61].
96
CDKN2A: This gene encodes p16, a protein that inhibits cyclin-dependent kinases (CDKs)
and prevents cell cycle progression[62].
ATM and CHEK2: These genes encode proteins involved in DNA damage repair, which is
crucial for maintaining genomic integrity and preventing mutations[63].
105
There are a number of drugs that are being developed to target the TP53 pathway in lung
65
cancer. These drugs work by either restoring the function of the p53 protein or by preventing
the activity of proteins that inhibit p53. Some of the most promising drugs targeting the TP53
pathway include:
13
APR-246: This drug is a small molecule that binds to the MDM2 protein and prevents it from
binding to p53. This allows p53 to function normally and suppress tumor growth[64].
SAHM1: This drug is a small molecule that mimics the activity of the p53 protein. This can
help to kill cancer cells that have lost their p53 function[65].
85
CHIR-124: This drug is a small molecule that inhibits the activity of the CDK1 and CDK2
proteins, which are involved in cell cycle regulation. This can help to prevent cancer cells
from dividing[66].
6. RB1 Pathway:
RB1 suppresses cell cycle progression by inhibiting E2F transcription factors. Dysregulation,
common in cancer, leads to uncontrolled proliferation. Therapeutic targeting aims to restore
cell cycle control in malignancies with RB1 pathway aberrations[12], [13].
21
The RB1 pathway is a tumor suppressor pathway that plays a critical role in cell cycle
regulation and preventing uncontrolled cell growth. Mutations in the RB1 gene, which
10
encodes the RB1 protein, are frequently found in various cancers, including lung cancer.
The key genes involved in the RB1 pathway in lung cancer include:
45
RB1: This gene encodes the RB1 protein, which acts as a tumor suppressor by inhibiting cell
cycle progression. Mutations in RB1 can lead to uncontrolled cell growth and cancer
development[67].
31
CDKN2A: This gene encodes the p16 protein, which is a cyclin-dependent kinase inhibitor
that helps to regulate cell cycle progression. Mutations in CDKN2A can also lead to
uncontrolled cell growth[68].
31
CDKN2B: This gene encodes the p15 protein, which is another cyclin-dependent kinase
inhibitor that helps to regulate cell cycle progression. Mutations in CDKN2B can also lead to
uncontrolled cell growth[69].
E2F1: This gene encodes the E2F1 transcription factor, which promotes cell cycle
progression. Mutations in E2F1 can lead to uncontrolled cell growth[70].
13
MYC: This gene encodes the MYC transcription factor, which promotes cell proliferation
and differentiation. Mutations in MYC can lead to uncontrolled cell growth and cancer
development[71].
Several drugs are being developed or investigated that target the RB1 pathway in lung cancer.
These drugs work by different mechanisms, such as:
Inhibiting CDK4/6: These drugs target the CDK4/6 kinases, which are downstream of the
RB1 protein and help to drive cell cycle progression. By inhibiting CDK4/6, these drugs can
prevent cancer cells from proliferating.
Restoring RB1 function: Some drugs are being developed that aim to restore the function of
the RB1 protein in cancer cells. These drugs could potentially be used to treat cancers with
RB1 mutations.
Targeting other genes in the pathway: Other drugs are being developed that target other genes
23
in the RB1 pathway, such as E2F1 and MYC. These drugs could potentially be used in
combination with other therapies to treat lung cancer[72].
7. Myc Pathway:
Myc regulates gene expression crucial for cell growth, metabolism, and proliferation.
Overexpression drives tumorigenesis in diverse cancers, highlighting its significance as a
therapeutic target for cancer treatment strategies [14].
13
The Myc pathway is a group of genes that play a role in cell growth and proliferation. In lung
3
cancer, mutations in Myc pathway genes are common and can lead to the development of
cancer cells. Some of the most common Myc pathway genes that are mutated in lung cancer
include:
54
MYC: This gene encodes the c-Myc protein, which is a transcription factor that regulates the
100
expression of other genes. Mutations in MYC can lead to the uncontrolled growth of cancer
cells[73].
88
MYCN: This gene encodes the N-Myc protein, which is another transcription factor that is
involved in cell growth and development. Mutations in MYCN are more common in small
cell lung cancer (SCLC)[74].
21
MYCL: This gene encodes the L-Myc protein, which is a third member of the Myc family.
Mutations in MYCL are less common than mutations in MYC or MYCN, but they can also
19
contribute to the development of lung cancer[74].
6
There are currently no drugs that are specifically approved for the treatment of lung cancer
that target the Myc pathway. However, there are a number of drugs that are in development
that are designed to target different parts of the Myc pathway. These drugs include:
MYC inhibitors: These drugs are designed to block the activity of the c-Myc protein. Some
examples of MYC inhibitors that are in development include Omomyc and Idasanutlin[75].
MYCN inhibitors: These drugs are designed to block the activity of the N-Myc protein. Some pro-inflammatory cytokines, decreases Nrf2, increases oxidative stress, promotes
37
examples of MYCN inhibitors that are in development include FWD1439 and ALK2 angiogenesis, and, in the end, starts tumour invasion, growth, and transformation [99]. Recent
inhibitors[76]. advances in molecular biology have clarified the importance of the Extracellular Matrix
(ECM) and VGEF in tumorigenesis[100]. The PI3K/Akt signalling pathways are activated
when expanding cancer cells meet the extracellular matrix (ECM). This increases the rate at
Apart from various pathways to most important factors for lung cancer are pollutant and which tumours originate and reduces the effectiveness of chemotherapy and radiation therapy
smoking in stopping the cell cycle [101]. VGEF, on the other hand, promotes cancer spread by
2
promoting the development of new blood vessels, increasing the density of microscopic
blood vessels, and increasing blood flow to developing tumour cells [102]. Apoptosis and its
27
The presence of polycyclic aromatic hydrocarbons, aromatic amines, and nitrosamines in air associated proteins play an important role in regulating excessive cell growth around
4
pollutants has been linked to mutation and the formation of DNA adducts, which bypasses signalling molecules and pathways [103].
the physiological repair mechanism, resulting in a change in the DNA and, ultimately, the
induction of tumorigenesis[77].
3. Conventional phytochemicals used for lung cancer
G-C/T-A base pair changes caused by smoking activate oncogenes like k-ras[78],[79]. The
point mutation induces activation of k-ras pro-oncogene accounting for almost 30% of all Phytochemicals derived from plants offer a promising substitute that can improve treatment
cases of adenocarcinoma with a poor prognosis [80]. Farnesylation inhibitors are being outcomes and lessen adverse effects in cancer patients. Numerous of them are bioactive,
investigated for their potential anti-tumour activity, which has been reported to work by naturally occurring substances with strong antitumor potential[104][105].
4
inhibiting the three primary ends of p21 of k-ras, which are otherwise activated by 19
Phytochemicals can inhibit cancer development and metastasis through a variety of
farnesyltransferases to initiate the tumorogenesis cascade[81].
mechanisms, including the stabilization of cancer-promoting molecules, the enhancement of
78
Furthermore, p53 mutations are a paramount cause of LC [82]. Almost 33% - 70% of LC the immune system, the prevention of carcinogen formation, the protection of healthy cells
cases are caused by a p53 gene mutation; normally, p53 regulates the sudden differentiation, from carcinogens, the reduction of inflammation, the regulation of hormones, the promotion
growth, and proliferation of cells; on mutation, it initiates the results in differentiation, of autophagy in damaged cells, the preservation of DNA integrity in healthy cells, the
proliferation, and tumorigenesis[83]. Mutations at the codons 157, 248, 249, and 273 cause scavenging of free radicals, and other actions[106],[107]. Traditional remedies play a
p53 suppression in LC[84]. Although p53 suppression is the primary reason for LC, recent momentous function in numerous healthcare frameworks across the globe[108].
39
research has stated that p16 and Rb tumour suppressor genes are also involved in the
regulation of the cell cycle [85]. The partial deletion of chromosomes is an important
determinant of LC [85]. LC often reports 2p, 9p, 3p, 17p, 18p, and 22p loss of oncogenes
4
[86], [87]. Losses of 4p, 9p, and 21p have been reported in squamous cell carcinoma, while
losses of 3p, 5p, 13p, and 17p have been reported in small cell carcinoma[86], [87]. However,
4
among the various chromosomal loci, loss of 3p (3p14-cen,3p21.3, and3p25) is the most
common in LC[88].
In EGF (Epidermal growth factor), there are also Mitogen-activated Protein
Kinases/Extracellular Signal-Regulatory Kinases (MAPK / ERK)[89], Phosphoinositide-3-
Kinases/Protein Kinase B Protein (PI3K / Akt)[90], Nuclear Factor Kappa-Light-Chain-
Enhancer of Activated B Cells/Nuclear Factor erythroid Two-Related Factor 2 (NFkB /
4
Nrf2)[91]. Vascular Endothelial Growth Factor (VEGF), as well as neuropeptide growth
factors, play important roles in the pathogenesis of lung cancer[92]. Early in the development
of cancer, macrophages release epiregulin, which interacts with EGFR and HER-2 to promote
cell proliferation[93]. RAF is phosphorylated in the first stage, which activates MEK1/2[94];
Tumour formation is triggered by more phosphorylation of ERK 1/2, which also increases the
synthesis of several growth factors [95], [96]. It is activated on Phosphatase, and Tensin
Homolog (PTEN), inhibition[97]. These pathways are also activated in response to exposure
to NF-kB, persistent oxidative stress, and the mammalian target of Rapamycin (mTOR) [98].
33
When oxidative stress or p53 gene suppression occurs, NF-kB relocates to the nucleus and
plays a critical role in inflammation. This shift promotes the generation of chemokines and
Fig No. 01-Modulation of TME by phytoconstituents- Various Mechanisms of actions of natural products are
depicted in the figure by which they modulate the tumour microenvironment. 1. Natural products inhibit
angiogenesis within the tumor microenvironment by targeting key factors such as VEGF signaling, thereby
37
reducing the formation of new blood vessels crucial for tumor growth and metastasis. 2. Natural products
control extracellular matrix (ECM) degradation in the tumor microenvironment, preventing the breakdown of
ECM components that facilitate tumor invasion and metastasis, ultimately hindering cancer progression. 3.
2
Natural products reduce the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor
microenvironment, which suppress anti-tumor immune responses and promote tumor growth, thus enhancing
immune surveillance against cancer cells. 4. Natural products regulate tumor-associated macrophages (TAMs)
within the tumor microenvironment, modulating their polarization towards an anti-tumor phenotype, which
2 of diseases [113]. Approximately 25% of newly discovered molecular entities that have
promotes immune-mediated tumor clearance and inhibits cancer progression. 5. Natural products function as
important immune checkpoint inhibitors within the tumor microenvironment, blocking inhibitory signals that
38
dampen anti-tumor immune responses, thereby unleashing the immune system to attack and eradicate cancer
cells more effectively.
Discussion of problems faced in conventional formulation.
7 pharmacokinetic issues, such as poor absorption and low bioavailability, complicate clinical
One of the major disadvantages of conventional therapies is the recurrence, as not all cancer
stem cells are eradicated from the body. In addition, the development of multi-drug resistance
(MDR) is a significant clinical challenge. Also, in many countries, social and economic
burdens incurred through treatment costs remain among the many hurdles to be overcome for
a global reduction in cancer incidence and mortality. Therefore, there is a pressing need to
identify novel approaches and therapies that may offer relatively cost-effective regimens with
less undesired side effects[109]
Phytochemicals have limitations when used for lung cancer treatment, including low
solubility, high doses requirement, limited evidence, poor bioavailability, and stability[110].
Need of phytonano formulation
3 5
Some phytochemicals have effects on cellular processes and signalling pathways with
potential antitumor properties. Beneficial anticancer effects of phytochemicals were observed
in both in vivo and in vitro investigations. Encapsulating natural bioactive compounds in
different drug delivery methods may improve their anticancer efficacy. Greater in vivo
stability and bioavailability, as well as a reduction in undesirable effects and an enhancement
3
in target-specific activity, will increase the effectiveness of bioactive compounds. It also
provides an idea of the bioavailability of phytochemicals, challenges, and limitations of
standard cancer therapy. It also encompasses recent patents on nanoparticle formulations
containing a natural anti-cancer molecule.
11
Most of the synthetic drugs used to treat cancer are targeted at rapidly dividing cells. As a
side effect, the body's quickly proliferating cells, under natural conditions such as bone
marrow, digestive tract, and hair follicle cell lines, are also affected. These side effects
include alopecia, cardiotoxicity, constipation, dry mouth, fertility issues, immunosuppression,
loss of appetite, mucositis, myelosuppression, nausea, neurotoxicity, neutropenia, and
thrombocytopenia[111].
9 aqueous solubility as well as rapid initial release when exposed to aqueous
Moreover, the successful delivery of bioactive phytochemicals as an ideal chemotherapeutic
agent faces several hurdles such as insufficient solubility, low stability, gastrointestinal
absorption and bioavailability, high first-pass metabolism in the liver, chemical degradation,
rapid clearance, and lack of selectivity[112]
Also, the potency of extracts or derivatives deteriorates due to failure in applying proper
extraction, isolation, and purification procedures. This review highlights the hurdles faced in
9
the efficient delivery of phytochemicals in cancer treatment, with some general strategies to
overcome them.
8. Phytochemicals as nano formulations
Herbal treatments are frequently used as an alternative to conventional drugs to treat a variety
achieved FDA approval come from botanical sources, demonstrating the importance of plants
in the development of novel medications[114].
46
Unfortunately, various barriers to effective Phyto-therapeutic delivery exist, including
physicochemical limits such as insufficient solubility and instability[115]. Furthermore,
trials[116]. Also, the pharmaceutical industry has substantial challenges translating Phyto
therapeutics, such as batch-to-batch variability and low efficacy[117]. The study has received
attention due to its safe and effective provision. Modern delivery techniques, such as
liposomes, nanoparticles, nanocapsules, and phytosomes, have outperformed traditional
systems in terms of phytomedicinal ingredient distribution[118]. This system improves
solubility, release pattern of drug, stability, pharmacokinetic, and tumor targeting as
discussed below and table No.1 stats various PC in nanoformulation
Solubility
102
The bulk of biologically active polyphenolic phytoconstituents have insufficient water
solubility, resulting in limited systemic absorption and low bioavailability when taken orally.
Furthermore, their weak solubility limits intravenous delivery[119]. The hydrophobic
complexation of the water-insoluble flavonoid resveratrol (RSV) within a phospholipid
bilayer that envelops casein micelles containing monascus yellow pigments (MYPs) is used
in the solubilization procedure [120][121]. The created multi-reservoir nanocarriers
efficiently reduced the aromatase activity of both drugs synergistically. This resulted in a
considerable improvement in antitumor efficacy, as evidenced by a significant decrease in
5
tumour volume from 1466.3 mm3 in the positive control group to 770.55 mm3 and 590.3
mm3 in the groups treated with free RSV/MYPs and nanocarriers, respectively [122].
Release pattern of drug
Rapid clearance and low bioavailability pose significant formulation challenges for highly
water-soluble herbal medicines[123]. Furthermore, the medication's rapid release causes
many adverse responses after administration since it enters the systemic circulation before
reaching its intended site of action [124],[125]. Berberine, an isoquinoline alkaloid, has high
environments[126]. To extend the release of the drug, Abdelmoneem et al. used two
5
strategies: hydrophobic ion pairing with sodium deoxycholate (SDC) and entrapment within
the hydrophobic core of amphiphilic casein micelles[127].
The use of micelles was efficient in providing sustained BRB release and enhancing tumour-
targeting efficacy. In contrast to free BRB, which released rapidly within an hour, the
application of genipin-crosslinked micelles reduced burst release significantly, with just 45-
52
55.5% of BRB released after 24 hours[127]. A study was conducted to evaluate the use of the
hydrophobic ion pairing (HIP) technique in conjunction with sodium lauryl sulphate (SLS)
before the incorporation of the material into lipid nanoparticles (NPs) [128]. The HIP
95
complexation procedure resulted in a considerable reduction in the first burst release of the
5 23
drug from NPs after 2 hours, dropping from 69.65% to 43.8%. Following that, after 24 hours,
the accumulated drug release for BER/SLSNPs with HIP complexation was 68.4%, compared
to 79.45% without it[128]. This study's findings indicated that HIP complexation has a
significant impact on drug release duration[128].
Stability
90
The chemical instability of many pharmacologically potent herbal medicines is a major
barrier to their clinical translation[129]. Numerous techniques, including nano-encapsulation,
have been used to improve the stability of these molecules and protect them against
premature breakdown. This increases their bioavailability [130]. Epigallocatechin-3-gallate
(EGCG) demonstrates the sensitivity of sensitive herbals to pH, temperature, and oxygen,
limiting its possible applications[131]. The great mucoadhesive characteristics of chitosan
nanoparticles in conjunction with lipid nanocarriers have inspired their use. As a result, they
have been used to encapsulate EGCG, boosting its adhesion to the intestinal epithelium and,
as a result, its absorption and bioavailability [132]. The combination usage of chitosan
nanoparticles and lipid nanocarriers has been motivated by their effective mucoadhesive
characteristics. This has resulted in EGCG entrapment, resulting in higher adsorption to the
intestinal wall and, as a result, improved absorption, and bioavailability [133]. The observed
5 Ki-67 expression in mice. This contrasts with the 93.76% expression shown in untreated mice
effect can be attributed to the agglomeration of nanoparticles at high pH values, which
suppresses the release of drugs and hence improves protective efficacy [134].
Pharmacokinetics
Several pharmacokinetic benefits of medication nanoencapsulation have been discovered,
including improved bioavailability, biodistribution, metabolic stability, membrane
permeability, and sustained activity [135]. Quercetin was efficiently encapsulated by creating
a compound with phosphatidylcholine via hydrogen bonding and hydrophobic contact [136].
The pharmacokinetic study found that when quercetin was encapsulated into phytosomes, it
was absorbed significantly better than unformulated quercetin delivered at the same dosage
2
[137]. The pharmacokinetic parameters of quercetin phytosomes, namely the maximum
concentration (Cmax) and area under the curve (AUC), were significantly larger than those of
free quercetin, according to the current study. The Cmax and AUC of quercetin phytosomes
were found to be 18 to 20-fold greater, respectively, than those of free quercetin [138].
77
A study found that incorporating resveratrol into zein nanocapsules dramatically improved its
oral bioavailability and pharmacokinetics [139]. When compared to the free drug cosolvent,
20
which had a half-life of 1.25 hours and a mean clearance of 1.02 ml/h, the nanocapsules had a
20
longer half-life of 8.16 hours and a lower mean clearance of 0.072 ml/h[139]. The drug's
improved pharmacokinetics are attributable to its integration into the lipidic matrix of the
nanocapsule, as well as its improved digestion resistance and oral stability due to
glutaraldehyde cross-linking to the water-soluble zein shell. [140]. Celastrol has been
thoroughly investigated by Freag et al., and the findings point to possible therapeutic
advantages in the management of inflammation and the treatment of cancer [141]. In
comparison to the crude suspension (Cmax = 90 Ng/ml), oral administration of CST
5
phytosomes resulted in a statistically significant increase in (Cmax = 460 Ng/ml) and an
AUC 0-8 of 410.7 % in rabbits.[141]. Phytosomes have been reported to improve drug
5
bioavailability by increasing solubility and absorption into the intestinal mucosa, which is
helped by phospholipids [142].
Enhanced tumour targeting
Active targeting nanoparticles offer numerous benefits, including improving drug selectivity
towards specific cells, selectively inducing cell death to avoid harming normal cells,
improving anticancer efficacy and accumulation within cancerous cells, and effectively
regulating drug release [143]. A study successfully targeted both quercetin and sorafenib to
hepatocellular cancer cells. This was accomplished by chemically linking carbodimide to the
shells of nanocapsules containing lactobionic acid and glycyrhetinic acid, respectively, to the
5
shell of the nanocapsule containing lactoferrin [144]. LA and GA decoration were used to
5
precisely target ASGP and GA receptors. Furthermore, LF can target liver cancer cells by
attaching to LDL-related protein receptors[145]. The improved tumour-targeting ability of
LF-nanocapsules reduced their interaction with tissues, resulting in less opsonization and
faster clearance[146].
The GA/LF nanocapsules had a better tumour-targeting impact, resulting in a 20% drop in
models of diethyl nitrosamide-induced HCC, showing a decrease in tumour cell growth.
Furthermore, the number of liver tumour nodules was reduced by more than 93%[145]. The
5
refined liver tumour-targeting strategy resulted in fewer side effects and increased safety, as
shown by a considerable improvement in ALT and AST levels [147]. Triptolide, a herbal
medicine with powerful anti-HCC activity, is associated with considerable systemic and male
reproductive toxicity[148]. This toxicity was considerably reduced by including Triptolide in
galactosylated-chitosan nanoparticles [149]. The condition is characterized by significant
5
decreases in the testes and epididymis indices, as well as the liver and kidney indices. The
substantial accumulation of nanoparticles in vivo in liver tumours can be due to their
internalisation via the asialoglycoprotein receptor, which has a tumour-targeting
function[148], [149].
40
Table no. 01- Phytochemical nano delivery system and its mechanism of action in lung
cancer.
Sr Natural Common Study Nano formulation Mode of Action Ref L. tumor- and cytotoxicity ],
no. Products Source bearing against LLC cells [161
1 Berberine Coptis A549, liquid crystalline The infiltration of [150 C57BL/ were greatly ]
chinensis H157, nanoparticles tumours. The ], 6J mice increased.
H358, activation of T- [151 Liposomes
H460, cells in the ] increased oral
H129 tumour is known bioavailability by
cell as T-cell 47 times as
lines activation. When compared to the
PD-L1 combines free medication.
with and inhibits 11 Genistein Genista A549 Gold nanoparticles Significantly [162
the function of tinctoria L. cell line more antitumor ],
CSN5, it causes activity than free [163
instability. The drug ]
activity of CSN5 4 Honokiol Magnolia H1299 Nanosuspension Interrupting the [164
is diminished by officinalis cell line connection ],
directly binding to between HDAC6 [165
CSN5 at Glu76. and Hsp90 causes ]
2 Catechin Camellia H1299 Chitosan coated- 4When compared [152 MMP-9 protein
hydrate sinensis cells Poly(Lactideco- to non-coated NP ], degradation.
Glycolide) and free CAT, an [153
nanoparticles in vivo ] 10 Myricetin Rosa Male Mesoporous silica A significant drop [166
pulmonokinetic canina L. BALB/c nanoparticles in the growth of ],
investigation (Rosa's hip) nude NCI-H1299 cells [167
showed a mice and A549, as well ]
considerable as a decrease in
improvement in cell viability.
pharmacokinetic Initiates apoptosis
parameters due to caspase-3
(Cmax, AUC). and PARP
13
3 Chlorophylli chlorophyll A549 Polymeric Modulation of the [154 activation.
n cells nanoparticles expression of ], 13 Naringenin Ficus carica A549 Nanoemulsion In the G3 / M and [168
Bax, Bcl-2, [155 cells pre-G1 phases, ],
caspase-3, and ] line naringenin [169
p53 resulted in nanoemulsion ]
significant greatly increased
cytotoxicity the rate of cellular
against A549 death and cellular
cells. death arrest. In an
4 Curcumin Curcuma A549; Liposomes The regulation of [156 apoptosis assay,
logna A549 the GLUT1/MT1- ], nanoemulsion
xenogra MMP/MMP2 [157 boosted the
ft mice pathway is being ] activity of baux
lowered. and cisplatin-3
while decreasing
5 Epigallocatech Camellia A549 Polymeric By decreasing [158 the expression of
in- 3-gallate sinensis and nanoparticles PD-4 ], cisplatin-2.
H1299 phosphorylation, [159 1 Parthenolide Tanacetum A549, Nanopolymer The Akt-STAT3- [170
cells the unbound ] parthenium H526 [DSPE-PEG2000] mTOR signalling ],
variant enhanced cell pathway is [171
apoptotic capacity lines blocked, resulting ]
in lung cancer in a decrease in
cells.
VEGF protein
12 Fisetin Rhus Cotinus LLC Liposomes Cellular uptake [160
expression and an
 inhibition of cycle progression
HUVEC motility. at the S stage, and
28 decreasing VEGF
8 Pterostilbene Pterocarpus A549, Ethoniosomes The self-renewal [172 and VEGFR2
santalinus H441 capacity in lung ],
protein synthesis.
cell cancer cells co- [173
lines cultured with M2- ] 16 Tetrandrine Stephania A549 Polymeric By raising the [182
TAMs is reduced, tetrandra S cells nanoparticles levels of tissue ],
resulting in the inhibitor MMP [183
2
decreased and decreasing ]
expression of β- the levels of
catenin, CD133, MMP-2/MMP-9
MUC1, NF-κB, in the body, the
and Sox2. This nanoparticles
phenomenon can block cell
be characterized migration and
as the suppression invasion more
of self-renewal successfully than
ability. a free medication.
14 Quercetin Curcuma A549 RGD modified The tailored [174 5 Theaflavin Black tea LL2- Gold nanoparticle Cellular invasion, [184
domestica bearing liposomes liposomes ], Lu3 cell
2
MMP-2 and ],
valeton C57BL/ demonstrated [175 line MMP-9 secretion, [185
6 mice considerable ] ]
and collagen
xenogra improvements in degradation by
ft cancer targeting type IV
and suppression. collagenases are
2 all suppressed.
6 Resveratrol Grape skin LLC; Lyotropic liquid G-MDSC [176
and seeds LLC- crystalline accumulation can ], 18 Vincristine Catharanthu H460 Polymeric The cytotoxicity [186
bearing nanoparticles be controlled by [177 s roseus NSCLC nanoparticles of targeted ],
mice triggering ] cell nanoparticles and [187
apoptosis and free vincristine ]
decreasing their against H460
recruitment. NSCLC cells is
much higher, due
7 Silymarin Silybum LLC- Polycaprolactone/ Tumour [178 to more free
marianum bearing Pluronic F68 progression can ], radical formation
mice be significantly [179 and reduced
slowed by ] mitochondrial
limiting tumour transmembrane
growth, inducing potential.
apoptosis, and
106
boosting the
infiltration and
activation of
CD8+ T
lymphocytes.
25
2 Tanshinone Salvia A549 Nanoemulsion The process of [180 4. A Nanoparticle-based Drug Delivery Strategy Used for Lung Cancer
IIA miltiorrhiza cell line suppressing cell ],
[181 Numerous nanomaterial solutions for the prevention, treatment, and diagnosis of cancer have
growth, triggering
programmed cell ] been developed because of nanotechnology[188]. The most advantageous feature of this
6
death, halting cell system is its ability to provide high loading capacity for therapeutic and imaging agents due
to nanoparticles' high surface area-to-volume ratio [189].
 62
The following are four significant nanoparticle-based drug delivery systems for lung cancer
29
that are of general application. These include Solid lipid nanoparticles, Polymeric
nanoparticles, Dendrimers, and Lipid-based polymeric micelles.

4.1. Solid lipid-based approaches

The drug delivery functions of solid lipid nanoparticles (submicron colloids) (particle sizes
8
ranging from 50 to 1000 nm) have been extensively studied, and the same approach has been
explored and found to be promising for the treatment of lung cancer[190]. Solid lipid
8
nanoparticles (SLN) are made from lipids. Triglycerides[191], Carnauba Wax[192], Cetyl
Alcohol[193], Emulsifying Wax[192], Beeswax[192], Cholesterol, and Cholesterol
Butyrate[194] are examples of natural and synthetic lipids[195]. According to studies, SLNs
38
have been used as carriers for a wide range of anticancer drugs, including doxorubicin,
paclitaxel, idarubicin, etoposide, and camptothecins [196]. Drugs can be administered to
SLNs to enhance alignment, mobility, and stability [197]. SLNs have been used to aid in the
diagnosis of pulmonary conditions and the administration of drugs to the respiratory system
[198]. When the lipids used in their composition are compatible, SLNs have a higher safety
profile. This compatibility contributes to their effectiveness in treating lung cancer [199].
These compounds offer several advantages, such as improved absorption by the body,
decreased harmful effects, enhanced drug targeting, and lower manufacturing expenses[200],
[201].
These molecules offer several advantages. They have increased bioavailability in living Fig No. 02 Solid lipid nanoparticle preparation by Hot microemulsion method. The hot
2
organisms, lower toxicity, improved selectivity for targeted drugs, and reduced production microemulsion method is used to create SLNs (solid lipid nanoparticles) of N6FA(N-6-
costs. [202]. Cancer treatment utilizing p53 gene conversion has shown greater effectiveness Furfuryl Adenine). With this method, an optically transparent mixture typically made up of
due to its role in triggering apoptosis, or programmed cell death[203],[204]. an emulsifier, a co-emulsifier, a lipid, and water is diluted. In a beaker of molten lipids, the
medication is added. In a different beaker, polysorbate 80, phospholipon 90 G, and water are
18
When compared to berberine alkaloids, solid lipid nanoparticles show a greater anti-cancer combined, and the temperature is raised to the lipid melting point. To create a transparent
action in NSCLC. [205]. Berberine hydrochloride, an isoquinoline alkaloid, is an effective microemulsion, this hot aqueous emulsifier mixture is immediately poured into the lipid melt
36
cancer treatment[206]. Berberine is an anticancer agent that inhibits cancer cell proliferation, while being magnetically stirred. The ice-cold water is immediately transferred into an
arrests the G1/G0 cell cycle, and promotes apoptosis [207]. The inability to dissolve in water equivalent volume of hot microemulsion (hot microemulsion: cold water =1:1 ) while being
has contributed to the limited clinical application and subsequent product development[208]. continuously homogenised for 15 minutes at 12,000 rpm. The crystallisation of the oil
The drawbacks of Berberine comprise a lack of oral assimilation and an elevated metabolic droplets in the hot microemulsion in the aqueous medium led to the formation of SLNs[215],
rate. [209]. [216], [217], [218].
68
Paclitaxel, an alkaloid anti-cancer drug, has been extensively used in the management of
NSCLC [210], [211], Breast Cancer[212], and Ovarian Cancer[212] for the past 30-40 years.
Researchers did an experiment in which they were able to deliver the active ingredient 4.2. Bio nanoparticles-approaches
paclitaxel straight into the lungs to boost the effectiveness of the treatment. The inhalable Nanoparticles can be employed to overcome the slow absorption, fast metabolism, and
solid lipids nanoparticles were found to be more successful in delivering the active elimination that are common to most natural products; thus, they can be employed to enhance
components epirubicin and doxorubicin, resulting in improved therapeutic advantages, Their bioavailability and focus on specific areas, such as the lungs[219]. Biopolymers are
21
according to the study's findings.[213], [214]. Fig no. 2 describes Solid lipid nanoparticle classified into three types depending on their properties and molecular structure.
preparation by the Hot microemulsion method. Polysaccharides are several types of chemicals that combine to form polysaccharides.
3
Cellulose, chitosan, dextran, hyaluronan, guar gum, pectin, sodium alginate, and starch, and
are all polysaccharides. Other types of protein are albumin, gelatin, milk proteins and nucleic
3
acids make up the final class [220]. To use BBN (Biopolymer nanocarrier) as a drug delivery
vehicle, particle size, electrical charge, and surface area must all be controlled [221]. BBN
provides a great opportunity for bioactive substances to be conveyed to the desired location, Teong et al. discovered that curcumin could be encapsulated in three different types of
garnering the interest of chemists, biologists, and researchers in the pharmaceutical nanoparticles: chitosan-based polymers, gelatin-based gels, and hyaluronic acid-based
field[222]. The main goals of BBN are to enhance the drug's solubility in water, amplify its nanoparticles, with 81%, 67%, and 78% encapsulation rates, respectively. Encapsulated
stability, diminish its degradation, improve its availability in the body, boost its biological curcumin nanoparticles were found to have a 45%, 40%, and 32% increase in apoptotic effect
effectiveness, make it more easily broken down by natural processes, decrease its on A549 cells, compared to pure curcumin, which had a 20% effect on A549 cells [241].
harmfulness, and make it more adaptable to forming gel[223]. Curcumin administered intravenously to rats resulted in higher amounts of curcumin PLGA
nanoparticles in the lung [242].
Polymeric nanoparticles are colloidal entities with spherical or irregular morphologies that
67
encapsulate or trap bioactive substances [224], [225]. Polymer nanoparticles are made from a Kumar et al. investigated the interaction of NAR/CS nanoparticles with mice lung cancer
41
variety of biodegradable materials, like polycaprolactone (PCL), polylactic acid (PLA), cells, such as A549 and 3T3-fibroblast cells, using in vitro assays [243]. In NCIH 460 cells,
polyglycolic acid (PLGA), chitosan, and gelatin. Organisms deteriorate PLA and PLGA into R-GNPs loaded with resveratrol increased cellular absorption and availability while
biodegradable monomeric building blocks suitable for biocompatibility[226]. PLA and decreasing cellular viability, intensifying cytotoxicity, increasing DNA impairment, and
13
PLGA are typically rapidly eliminated by the host's immune system when administered amplifying levels of intracellular reactive oxygen species (ROS) [244]. Singh et al.
22
intravenously[227]. To combat this problem and increase its lifespan, nanoparticles are investigated the effects of EGCG-encased PLGA nanoparticles on A549 lung cancer cells.
frequently encased in polyethylene glycol (PEG), a polymer that aids immune system The IC50 values for EGCG encased in PLGA and released EGCG were 9 μm and 60 μm,
clearance [228]. Chitosan is a natural polysaccharide known for its mucoadhesive, respectively. This suggests that the amount of EGCG encapsulated in PLGA required to
immunological, and non-toxic properties [229]. provide an identical anti-protective impact against A549 cells was more than 6X. [245]. Duan
41
et al. conducted a study that demonstrated the synergistic effects of phenolic compounds
when combined with established chemotherapy drugs[246]. Curcumin has been shown to
BBN production involves a wide range of techniques, including spray drying, electro improve the body's ability to break down doxycycline while decreasing its side effects [247].
3
spraying, and high-pressure homogenization. Supercritical fluid, electromagnetic spinning, Fig no.03 describes the method of preparation of BBN.
emulsion dispersion, reverse micelle, and emulsified-droplet coalescence are some more
6
approaches [230]. Viral nanoparticles (VNP) have attracted attention in the field of
biomedical applications, especially in drug delivery, due to their biocompatibility, versatility,
and ability to incorporate various functional moieties through surface modifications[231].
61
VNPs created from viruses discovered in plants, animals, and bacteria have been used in
various biomedical applications like biomonitoring, bio-imaging, drug and gene delivery, and
vaccine development[232]. Veljanski et al. carried out research in 2012, in which they
merged conventional chemotherapy drugs with genetically altered Oncolytic Viruses (OVs)
as a means of treating lung cancer. This research showed that the deficiency of chemotherapy
6
in targeting cancer stem cells is effectively compensated by OV-mediated gene therapy[233],
[234]. Robertson et al. 2011 showcased the application of engineered T4 virus nanoparticles
10
as molecular probes using a comparable approach and further employed this technique to
investigate the mechanisms of uptake in lung cancer (A549) cells[235].
Gelatin, a protein-based biopolymer, is distinguished by its biocompatibility,
biodegradability, low toxicity, and low antigenicity[236]. Polymer nanoparticles have
physicochemical qualities that can be controlled, as well as great stability,
uniformity, encapsulation, and release of drugs capabilities [237]. Because of its FDA
approval, PLGA is the most often used polymer for nanoparticle distribution. In colloidal
suspensions, it is stable and safe, and its controlled release properties have been proven [238].
104
Whether coated with chitosan or not, PLGA nanoparticles are compatible with A549 cells at
concentrations of up to 5 mg/mL[239]. When the medicine is encapsulated with PLGA
nanoparticles, oral administration enhances bioavailability, causes long-lasting drug release,
30
and extends the drug's half-life. The study also discovered that using PLGA-PEG Fig no.03, The method of preparation of BBN. Different methods are employed to generate
2
nanoparticles enhanced peak concentration by 2.9% and 7.4%, respectively [240]. the nanoparticles, depending on the medicinal product to be incorporated into the polymer
2
NPs. In the solvent evaporation process, an oil-in-water (o/w) emulsion must first be
2
prepared, which results in the formation of nanospheres. The emulsification/Solvent
 24
Diffusion Method entails the creation of an o/w emulsion between an aqueous solution
containing a surfactant and a sparingly water-miscible solvent comprising a biopolymer and
2
medication. The salting-out approach is based on the separation of a hydro-miscible solvent
from an aqueous solution via a salting-out phenomenon that has the potential to produce
nanospheres. Two miscible solvents are needed for the nanoprecipitation process, commonly
known as the solvent displacement method[248], [249], [250], [251], [252], [253], [254],
[255].
4.3. Dendrimers
Dendrimers are synthetic polymeric molecules that are symmetrical, nanosized, and have
highly organized, frequently branched structures[256], [257]. They are good for drug delivery
because they have anionic, neutral, or cationic functional groups[258]. These molecules have
a globular shape and are monodisperse and homogeneous [259]. Dendrimers are created
using a precise polymeric technique that involves electrostatic and hydrophobic interactions.
Surface modification may improve the biodegradability of dendrimers [260]. Nanocarriers
have enormous potential for cancer treatment due to their symmetrical construction, massive
load capacity, and ability to degrade naturally [261].
81
Dendrimers have emerged as a viable solution to the problems associated with therapeutic
candidates that lack solubility, toxicity, or stability. They have a lot of potential as carriers for
increasing the therapeutic value of these medicines[262]. Dendrimers' capacity to use precise
ligands for targeted pharmaceutical delivery to specific tissues increases therapeutic efficacy,
making them a promising medium for lung cancer treatment [263]. Several lung cancer drugs
are coupled with dendrimers to boost their efficacy and reduce undesirable side effects[264].
8
When combined with doxorubicin, the pH-reactive property of fifth-generation PEGylated
poly(amidoamine) dendrimers increased therapy efficacy and specific targeting of lung
72
cancer [265]. PEGylated fifth-generation poly(amidoamine) dendrimers are used to improve
the water solubility and targeted medication delivery of imatinib into cancer cells[266], [267].
Fig No. 04 depicts the approaches for the synthesis of dendrimers.
Fig No.04- The approaches for the synthesis of dendrimers are synthesised using two
methods. In the Divergent Method, dendrimers are prepared using ammonia as the trivalent
core. The Convergent Method involves the Synthesis of branches, wedges, or dendrons [268].
86
4.4. Lipid-based polymeric micelles
Lipid-based polymeric micelles are a form of nanoparticle with a hydrophobic core capable
of encapsulating drugs and a hydrophilic shell that allows for extended circulation time. This
property permits them to accumulate in solid tumours after injection, outperforming
conventional nanoparticle solutions[269]. Kim and colleagues successfully created a novel
polymeric micelle arrangement of paclitaxel without the use of Cremophor. This formulation
10
has been approved for the treatment of advanced non-small cell lung cancer (NSCLC) in
South Korea and numerous European countries [270]. Li et al. carried out a research
investigation and disclosed outcomes regarding the utilization of aggregation-induced
emission in polymeric micelles laden with cisplatin for cellular visualization and therapy
[271].
Paclitaxel and itraconazole encapsulated polymeric micelles have been shown to have lower
34
toxicity when it was used in the treatment of NSCLC [272]. The goal of this study was to see
how well polymeric micelles containing docetaxel combined with alpha conotoxin delivered
10
docetaxel to a variety of A549 Non-Small Cell Lung Cell (NSCLC) cell lines [273]. Reshma
8
et al. investigated the efficacy of paclitaxel-loaded galactoxyloglucan nanoparticles in lung
cancer cells, identifying them as a possible drug-resistance solution. Notably, they were able
to inhibit the production of multi-drug resistance proteins [274]. Fig No. 05- Depicts method
of preparation of polymeric micelles by oil in water emulsion
63
Fig No. 05- Method of preparation of polymeric micelles by oil in water emulsion. The oil-
in-water emulsion approach is used to create polymeric micelles of drug-loaded chitosan
derivatives. To create polymeric micellar solutions, chitosan derivatives are dispersed and
50
ultrasonically processed in distilled water. In another beaker drug is dissolved in chloroform.
2
After that, the organic drug solution is gradually added to the aqueous phase, combined at a

speed of 1000 rpm on a magnetic stirrer until the chloroform has completely evaporated, then
allowed for 24 hours to reach equilibrium[275].
5. Localized pulmonary approaches
73
Pulmonary drug delivery is a non-invasive method of administering a drug or bioactive
compound through inhalation[276]. Drug delivery through the pulmonary route offers
numerous advantages, encompassing both local and systemic applications. These advantages
6
primarily stem from its ability to achieve high bioavailability by circumventing the first-pass
metabolism and facilitating a rapid onset of action through direct targeting of the intended
site (lung carcinoma cells[277]), self-administration (like how asthma patients use inhalation
5
devices), non-invasive administration, and increased patient compliance[278], [279]. One of
the major difficulties with cancer chemotherapy is the fact that the anticancer agent is not
specifically targeted/distributed and the serious side effects that can result[280].
However, nanoparticles sprayed will not be able to enter your lungs directly. They are blown
out when you breathe them in and will not settle in your alveoli because they are too small (<
1 μm)[281]. The ideal particle size for getting into your lungs is between 1 and 5 μm [282].
Excipients such as leucine can be used to reduce the size of nanoparticles during the spray-
91
drying process to generate microparticles. Dry powder inhalers (DPIs) can deliver these
microparticles to the lungs. DPIs are a type of portable solid powder delivery system that
does not require propellants[276]. When compared to aerosols and nebulizers, DPIs often
provide a more stable profile for the loaded bioactive compound[283].
Lots of different drugs have been tested to see if they can help with local or systemic
pulmonary delivery[284]. Polymeric nanoparticles are used to deliver micromolecules,
genetic material, and protein/peptides into the lungs[285], [286], [287], [288], [289], [290],
[291]. Scutellarin, a flavone, was mixed into polymeric microparticles made of
sodium hyaluronate, polyvinylpyrrolidone (PVP), and poly (vinyl alcohol) (PVA)[292]. The
average particle size ranged from 1.95 to 2.83 μm, making it suitable for inhalation use[293].
45
The particles were given through the pulmonary pathway and later assessed for their ability to
be absorbed by the body [294]. The study discovered that inhaling scutellarin had a 77%
higher bioavailability than taking it orally, which is 30 times higher[295].
It has been discovered that combining polymer nanoparticles with standard anticancer drugs
like cisplatin and doxorubicin can improve efficacy or reduce negative effects [296]. With a
slow-release profile, the microparticles were found to be in the optimal range of 1-5 μm[297].
The research findings revealed that intravenous distribution of the microspheres resulted in a
6 ointment and cyclophosphamide has demonstrated its ability to impede the development and
higher medicine concentration in the kidney and liver than in the lung. In contrast, pulmonary
administration resulted in a significant buildup of the medicine in the lung, with limited
deposition in other organs [296].
Furthermore, 6 hours after pulmonary administration, paclitaxel and quercetin concentrations
47
in the lung remained high (206.27 g/g). At the same time, they were comparatively low in the
heart (2.61 μg/g), kidney (5.01 μg/g), liver (8.82 μg/g), and spleen (6.94 μg/g)[296].
However, 6 hours after intravenous administration, paclitaxel concentrations were less than 5
μg/g in all organs, and quercetin was found to increase paclitaxel circulatory time [296].
Results indicate that pulmonary microparticle delivery not only increased drug retention time,
30
but also allowed for drug accumulation in the lung with minimal drug accumulation in other
organs, resulting in fewer adverse side effects.
7. A combination phytochemical nano formulations and anticancer drugs for lung
cancer
The combination treatment demonstrated consistent therapeutic efficacy in treating different
types of solid tumours [298], [299]. Tumour drug resistance hinders successful treatment,
leading to tumour recurrence or treatment failure. Combining natural products with
anticancer drugs may improve therapeutic outcomes. Natural products are more effective,
less toxic, and control signal pathways to enhance immunogenicity[300]. The increasing
amount of scientific proof indicates that the utilization of a blend of natural components and
anti-cancer drugs might result in enhanced therapeutic effects.
The growth of advanced pharmaceutical delivery systems has been made possible by
29
technological progress[301]. Biomaterial carriers utilized in cancer therapy comprise a
diverse array of both natural and synthetic materials. The treatment of tumours requires the
precise targeting of therapeutic agents to tumour cells[302]. Both drugs and materials have
been discovered to aid in the localization of active compounds and to either decrease or
enhance the impact of active substances on both healthy and cancerous cells. Certain
substances possess properties that can combat cancer, and when combined with medications,
they enhance its efficacy.
To enhance the bioavailability of drugs, various forms of drug delivery systems are available,
including nanoscale, microscale, and macroscale systems[303]. Polysaccharides are
frequently blended with other polymers to give them the properties they require, such as the
ability to encapsulate, stabilize, and release pharmaceuticals. Pectin, for example, is a
biocompatible and biodegradable natural, high-quality macromolecule polymer utilized for
medication delivery[304], [305]. Furthermore, multiple studies have demonstrated that the
protein pectin can inhibit cancer cell proliferation[306], [307].
44
The combination of anlotinib and Brucea Javanica oil, a traditional Chinese remedy, has been
proven to have a stronger impact on suppressing the growth, angiogenesis, and metastasis of
44
liver cancer associated with SCLC. Furthermore, the combination of anlotinib and Brucea
2
Javanica oil has been linked to a reduction in weight loss in both a weight loss model and
normal mice following anlotinib treatment[308].
By suppressing the inflammatory surroundings of the tumour, the fusion of fei-liu-ping
69
13
infiltration of lung cancer. Consequently, it can be employed either independently or in
conjunction with the established treatment for pneumonia associated with inflammation[309].
2
In research conducted by Liu et al., they showed that the combination of fei-liu-ping ointment
and celecoxib had a suppressive impact on the inflammatory microenvironment of the tumour
in an LLC xenograft model[310].
22
The protein Disintegrin and metalloproteinase (ADAM9), which is categorized as a type I
transmembrane protein, exhibits an increased expression level in various forms of cancer,
such as lung cancer[311], [312], [313]. The study conducted by Lin and his colleagues
showed that a refined version of ADAM9 enables cancer cell invasion to multiply using
connections formed between tumours and stromal cells[314]. Therefore, it has been
 2 98
discovered that Resveratrol hampers the manifestation of ADAM9 protein in A549 and Bm7 apoptosis in the same cell line.
4
cells through the process of ubiquitin-mediated peptide formation. Moreover, a coherent anti- 7 Thymoquinone and Female The combination of thymoquinone and low-dose [327]
tumour result was observed when Resveratrol was concurrently administered with Dasatinib cisplatin SCID cisplatin (2.5 mg/kg i.p. weekly) had no negative
mice effects on hepatic or renal function. This finding
(DAT) or 5-fluorouridine (5-FU)[315]. Research has illustrated that the utilization of
supports the notion that combining thymoquinone 4
carnositol, ginsensoide Rh2, and ginseng aqueous extract augments cisplatin antitumor and cisplatin is a valuable therapeutic approach for
potency by diminishing the manifestation of Pd-L1, stifling MDSCs, and regulating the LC, as thymoquinone effectively suppresses NF-kB
polarization of macrophages[316], [317]. and counteracts cisplatin resistance caused by NF-
kB overexpression, thereby increasing the drug's
Another study found that quercetin worked synergistically with curcumin to treat lung cancer efficacy.
10
in animals. By altering the p53 gene, the combination of quercetin and curcumin resulted in 8 Tetrandrine, Human The combination of cisplatin and gemcitabine has a [328]
101
considerable chemoprevention and promoted apoptosis of lung cancer cells [318]. The gemcitabine and trial synergistic antineoplastic effect, increasing
combination of lactone deoxyelethephantopin and cisplatin has been demonstrated to cisplatin treatment efficacy. Furthermore, tetrandrine
administration has been proven to improve patient
diminish lung metastases in B16 melanoma mice, as well as to reduce cisplatin's adverse survival rates while simultaneously reducing the
effects in animals. It also aids in the reduction of lung metastasis caused by nephrosis, side effects of chemotherapy.
haematological difficulties, and weight loss[319]. Apigenin in conjunction with 9 Paclitaxel and Human Weekly Paclitaxel treatment has been shown to [329]
8
therapeutically active tyroservatide has demonstrated encouraging results in the treatment of carboplatin/cisplatin trial effectively lower toxicity levels while
lung cancer patients[320]. Table No.03 discusses the mechanism of action of a combination simultaneously improving the efficacy
4
and intensity
of synthetic drug and phytochemical drug formulation. of the pharmaceutical dosage. Paclitaxel on days 1
and 8, combined with cisplatin once every three
Table No.03 Combination drugs (synthetic and phytochemical) in the treatment of lung weeks, is well-tolerated.
51
cancer. 10 Curcumin and H520 Both drugs induce apoptosis by raising the [330]
vinorelbine cells expression of Bax and Bcl-xs and lowering the
Sr Combination Study Results Refs. expression of Bcl-2 and Bcl-XL.
No. Drugs
1 Cisplatin and Cisplatin Fisetin suppressed cellular viability while also [321]
Fisetin resistant blocking the MAPK/survivin pathway, potentially
A549-CR reversing cisplatin resistance.
cells 6. The evaluation parameters for phytochemical nano formulations
22
2 Paclitaxel and HepG2 The downregulation of NF-kB and MMP-9 by [322] Particle size, zeta potential, drug-loading capacity, encapsulation efficiency, surface
Phloretin cell phloretin could reveal the improved inhibitory functionalization, in vitro release profile, biocompatibility, cytotoxicity, rheological
xenograft action of paclitaxel.
properties, in vivo pharmacokinetics, and stability in biological fluids are among84
the
tumor
in mice
assessment criteria for phytochemical nano formulation. The optimization of these
3 Genistein and H460 Preconditioning with genistein, followed by low- [323] parameters is important for the development of effective and safe nano formulations of
docetaxel cells dose docetaxel delivery, results in increased phytochemicals for drug delivery applications. These parameters help to tailor formulations
56
suppression of cell growth and induction of to specific therapeutic goals, enhance bioavailability and minimize potential side
apoptosis, outperforming the individual effects of effects[331].
either medication.
4 Paclitaxel and A549 In the framework of paclitaxel-emodin combination [324]
Nano formulations are essential formulations made with a delivery vehicle known as a
4 nanoparticle that will assist in delivering the medicine to the desired spot while improving the
emodin xenograft therapy, emodin has been shown to increase Bax
model and caspase-3 expression while decreasing Bcl-2, p- physiochemical properties of the drugs. Nanotechnology or nano formulations have picked
Akt, and p-ERK levels. The combination of these the interest of the pharmaceutical industry 89
as they help to overcome the solubility,
variables increases paclitaxel-induced apoptosis. bioavailability, and efficacy issues of some of the drugs also providing the targeted delivery
99
5 Alpinetin and cis- A549 Alpinetin was found to be more effective at [325] of the drug.
diammined increasing the responsiveness of drug-resistant lung
dichloridoplatium cancer cells to cisdiammined dichloridoplatium. It The challenge lies in the formulation, in selection of a nano vehicle that is a delivery system
also inhibited cellular growth, aided apoptosis, and which should be compatible with the drug to be administered. After the 55
drug release, the
hampered the PI3K/Akt signalling pathway. empty nano vehicles remaining in the body may lead to toxicity which can be reduced by
6 Solamargine and H661 and Concurrent administration of solamargine and [326] using natural nano delivery systems. The nano delivery system could use excipients like gold
trastuzumab H69 cells trastuzumab results in increased reduction of cell or silver nanoparticles,
87
phospholipids, and dendrimers. The fundamental part is to evaluate
growth, but concomitant administration of the nanoparticles for particle size, surface charge, entrapment efficacy, drug release, and
26
solamargine and low-toxic epirubicin promotes toxicity of nanoparticle. Nanoparticles are of different shapes, sizes, and structures and may
be conical, cylindrical, spherical, tubular, hollow core, spiral, etc., or irregular with the size of diameter layer. The
NPs varying from 1 to 100 nm[332], [333]. marinoso effective
mes were cytotoxic
The methods usually adopted for particle size evaluation include Cryo TEM, and dynamic formed. effect was
light scattering techniques.
43
Typically, Cryo TEM is used for morphology
12
study. As a seen at 72
separation approach for analysing the size and size distribution of liposomal nanoparticles, hr on A549
asymmetric-flow field-flow fractionation (AF4) has proved its robustness and efficiency. cells and
after 24 hrs
12
Determination of the composition of nanoparticles involves finding the concentration of each on HUVEC
12 cells.
component. Usually, a centrifugal filter machine like microcon is used. the
free/unencapsulated drug concentration and actual encapsulated drug concentration are 16 16
determined. Usually, HPLC, a UV detection method coupled with LCMS could be used. The Curcumin Liposomes Nanoparti Zeta 90.89% and drug Surface
97
zeta potential technique is used to determine the surface properties of nanoparticles. The and thin film hydration- cle size potential 80.41% for release of charge,
purity of the drug is to be assessed by studying the correct structure and assay procedures. bromocriptin sonication method. achieved evaluated the liposome- liposome- electrostatic
The excipients are usually added for stability and shelf life. The nanomaterial composition e (BR) Excipient used
16
curcumin and BR , nano-
103 Soybean liposome-BR nanoparticl nutraceutic
should be assessed for purity. The quality of the starting material is important to formulate a
phospholipids with nanoparticles es (60%) is al
quality and stable product[334].
75% phosphatidyl- , greater than liposomal
12
The stability can be assessed by size distribution and size as a function of time. The choline, 2-stearoyl- respectively. that of formulation
aggregation should be monitored. The centrifugal stability, storage conditions, and the effect sn-glycerol-3- liposome- [337]
29 phosphoenol- curcumin
of temperature are some of the factors that may affect the stability of the product. It is critical
amine, and sodium nanoparticl
to monitor medication leakage, release, and degradation in real-time. As stipulated by the
12 12 salt es (20%) at
FDA, ensuring batch-to-batch consistency is critical for translational purposes. Batch-to- the same
batch consistency should be evaluated by selecting relevant factors (such as lot release time.
criteria) that are directly related to the desired in vivo outcome [335]. In Table No. 02 the Enhanced
curcumin nanoparticle physiochemical parameters have been discussed. solubility
and
Table no. 02 the curcumin nanoparticle physiochemical parameter bioavailabil
ity.
Phytochemic Method of Evaluation Parameters
al preparation of Cytotoxicit
Nano formulation y effect
studied
43
Particle Zeta Entrapment Activity Stability
size potential Efficiency Study
Curcumin Marinosomes The The The higher More Surface
formed.
14
particle negative the lipid antioxidant charge,
The thin drug-lipid size charge of weight activity in Oxidative
film method after distributio zeta higher the curcumin Physical,
refluxing n single potential entrapment marinosom electrostatic
The drug is peak. values
14
capacity.
14
es than the , stable
refluxed with the High could be high free controlled 9. Challenges in Targeting Lung Cancer Using Phytochemical nanodelivery system
lipids for 2 h. power due to the encapsulation curcumin release
Plant-based goods have been used as cures and therapeutic products since the dawn of time.
Krill lipid extract sonication. partition efficiency (> which may nano-
was used. The higher of the 90%) at a be because nutraceutic The fundamental challenge in using plant-derived phytochemicals for therapeutic reasons is
the negativel lipid/drug of the al their scarcity, high hydrophilic content, or low lipid solubility, which limits membrane
concentrat y charged ratio of 15/1 synergistic liposomal permeability. Furthermore, the metabolic enzymes (Phase I and Phase II) that hydrolyze,
ion of phospholi (w/w) antioxidant formulation oxidize, and decrease the chemical carry out excessive metabolism, increasing its clearance
lipid pids and effect of [336] rate even further[338]. In humans, for example, an oral dose of 3.6g of curcumin per day is
smaller the free fatty phospholipi 15
size. acids into d on required to achieve 11.1 NMol/L serum levels, as the lower amount is undetectable in
Uniform the lipid curcumin.
plasma[339]. Furthermore, a minimum of 5g of Resveratrol per day is required to induce biological effects [353]. For instance, rod-shaped nanoparticles are more toxic and dangerous
apoptosis[340]. than sphere-shaped nanoparticles [354]. Moreover, the macrophages may not consistently
possess the capacity to fully assimilate elongated fibres, thereby impeding their elimination
Some treatments, including tailored methods, nano-associative delivery, and photothermal
from the organism and resulting in inflammatory responses [355]. A complicating factor that
therapy (PTT), can overcome these weaknesses and open opportunities for research and
93 further adds complexity is the capacity to modify the surface composition of nanoparticles,
oncology specialists[341]. Sulforaphane is used as a chemical prodrug for the treatment of
consequently modifying the bio-responsiveness. For example, carbon nanotubes are often
chemically caused cancers of the lungs, skin, abdomen, colorectal cancer, oral cancer, and
considered resistant to biodegradation, but when carbon nanotubes are functionalized, they
bladder cancer due to its activity as a particular Nrf- 2 signalling inducer [342]. Another
may exhibit solubility in water and can be quickly excreted through renal mechanisms [356].
focused technique is apocynin, which binds to tubulin and causes depolarization in the
94 Because there are so many ways to vary the shape, size, and chemistry of particles, and
microtubule network, culminating in autophagy-induced cell death. This depolarization 17
because even minor changes in the physicochemical qualities can have a significant impact
inhibits lung cancer growth, progression, and invasion[343]. As a result, the focused strategy
on how they behave, it's critical to assess the safety of each substance separately.
of using phytochemicals lowers bioavailability, metabolism, and non-selectivity-related
15
restrictions[344]. Extensive research has been conducted on nano-mediated target delivery of
phytochemicals for cancer treatment. It has been discovered to improve the pharmacokinetic
11. The Future of phytochemical nano formulations in Lung Cancer Treatment
qualities of a variety of important medications while also lowering their related negative
effects[345]. Herbal medicines are currently chosen because they are more economical and readily
available on the market; however, advancements in their composition and drug delivery
Nano-carriers move swiftly through the tiny capillaries and may be easily accessible to
mechanisms are required. Lung cancer is a particularly deadly and widespread type of cancer.
tumour cells, enhancing the bioavailability of important medications. Nano-carriers also
To cure it, we must first understand how lung cancer works by employing potent biomarkers
ensure consistent and regulated medication release at the site of the target[346]. This strategy
15 at various phases of the disease, such as forecasting, diagnosing, and prognosticating.
is based mostly on the idea that nanoparticles attach to specific target receptors that are 24
Because of the various types of research now undertaken in the field of herbal medical goods,
overstimulated in cancer cells, facilitating receptor-mediated entrance into the cell[347].
15 a wide range of compounds will be available. Modifying ingredients can make progress in
There are nano-drug delivery methods available that can target specific biomarkers of lung
producing semi-synthetic therapeutic medicines.
cancer using potent natural products such as dendrimers, micro-organisms nanotubes,
nanoparticles, and liposomes [348]. Theranostics, which is formed from the phrase therapeutics and diagnostics, refers to a
3
holistic approach that includes the use of pharmaceuticals for both cancer diagnosis and
A recent review found that clinical research on herbal medicines has its own set of limitations
therapy. Theranostic approaches strive to integrate diagnostic and treatment strategies to
and obstacles[349]. Comprehensive evaluations of herbal therapeutic items can be difficult
optimise patient outcomes. Furthermore, it aids in combating chemo responsiveness in breast
due to the range of herbal therapies. As a result, it is recommended that quality control be
cancer[357]. DOX and CUR administration mechanisms are pH-dependent and serve as a
performed for cancer research including herbal medicine and plant-based substances, as well
chemical preservative. The magnetic NC's surface was covered with hydroxyapatite, which
as pharmacokinetics investigations with herbal medical products. In addition, the components
underwent cross-linking with b-cyclodextrin, thereby enhancing the bioavailability of
of herbal medical items have been shown to have antitumor effects against lung cancer.
curcumin. The assessment of therapeutic efficacy was based on the observed reduction in
Because therapeutic performance may fluctuate between batches, the Quality of Life (QoL)
tumour dimensions[358]. In an alternative investigation, nano-curcumin was jointly
of herbal medicinal products should be of particular importance[350].
administered with UCNPs (Rare Earth Doped Up Conversion Nanoparticle). PLGA (Lactic-
25
Furthermore, in the available literature on the use of herbal medicinal items in lung cancer Co-Glycolic Acid) was utilized to facilitate the enduring dispensation of the medication and
treatment, the lack of a consistent methodology, the potential for bias, and the small number its liberation, aiming to reduce non-specific tissue absorption and enhance the solubility in
of patients included in the study have been repeatedly highlighted[351]. Clinical trials water[359].
utilizing phytochemical substances, on the other hand, have some difficulties, such as a lack
Another extensively used targeted delivery technology is PTT (Photo Thermal Therapy). This
of consistent batch distribution during the randomized-control research[352]. Therefore, to
technology saves time and regulates the distribution of vital medicine, lowering the
confirm the adequacy of phytochemicals as well as to overcome the difficulties of clinical
likelihood of severe side effects linked with the surrounding healthy tissues greatly[360].
trials, novel specific methods are continually sought to overcome the difficulties associated
Near-infrared light also illustrates the possibility of using an external stimulus in photo
with phytochemicals.
thermotherapy. Because of its low invasiveness and absence of injury to peripheral healthy
10. Nanotoxicology tissues, photo thermotherapy has received much attention as a cancer treatment[361].
To maximize nanoparticles' potential for therapeutic usage, nanomaterials require a thorough In the coming times, as novel advancements unfold, the limitations concerning
understanding of their biocompatibility, bioavailability, and biodegradability. Nanoparticles' phytochemicals might be eliminated. To illustrate, the incorporation of therapy could serve as
17
physicochemical qualities, such as size, surface charge, and shape, will influence their an additional treatment or a treatment that works in harmony. To exemplify, the
supplementary treatment could aid in diminishing the volume of a tumour through a
particular medication, all the while activating the cellular mechanisms that lead to the demise
of the cells through another medication [362]. The additive and synergy treatment approach
further diminishes the curative measure of an individual medication. The combined therapy
approach may additionally avert harm to conventional cells; this can arise if both medications
serve as an opponent to harm in healthy cells[363]. Another major component in overcoming
barriers to use is the synthesis of phytochemical derivatives. These compounds are projected
to have increased bioavailability and potency, boosting the phytochemical's medicinal
potential as an anti-cancer agent[364]. AT-101, for example, is a Gossypol derivative with
15
lower toxicity that has been examined in 24 clinical studies against various cancers such as
leukaemia, lymphoma, and lung cancer [365].
12. CONCLUSION
Cancer development is a complex process 3
and has a dynamic tumour microenvironment,
which remains a challenge for treatment. The development of metastasis, drug resistance, and
reoccurrence the some 57
of the major concerns in the treatment of cancer. Scientists are
continuously working to understand the influence of the tumour microenvironment and the
targeted drug delivery system to minimize the side effects. Hence the use of phytochemicals
along with synthetic drugs either supplement or in combination to combat tumor growth
could add advantage to overcome the cancer challenge and limitations of existing treatments.
Many phytochemicals in plants 24
have shown various health benefits. Several
phytochemicals/phytoconstituents have been studied for their ability to inhibit lung cancer
cell growth and promote apoptosis. The phytochemicals could be the alternative,
biocompatible approach.
32
The main obstacle to using phytochemicals in the treatment of lung cancer is bioavailability.
The nanotechnology provides innovative solutions to improve drug delivery for lung cancer
treatment. The nanoparticles are loaded with drugs or in combination with phytochemicals
made of biocompatible materials engineered for targeted delivery to lung cancer cells with
enhanced bioavailability ensuring therapeutic concentration reaches the targeted site that
reduces systemic exposure and toxicity.
13. REFERENCES
[1] S. S. Ramalingam, T. K. Owonikoko, and F. R. Khuri, “Lung cancer: New biological
insights and recent therapeutic advances,” CA Cancer J Clin, vol. 61, no. 2, pp. 91–
112, Mar. 2011, doi: 10.3322/caac.20102.
[2] F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, “Global
cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide
for 36 cancers in 185 countries,” CA Cancer J Clin, vol. 68, no. 6, pp. 394–424, Nov.
2018, doi: 10.3322/caac.21492.
[3] R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2018.,” CA Cancer J Clin,
vol. 68, no. 1, pp. 7–30, Jan. 2018, doi: 10.3322/caac.21442.
[4] E. Rodriguez and R. C. Lilenbaum, “Small Cell Lung Cancer: Past, Present, and
Future,” Curr Oncol Rep, vol. 12, no. 5, pp. 327–334, Sep. 2010, doi: 10.1007/s11912-
010-0120-5.
[5] R. L. Siegel, K. D. Miller, H. E. Fuchs, and A. Jemal, “Cancer statistics, 2022,” CA
Cancer J Clin, vol. 72, no. 1, pp. 7–33, Jan. 2022, doi: 10.3322/caac.21708.
[6] WHO, “Lung cancer,” https://www.who.int/news-room/fact-sheets/detail/lung-cancer.
[7] H. Witschi, “A Short History of Lung Cancer,” Toxicological Sciences, vol. 64, no. 1,
pp. 4–6, Nov. 2001, doi: 10.1093/toxsci/64.1.4.
[8] H. C. Hassing, T. B. Twickler, J. J. P. Kastelein, M. J. M. Cramer, and F. R. Cassee,
“Air pollution as noxious environmental factor in the development of cardiovascular
disease.,” Neth J Med, vol. 67, no. 4, pp. 116–21, Apr. 2009, Accessed: Sep. 18, 2023.
[Online]. Available: http://www.ncbi.nlm.nih.gov/pubmed/19581654
[9] Y. Chen, A. Ebenstein, M. Greenstone, and H. Li, “Evidence on the impact of
sustained exposure to air pollution on life expectancy from China’s Huai River
policy.,” Proc Natl Acad Sci U S A, vol. 110, no. 32, pp. 12936–41, Aug. 2013, doi:
10.1073/pnas.1300018110.
[10] O. Catelinois et al., “Lung cancer attributable to indoor radon exposure in france:
impact of the risk models and uncertainty analysis.,” Environ Health Perspect, vol.
114, no. 9, pp. 1361–6, Sep. 2006, doi: 10.1289/ehp.9070.
[11] O. Y. Gorlova, S.-F. Weng, Y. Zhang, C. I. Amos, and M. R. Spitz, “Aggregation of
cancer among relatives of never-smoking lung cancer patients.,” Int J Cancer, vol.
121, no. 1, pp. 111–8, Jul. 2007, doi: 10.1002/ijc.22615.
[12] T. Yano, “Therapeutic strategy for postoperative recurrence in patients with non-small
cell lung cancer,” World J Clin Oncol, vol. 5, no. 5, p. 1048, 2014, doi:
10.5306/wjco.v5.i5.1048.
[13] E. Braunwald, A. S. Fauci, D. L. Kasper, S. L. Hauser, D. L. Longo, and J. L.
Jameson, “Harrisons principles of internal medicine - 15th edition,” pp. 1187–1187,
2001, Accessed: Sep. 18, 2023. [Online]. Available:
https://pesquisa.bvsalud.org/portal/resource/pt/lil-642226
[14] F. Villanueva, A. Notario, A. Tapia, J. Albaladejo, B. Cabañas, and E. Martínez,
“Ambient levels of volatile organic compounds and criteria pollutants in the most
industrialized area of central Iberian Peninsula: intercomparison with an urban site,”
Environ Technol, vol. 37, no. 8, pp. 983–996, Apr. 2016, doi:
10.1080/09593330.2015.1096309.
[15] D.-C. Shin, Hazardous air pollutants : case studies from Asia. Accessed: Sep. 18,
2023. [Online]. Available:
https://books.google.co.in/books?hl=en&lr=&id=ewrYCwAAQBAJ&oi=fnd&pg=PA
47&ots=uxxRYBUmWc&sig=05-
zj7RXSq5fCM1ex868RvYEQdM&redir_esc=y#v=onepage&q&f=false
[16] European Environment Agency., Benefits of an ambitious implementation of the
Industrial Emissions Directive in the power sector.
[17] European Environment Agency., Digital technologies will deliver more efficient waste
management in Europe.
[18] M. A. den Bakker and R.-J. van Suylen, “Primary pulmonary sarcomatous and mixed
epithelial-mesenchymal neoplasms,” Journal of Diagnostic Pathology, vol. 12, no. 2,
p. 1, Dec. 2017, doi: 10.4038/jdp.v12i2.7739.
[19] Z. M. Mohaidat, H. Z. Al-jamal, A. M. Bany-Khalaf, A. M. Radaideh, and Z. A.
Audat, “Giant cell tumor of bone: Unusual features of a rare tumor,” Rare Tumors, vol.
11, p. 203636131987889, Jan. 2019, doi: 10.1177/2036361319878894.
[20] C. Zhang et al., “Identification of lncRNA, miRNA and mRNA expression profiles
and ceRNA Networks in small cell lung cancer,” BMC Genomics, vol. 24, no. 1, p.
217, Apr. 2023, doi: 10.1186/s12864-023-09306-4.
[21] K. Krpina, S. Vranić, K. Tomić, M. Samaržija, and L. Batičić, “Small Cell Lung
Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future
Perspectives,” Biomedicines, vol. 11, no. 7, p. 1982, Jul. 2023, doi:
10.3390/biomedicines11071982.
[22] S. Sundaresan, Ed., Clinical Diagnosis and Management of Squamous Cell
Carcinoma. IntechOpen, 2023. doi: 10.5772/intechopen.94812.
[23] F. M. Sullivan and M. van Beusekom, “Early diagnosis of lung cancer in people most
at risk,” British Journal of General Practice, vol. 70, no. 701, pp. 572–573, Dec. 2020,
doi: 10.3399/bjgp20X713537.
[24] 統計處, “109年國人死因統計結果,” 統計處, Jun. 2021, Accessed: Sep. 18, 2023.
[Online]. Available: https://www.mohw.gov.tw/cp-5017-61533-1.html
[25] M. A. Beckles, S. G. Spiro, G. L. Colice, and R. M. Rudd, “Initial evaluation of the
patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic
syndromes.,” Chest, vol. 123, no. 1 Suppl, pp. 97S-104S, Jan. 2003, doi:
10.1378/chest.123.1_suppl.97s.
[26] M. P. Rivera, A. C. Mehta, and M. M. Wahidi, “Establishing the diagnosis of lung
cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest
Physicians evidence-based clinical practice guidelines.,” Chest, vol. 143, no. 5 Suppl,
pp. e142S-e165S, May 2013, doi: 10.1378/chest.12-2353.
[27] M. López Rodríguez and L. Cerezo Padellano, “Toxicity associated to radiotherapy
treatment in lung cancer patients.,” Clin Transl Oncol, vol. 9, no. 8, pp. 506–12, Aug.
2007, doi: 10.1007/s12094-007-0094-4.
[28] S. G. Spiro and J. C. Porter, “Lung Cancer—Where Are We Today?,” Am J Respir
Crit Care Med, vol. 166, no. 9, pp. 1166–1196, Nov. 2002, doi: 10.1164/rccm.200202-
070SO.
[29] M. López Rodríguez and L. Cerezo Padellano, “Toxicity associated to radiotherapy
treatment in lung cancer patients.,” Clin Transl Oncol, vol. 9, no. 8, pp. 506–12, Aug.
2007, doi: 10.1007/s12094-007-0094-4.
[30] PDQ Adult Treatment Editorial Board, Non-Small Cell Lung Cancer Treatment
(PDQ®): Health Professional Version. 2002. Accessed: Sep. 18, 2023. [Online].
Available: http://www.ncbi.nlm.nih.gov/pubmed/17873159
[31] “Late complications of radiotherapy,” Drug Ther Bull, vol. 35, no. 2, pp. 13–16, Feb.
1997, doi: 10.1136/dtb.1997.35213.
[32] R. J. Aur et al., “Childhood acute lymphocytic leukemia: study VIII.,” Cancer, vol. 42,
no. 5, pp. 2123–34, Nov. 1978, doi: 10.1002/1097-0142(197811)42:5<2123::aid-
cncr2820420507>3.0.co;2-5.
[33] R. A. Price and P. A. Jamieson, “The central nervous system in childhood leukemia. II.
Subacute leukoencephalopathy.,” Cancer, vol. 35, no. 2, pp. 306–18, Feb. 1975, doi:
10.1002/1097-0142(197502)35:2<306::aid-cncr2820350203>3.0.co;2-j.
[34] L. L. Gunderson and J. A. Martenson, “Gastrointestinal Tract Radiation Tolerance,”
pp. 277–298. doi: 10.1159/000416590.
[35] P. L. Zentler-Munro and E. M. Bessell, “Medical management of radiation enteritis —
An algorithmic guide,” Clin Radiol, vol. 38, no. 3, pp. 291–294, May 1987, doi:
10.1016/S0009-9260(87)80074-0.
[36] S. Korzeniowski, “Late side effects and complications in breast cancer patients treated
by postoperative radiotherapy,” Reports of Practical Oncology & Radiotherapy, vol. 3,
no. 2, pp. 27–33, 1998, doi: 10.1016/S1507-1367(98)70163-4.
[37] M. D. Leslie and S. Dische, “Parotid gland function following accelerated and
conventionally fractionated radiotherapy,” Radiotherapy and Oncology, vol. 22, no. 2,
pp. 133–139, Oct. 1991, doi: 10.1016/0167-8140(91)90009-6.
[38] F. Wirsdörfer, S. de Leve, and V. Jendrossek, “Combining Radiotherapy and
Immunotherapy in Lung Cancer: Can We Expect Limitations Due to Altered Normal
Tissue Toxicity?,” Int J Mol Sci, vol. 20, no. 1, p. 24, Dec. 2018, doi:
10.3390/ijms20010024.
[39] S.-J. Jeong, W. Koh, B. Kim, and S.-H. Kim, “Are there new therapeutic options for
treating lung cancer based on herbal medicines and their metabolites?,” J
Ethnopharmacol, vol. 138, no. 3, pp. 652–661, Dec. 2011, doi:
10.1016/j.jep.2011.10.018.
[40] A. Bishayee and G. Sethi, “Bioactive natural products in cancer prevention and
therapy: Progress and promise,” Semin Cancer Biol, vol. 40–41, pp. 1–3, Oct. 2016,
doi: 10.1016/j.semcancer.2016.08.006.
[41] S. S M et al., “A spotlight on alkaloid nanoformulations for the treatment of lung
cancer.,” Front Oncol, vol. 12, p. 994155, 2022, doi: 10.3389/fonc.2022.994155.
[42] R. V. Priyadarsini and S. Nagini, “Cancer chemoprevention by dietary
phytochemicals: promises and pitfalls.,” Curr Pharm Biotechnol, vol. 13, no. 1, pp.
125–36, Jan. 2012, doi: 10.2174/138920112798868610.
[43] S. Wang, J. Zhang, M. Chen, and Y. Wang, “Delivering flavonoids into solid tumors
using nanotechnologies.,” Expert Opin Drug Deliv, vol. 10, no. 10, pp. 1411–28, Oct.
2013, doi: 10.1517/17425247.2013.807795.
[44] S. Wang, J. Zhang, M. Chen, and Y. Wang, “Delivering flavonoids into solid tumors
using nanotechnologies.,” Expert Opin Drug Deliv, vol. 10, no. 10, pp. 1411–28, Oct.
2013, doi: 10.1517/17425247.2013.807795.
[45] G. Zhang, X. Zeng, and P. Li, “Nanomaterials in cancer-therapy drug delivery
system.,” J Biomed Nanotechnol, vol. 9, no. 5, pp. 741–50, May 2013, doi:
10.1166/jbn.2013.1583.
[46] C. Hao, X. Li, Z. Wang, L. Liu, F. He, and Z. Pan, “Optically activated MEK1/2
inhibitors (Opti-MEKi) as potential antimelanoma agents,” Eur J Med Chem, vol. 251,
p. 115236, May 2023, doi: 10.1016/j.ejmech.2023.115236.
[47] J. H. Strickler et al., “Prevalence of KRAS G12C Mutation and Co-mutations and
Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic
Literature Review,” Oncologist, vol. 28, no. 11, pp. e981–e994, Nov. 2023, doi:
10.1093/oncolo/oyad138.
[48] C. H. Law, F. L. Chan, and V. W. Y. Lui, “Abstract 546: Targeting BRAF mutations in
head and neck cancer,” Cancer Res, vol. 83, no. 7_Supplement, pp. 546–546, Apr.
2023, doi: 10.1158/1538-7445.AM2023-546.
[49] M. S. Lee et al., “Preliminary results from ERAS-007 plus encorafenib and cetuximab
(EC) in patients (pts) with metastatic BRAF V600E mutated colorectal cancer (CRC)
in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated
protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies
(GI cancers).,” Journal of Clinical Oncology, vol. 41, no. 16_suppl, pp. 3557–3557,
Jun. 2023, doi: 10.1200/JCO.2023.41.16_suppl.3557.
[50] M. L. Jenkins, H. Ranga-Prasad, M. A. H. Parson, N. J. Harris, M. K. Rathinaswamy,
and J. E. Burke, “Oncogenic mutations of PIK3CA lead to increased membrane
recruitment driven by reorientation of the ABD, p85 and C-terminus,” Nat Commun,
vol. 14, no. 1, p. 181, Jan. 2023, doi: 10.1038/s41467-023-35789-6.
[51] K. K. Zhang, C. M. Burns, M. E. Skinner, D. B. Lombard, R. A. Miller, and S. J.
Endicott, “PTEN is both an activator and a substrate of chaperone-mediated
autophagy,” Journal of Cell Biology, vol. 222, no. 9, Sep. 2023, doi:
10.1083/jcb.202208150.
[52] M.-C. Hung, W.-P. Wang, and Y.-H. Chi, “AKT phosphorylation as a predictive
biomarker for PI3K/mTOR dual inhibition-induced proteolytic cleavage of mTOR
companion proteins in small cell lung cancer,” Cell Biosci, vol. 12, no. 1, p. 122, Dec.
2022, doi: 10.1186/s13578-022-00862-y.
[53] B. Y. Shim, S.-B. Lee, H. Kim, H. S. Park, and H. J. An, “Preclinical evidence for
synergistic effects of autophagy inhibitor and alpelisib in PI3KCA mutated non-small
cell lung cancer: Implications for future clinical trials.,” Journal of Clinical Oncology,
vol. 41, no. 16_suppl, pp. e21022–e21022, Jun. 2023, doi:
10.1200/JCO.2023.41.16_suppl.e21022.
[54] Z. Wang, H. Zhou, J. Xu, J. Wang, and T. Niu, “Safety and efficacy of dual PI3K-δ, γ
inhibitor, duvelisib in patients with relapsed or refractory lymphoid neoplasms: A
systematic review and meta-analysis of prospective clinical trials,” Front Immunol,
vol. 13, Jan. 2023, doi: 10.3389/fimmu.2022.1070660.
[55] T. K. Moyo et al., “PI3K Inhibition Restores and Amplifies Response to Ruxolitinib in
Patients with Myelofibrosis,” Clinical Cancer Research, vol. 29, no. 13, pp. 2375–
2384, Jul. 2023, doi: 10.1158/1078-0432.CCR-22-3192.
[56] Y. Ko et al., “S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite
activates NRF2 signaling,” Proceedings of the National Academy of Sciences, vol.
120, no. 20, May 2023, doi: 10.1073/pnas.2300763120.
[57] M. Iglesia et al., “STK11 alterations as predictive biomarkers of resistance to immune
checkpoint inhibitors in multiple cancers with mismatch repair gene alterations.,”
Journal of Clinical Oncology, vol. 41, no. 16_suppl, pp. 2619–2619, Jun. 2023, doi:
10.1200/JCO.2023.41.16_suppl.2619.
[58] L. Yang et al., “A subset of <scp>VEGFR‐TKIs</scp> activates <scp>AMPK</scp>
in <scp>LKB1</scp> ‐mutant lung cancer,” Cancer Sci, vol. 114, no. 4, pp. 1651–
1662, Apr. 2023, doi: 10.1111/cas.15677.
[59] B. Mao, Q. Zhang, L. Ma, D.-S. Zhao, P. Zhao, and P. Yan, “Overview of Research
into mTOR Inhibitors,” Molecules, vol. 27, no. 16, p. 5295, Aug. 2022, doi:
10.3390/molecules27165295.
[60] S. Dilmac and B. Ozpolat, “Mechanisms of PARP-Inhibitor-Resistance in BRCA-
Mutated Breast Cancer and New Therapeutic Approaches,” Cancers (Basel), vol. 15,
no. 14, p. 3642, Jul. 2023, doi: 10.3390/cancers15143642.
[61] S. Y. Sun and A. Crago, “MDM2 Implications for Potential Molecular Pathogenic
Therapies of Soft-Tissue Tumors,” J Clin Med, vol. 12, no. 11, p. 3638, May 2023,
doi: 10.3390/jcm12113638.
[62] L. Geyer et al., “DIPG-33. P16 IMMUNOHISTOCHEMICAL EXPRESSION AS A
SURROGATE ASSESSMENT OF CDKN2A ALTERATION IN GLIOMAS
LEADING TO PROGNOSTIC SIGNIFICANCES,” Neuro Oncol, vol. 25, no.
Supplement_1, pp. i20–i20, Jun. 2023, doi: 10.1093/neuonc/noad073.080.
[63] M. Mehdi et al., “ATM or CHEK2 alterations: Potential biomarkers of improved
outcomes with irinotecan-containing chemotherapy in advanced pancreatic ductal
adenocarcinoma.,” Journal of Clinical Oncology, vol. 41, no. 4_suppl, pp. 754–754,
Feb. 2023, doi: 10.1200/JCO.2023.41.4_suppl.754.
[64] Z. Wang et al., “The anti-cancer agent APR-246 can activate several programmed cell
death processes to kill malignant cells,” Cell Death Differ, vol. 30, no. 4, pp. 1033–
1046, Apr. 2023, doi: 10.1038/s41418-023-01122-3.
[65] X. Cheng et al., “Leveraging the multivalent p53 peptide-MdmX interaction to guide
the improvement of small molecule inhibitors,” Nat Commun, vol. 13, no. 1, p. 1087,
Feb. 2022, doi: 10.1038/s41467-022-28721-x.
[66] P. Mahajan, G. Chashoo, M. Gupta, A. Kumar, P. P. Singh, and A. Nargotra, “Fusion
of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors,”
J Chem Inf Model, vol. 57, no. 8, pp. 1957–1969, Aug. 2017, doi:
10.1021/acs.jcim.7b00293.
[67] K. Jeyaprakash, K. Thirumalairaj, U. Kim, V. Muthukkaruppan, and A. Vanniarajan,
“RB1 transcript analysis detects novel splicing aberration in retinoblastoma,” Pediatr
Blood Cancer, vol. 70, no. 6, Jun. 2023, doi: 10.1002/pbc.30290.
[68] J. Xing and C. C. Griffith, “CDKN2A/p16 evaluation in cytology specimens,” Cancer
Cytopathol, vol. 131, no. 11, pp. 672–676, Nov. 2023, doi: 10.1002/cncy.22701.
[69] J. Xing and C. C. Griffith, “CDKN2A/p16 evaluation in cytology specimens,” Cancer
Cytopathol, vol. 131, no. 11, pp. 672–676, Nov. 2023, doi: 10.1002/cncy.22701.
[70] Z. Fang et al., “E2F1 promotes cell cycle progression by stabilizing spindle fiber in
colorectal cancer cells,” Cell Mol Biol Lett, vol. 27, no. 1, p. 90, Dec. 2022, doi:
10.1186/s11658-022-00392-y.
[71] L. Vízkeleti and S. Spisák, “Rewired Metabolism Caused by the Oncogenic
Deregulation of MYC as an Attractive Therapeutic Target in Cancers,” Cells, vol. 12,
no. 13, p. 1745, Jun. 2023, doi: 10.3390/cells12131745.
[72] H. Majeski et al., “Discovery of CDK4/6 bifunctional degraders for ER+/HER2-
breast cancer.,” Journal of Clinical Oncology, vol. 41, no. 16_suppl, pp. 1083–1083,
Jun. 2023, doi: 10.1200/JCO.2023.41.16_suppl.1083.
[73] R. Alexandrova and Č. Podlipnik, “MYC oncogenes as potential anticancer targets,” in
Oncogenic Viruses, Elsevier, 2023, pp. 191–219. doi: 10.1016/B978-0-12-824156-
1.00011-X.
[74] M. Lee et al., “Alterations and Co-Occurrence of C-MYC, N-MYC, and L-MYC
Expression are Related to Clinical Outcomes in Various Cancers,” Int J Stem Cells,
vol. 16, no. 2, pp. 215–233, May 2023, doi: 10.15283/ijsc22188.
[75] M. F. Zacarías-Fluck et al., “Reducing MYC’s transcriptional footprint unveils a good
prognostic gene signature in melanoma,” Genes Dev, vol. 37, no. 7–8, pp. 303–320,
Apr. 2023, doi: 10.1101/gad.350078.122.
[76] S. Martínez Martín et al., “Omomyc downregulates MYC transcriptional signature in
preclinical models of solid tumours and shows long half-life in tumour tissue,” Eur J
Cancer, vol. 174, p. S44, Oct. 2022, doi: 10.1016/S0959-8049(22)00918-2.
[77] M. A. Iqbal, S. Arora, G. Prakasam, G. A. Calin, and M. A. Syed, “MicroRNA in lung
cancer: role, mechanisms, pathways and therapeutic relevance.,” Mol Aspects Med,
vol. 70, pp. 3–20, Dec. 2019, doi: 10.1016/j.mam.2018.07.003.
[78] R. J. C. Slebos, R. H. Hruban, O. Dalesio, W. J. Mooi, G. J. A. Offerhaus, and S.
Rodenhuis, “Relationship Between K-ras Oncogene Activation and Smoking in
Adenocarcinoma of the Human Lung,” JNCI: Journal of the National Cancer Institute,
vol. 83, no. 14, pp. 1024–1027, Jul. 1991, doi: 10.1093/jnci/83.14.1024.
[79] W. Hou et al., “Cigarette Smoke Induced Lung Barrier Dysfunction, EMT, and Tissue
Remodeling: A Possible Link between COPD and Lung Cancer.,” Biomed Res Int, vol.
2019, p. 2025636, 2019, doi: 10.1155/2019/2025636.
[80] W. Duan et al., “Type of TP53 mutation influences oncogenic potential and spectrum
of associated K-ras mutations in lung-specific transgenic mice.,” Int J Cancer, vol.
145, no. 9, pp. 2418–2426, Nov. 2019, doi: 10.1002/ijc.32279.
[81] J. Ramelow et al., “The oncogenic potential of a mutant TP53 gene explored in two
spontaneous lung cancer mice models.,” BMC Cancer, vol. 20, no. 1, p. 738, Aug.
2020, doi: 10.1186/s12885-020-07212-6.
[82] Y. Zhang et al., “p53 sensitizes chemoresistant non-small cell lung cancer via
elevation of reactive oxygen species and suppression of EGFR/PI3K/AKT signaling.,”
Cancer Cell Int, vol. 19, p. 188, 2019, doi: 10.1186/s12935-019-0910-2.
[83] S. Yan et al., “FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung
Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway.,”
Front Pharmacol, vol. 12, p. 764699, 2021, doi: 10.3389/fphar.2021.764699.
[84] K. Sugimoto et al., “Mutations of the p53 gene in lymphoid leukemia,” Blood, vol. 77,
no. 6, pp. 1153–1156, Mar. 1991, doi: 10.1182/blood.V77.6.1153.1153.
[85] P. P. Massion and D. P. Carbone, “The molecular basis of lung cancer: molecular
abnormalities and therapeutic implications,” Respir Res, vol. 4, no. 1, p. 12, Dec. 2003,
doi: 10.1186/1465-9921-4-12.
[86] J. Siemanowski, C. Heydt, and S. Merkelbach‐Bruse, “Predictive molecular pathology
of lung cancer in Germany with focus on gene fusion testing: Methods and quality
assurance,” Cancer Cytopathol, vol. 128, no. 9, pp. 611–621, Sep. 2020, doi:
10.1002/cncy.22293.
[87] T. R. Devereux, J. A. Taylor, and J. C. Barrett, “Molecular Mechanisms of Lung
Cancer,” Chest, vol. 109, no. 3, pp. 14S-19S, Mar. 1996, doi:
10.1378/chest.109.3_Supplement.14S.
[88] K. Hibi et al., “Three distinct regions involved in 3p deletion in human lung cancer.,”
Oncogene, vol. 7, no. 3, pp. 445–9, Mar. 1992.
[89] A. Zlobin, J. C. Bloodworth, and C. Osipo, “Mitogen-Activated Protein Kinase
(MAPK) Signaling,” in Predictive Biomarkers in Oncology, Cham: Springer
International Publishing, 2019, pp. 213–221. doi: 10.1007/978-3-319-95228-4_16.
[90] M. J. Fry, “Phosphoinositide (PI) 3-Kinase Assays,” 2009, pp. 1–18. doi: 10.1007/978- [103] C. Cao, L. Zhu, Y. Chen, C.-H. Wang, J. ShenTu, and Y.-L. Zheng, “Physalin B
1-60327-115-8_22. induces G2/M cell cycle arrest and apoptosis in A549 human non-small-cell lung
cancer cells by altering mitochondrial function,” Anticancer Drugs, vol. 30, no. 2, pp.
[91] R. M. Memmott and P. A. Dennis, “The Role of the Akt/mTOR Pathway in Tobacco
128–137, Feb. 2019, doi: 10.1097/CAD.0000000000000701.
Carcinogen–Induced Lung Tumorigenesis,” Clinical Cancer Research, vol. 16, no. 1,
pp. 4–10, Jan. 2010, doi: 10.1158/1078-0432.CCR-09-0234. [104] D. Bisht, D. Kumar, D. Kumar, K. Dua, and D. K. Chellappan, “Phytochemistry and
pharmacological activity of the genus artemisia,” Arch Pharm Res, vol. 44, no. 5, pp.
[92] P. S. Hodkinson, A. MacKinnon, and T. Sethi, “Targeting Growth Factors in Lung
439–474, May 2021, doi: 10.1007/s12272-021-01328-4.
Cancer,” Chest, vol. 133, no. 5, pp. 1209–1216, May 2008, doi: 10.1378/chest.07-
2680. [105] “Anticancer Potentials of Other Herbs,” in Cancer Inhibitors from Chinese Natural
Medicines, Taylor & Francis Group, 6000 Broken Sound Parkway NW, Suite 300,
[93] X. Xu et al., “Muc1 knockout potentiates murine lung carcinogenesis involving an
Boca Raton, FL 33487-2742: CRC Press, 2016, pp. 685–716. doi:
epiregulin-mediated EGFR activation feedback loop,” Carcinogenesis, vol. 38, no. 6,
10.1201/9781315366753-15.
pp. 604–614, Jun. 2017, doi: 10.1093/carcin/bgx039.
[106] L. M. F. Merlo, J. W. Pepper, B. J. Reid, and C. C. Maley, “Cancer as an evolutionary
[94] C. D. Pham, R. B. Arlinghaus, C. F. Zheng, K. L. Guan, and B. Singh,
and ecological process,” Nat Rev Cancer, vol. 6, no. 12, pp. 924–935, Dec. 2006, doi:
“Characterization of MEK1 phosphorylation by the v-Mos protein.,” Oncogene, vol.
10.1038/nrc2013.
10, no. 8, pp. 1683–8, Apr. 1995.
[107] H. F. Smit, H. J. Woerdenbag, R. H. Singh, G. J. Meulenbeld, R. P. Labadie, and J. H.
[95] A. C. MacKinnon, J. Kopatz, and T. Sethi, “The molecular and cellular biology of lung
Zwaving, “Āyurvedic herbal drugs with possible cytostatic activity,” J
cancer: identifying novel therapeutic strategies,” Br Med Bull, vol. 95, no. 1, pp. 47–
Ethnopharmacol, vol. 47, no. 2, pp. 75–84, Jul. 1995, doi: 10.1016/0378-
61, Sep. 2010, doi: 10.1093/bmb/ldq023.
8741(95)01255-C.
[96] S. Maddika et al., “Akt is transferred to the nucleus of cells treated with apoptin, and it
[108] O. Grundmann, “Traditional medicines: bridging the gaps for a better future,”
participates in apoptin-induced cell death,” Cell Prolif, vol. 40, no. 6, pp. 835–848,
Alternative Medicine Studies, vol. 1, no. 1, p. 13, Oct. 2011, doi:
Dec. 2007, doi: 10.1111/j.1365-2184.2007.00475.x.
10.4081/ams.2011.e13.
[97] H. Li et al., “Interleukin-22 secreted by cancer-associated fibroblasts regulates the
[109] R. Doll and R. Peto, “The causes of cancer: quantitative estimates of avoidable risks of
proliferation and metastasis of lung cancer cells via the PI3K-Akt-mTOR signaling
cancer in the United States today.,” J Natl Cancer Inst, vol. 66, no. 6, pp. 1191–308,
pathway.,” Am J Transl Res, vol. 11, no. 7, pp. 4077–4088, 2019.
Jun. 1981.
[98] A. Iqubal et al., “Nerolidol ameliorates cyclophosphamide-induced oxidative stress,
[110] G. Kumar, T. Virmani, A. Sharma, and K. Pathak, “Codelivery of Phytochemicals with
neuroinflammation and cognitive dysfunction: Plausible role of Nrf2 and NF- κB,”
Conventional Anticancer Drugs in Form of Nanocarriers,” Pharmaceutics, vol. 15, no.
Life Sci, vol. 236, p. 116867, Nov. 2019, doi: 10.1016/j.lfs.2019.116867.
3, p. 889, Mar. 2023, doi: 10.3390/pharmaceutics15030889.
[99] A. Iqubal et al., “Molecular mechanism involved in cyclophosphamide-induced
[111] İ. Altun and A. Sonkaya, “The Most Common Side Effects Experienced by Patients
cardiotoxicity: Old drug with a new vision,” Life Sci, vol. 218, pp. 112–131, Feb.
Were Receiving First Cycle of Chemotherapy.,” Iran J Public Health, vol. 47, no. 8,
2019, doi: 10.1016/j.lfs.2018.12.018.
pp. 1218–1219, Aug. 2018.
[100] X. He, B. Lee, and Y. Jiang, “Extracellular matrix in cancer progression and therapy,”
[112] V. K. Singh, D. Arora, M. I. Ansari, and P. K. Sharma, “Phytochemicals based
Medical Review, vol. 2, no. 2, pp. 125–139, Apr. 2022, doi: 10.1515/mr-2021-0028.
chemopreventive and chemotherapeutic strategies and modern technologies to
[101] S. Brassart-Pasco, S. Brézillon, B. Brassart, L. Ramont, J.-B. Oudart, and J. C. overcome limitations for better clinical applications,” Phytotherapy Research, vol. 33,
Monboisse, “Tumor Microenvironment: Extracellular Matrix Alterations Influence no. 12, pp. 3064–3089, Dec. 2019, doi: 10.1002/ptr.6508.
Tumor Progression,” Front Oncol, vol. 10, Apr. 2020, doi: 10.3389/fonc.2020.00397.
[113] D. A. Hafez, K. A. Elkhodairy, M. Teleb, and A. O. Elzoghby, “Nanomedicine-based
[102] J. Zhang et al., “RETRACTED ARTICLE: Chrysophanol exhibits anti-cancer approaches for improved delivery of phyto-therapeutics for cancer therapy,” Expert
activities in lung cancer cell through regulating ROS/HIF-1a/VEGF signaling Opin Drug Deliv, vol. 17, no. 3, pp. 279–285, Mar. 2020, doi:
pathway,” Naunyn Schmiedebergs Arch Pharmacol, vol. 393, no. 3, pp. 469–480, Mar. 10.1080/17425247.2020.1723542.
2020, doi: 10.1007/s00210-019-01746-8.
[114] M. S. Kinch, A. Haynesworth, S. L. Kinch, and D. Hoyer, “An overview of FDA-
approved new molecular entities: 1827–2013,” Drug Discov Today, vol. 19, no. 8, pp.
1033–1039, Aug. 2014, doi: 10.1016/j.drudis.2014.03.018.
[115] T. Gunasekaran, T. Haile, T. Nigusse, and M. D. Dhanaraju, “Nanotechnology: an
effective tool for enhancing bioavailability and bioactivity of phytomedicine,” Asian
Pac J Trop Biomed, vol. 4, pp. S1–S7, May 2014, doi: 10.12980/APJTB.4.2014C980.
[116] “Approaches for Improving Bioavailability of Poorly Soluble Drugs,” in
Pharmaceutical Dosage Forms - Tablets, CRC Press, 2008, pp. 67–120. doi:
10.3109/9781420020298-6.
[117] P. Silva, B. Bonifácio, M. Ramos, K. Negri, T. Maria Bauab, and M. Chorilli,
“Nanotechnology-based drug delivery systems and herbal medicines: a review,” Int J
Nanomedicine, p. 1, Dec. 2013, doi: 10.2147/IJN.S52634.
[118] A. Elzoghby, “Editorial (Thematic Issue: Nanocarriers Based on Natural Polymers as
Platforms for Drug and Gene Delivery Applications),” Curr Pharm Des, vol. 22, no.
22, pp. 3303–3304, May 2016, doi: 10.2174/1381612822999160511151612.
[119] H. Kaur and G. Kaur, “A Critical Appraisal of Solubility Enhancement Techniques of
Polyphenols,” J Pharm (Cairo), vol. 2014, pp. 1–14, Mar. 2014, doi:
10.1155/2014/180845.
[120] S. W. El-Far, M. W. Helmy, S. N. Khattab, A. A. Bekhit, A. A. Hussein, and A. O.
Elzoghby, “Phytosomal bilayer-enveloped casein micelles for codelivery of monascus
yellow pigments and resveratrol to breast cancer,” Nanomedicine, vol. 13, no. 5, pp.
481–499, Mar. 2018, doi: 10.2217/nnm-2017-0301.
[121] S. W. El-Far, M. W. Helmy, S. N. Khattab, A. A. Bekhit, A. A. Hussein, and A. O.
Elzoghby, “Folate conjugated vs PEGylated phytosomal casein nanocarriers for
codelivery of fungal- and herbal-derived anticancer drugs,” Nanomedicine, vol. 13, no.
12, pp. 1463–1480, Jun. 2018, doi: 10.2217/nnm-2018-0006.
[122] T. C. Almeida et al., “Polymeric micelles containing resveratrol: development,
characterization, cytotoxicity on tumor cells and antimicrobial activity,” Brazilian
Journal of Pharmaceutical Sciences, vol. 56, 2020, doi: 10.1590/s2175-
97902019000418401.
[123] D. Mohapatra, A. K. Agrawal, and A. N. Sahu, “Exploring the potential of solid
dispersion for improving solubility, dissolution &amp; bioavailability of herbal
extracts, enriched fractions, and bioactives,” J Microencapsul, vol. 38, no. 7–8, pp.
594–612, Nov. 2021, doi: 10.1080/02652048.2021.1963342.
[124] Z. Chen, Q. Zhu, J. Qi, Y. Lu, and W. Wu, “Sustained and controlled release of herbal
medicines: The concept of synchronized release,” Int J Pharm, vol. 560, pp. 116–125,
Apr. 2019, doi: 10.1016/j.ijpharm.2019.01.074.
[125] J. Zhou et al., “Chitosan Hydrogel Delivery System Containing Herbal Compound
Functions as a Potential Antineuroinflammatory Agent,” ACS Omega, vol. 4, no. 6, pp.
10185–10191, Jun. 2019, doi: 10.1021/acsomega.9b00971.
[126] U. Shah et al., “Review on Determination of Berberine in Biological and
Pharmaceutical Matrices: An Analytical and Therapeutic Perspective,” Curr Pharm
Anal, vol. 19, no. 5, pp. 379–398, Jun. 2023, doi:
10.2174/1573412919666230505095457.
[127] M. A. Abdelmoneem et al., “Dual-targeted casein micelles as green nanomedicine for
synergistic phytotherapy of hepatocellular carcinoma,” Journal of Controlled Release,
vol. 287, pp. 78–93, Oct. 2018, doi: 10.1016/j.jconrel.2018.08.026.
[128] D. M. Kabary, M. W. Helmy, K. A. Elkhodairy, J.-Y. Fang, and A. O. Elzoghby,
“Hyaluronate/lactoferrin layer-by-layer-coated lipid nanocarriers for targeted co-
delivery of rapamycin and berberine to lung carcinoma,” Colloids Surf B
Biointerfaces, vol. 169, pp. 183–194, Sep. 2018, doi: 10.1016/j.colsurfb.2018.05.008.
[129] Y. C. Loh, C. W. Oo, W. Y. Tew, and M. F. Yam, “Herbal Medicines as Sources of an
Evidence-Based Pharmacological Research Paradigm: improving research translation,”
J Pharmacopuncture, vol. 25, no. 1, pp. 68–69, Mar. 2022, doi:
10.3831/KPI.2022.25.1.68.
[130] J. Zhou et al., “A nano-delivery system based on preventing degradation and
promoting absorption to improve the oral bioavailability of insulin,” Int J Biol
Macromol, vol. 244, p. 125263, Jul. 2023, doi: 10.1016/j.ijbiomac.2023.125263.
[131] R. Shtay, J. K. Keppler, K. Schrader, and K. Schwarz, “Encapsulation of (─)-
epigallocatechin-3-gallate (EGCG) in solid lipid nanoparticles for food applications,” J
Food Eng, vol. 244, pp. 91–100, Mar. 2019, doi: 10.1016/j.jfoodeng.2018.09.008.
[132] B. Hu, Y. Ting, X. Zeng, and Q. Huang, “Bioactive Peptides/Chitosan Nanoparticles
Enhance Cellular Antioxidant Activity of (−)-Epigallocatechin-3-gallate,” J Agric
Food Chem, vol. 61, no. 4, pp. 875–881, Jan. 2013, doi: 10.1021/jf304821k.
[133] F. Liu et al., “pH and temperature stability of (−)-epigallocatechin-3-gallate-β-
cyclodextrin inclusion complex-loaded chitosan nanoparticles,” Carbohydr Polym, vol.
149, pp. 340–347, Sep. 2016, doi: 10.1016/j.carbpol.2016.04.100.
[134] M. A. Abdelmoneem et al., “Dual-Targeted Lactoferrin Shell-Oily Core Nanocapsules
for Synergistic Targeted/Herbal Therapy of Hepatocellular Carcinoma,” ACS Appl
Mater Interfaces, vol. 11, no. 30, pp. 26731–26744, Jul. 2019, doi:
10.1021/acsami.9b10164.
[135] X. Montané et al., “Present trends in the encapsulation of anticancer drugs,” Physical
Sciences Reviews, vol. 8, no. 2, pp. 327–344, Feb. 2023, doi: 10.1515/psr-2020-0080.
[136] A. Riva, M. Ronchi, G. Petrangolini, S. Bosisio, and P. Allegrini, “Improved Oral
Absorption of Quercetin from Quercetin Phytosome®, a New Delivery System Based
on Food Grade Lecithin,” Eur J Drug Metab Pharmacokinet, vol. 44, no. 2, pp. 169–
177, Apr. 2019, doi: 10.1007/s13318-018-0517-3.
[137] S. S. Das et al., “Liquid Chromatography–Electrospray Ionization Tandem Mass
Spectrometry Estimation of Quercetin-Loaded Nanoemulsion in Rabbit Plasma: In
Vivo – In Silico Pharmacokinetic Analysis Using GastroPlus,” ACS Omega, vol. 8, no.
13, pp. 12456–12466, Apr. 2023, doi: 10.1021/acsomega.3c00429.
[138] W. W. NANDAYASA, FEBRIYENTI, and H. LUCIDA, “OPTIMIZATION AND
CHARACTERIZATION OF QUERCETIN VITAMIN C NANO-PHYTOSOME
FORMULATION,” International Journal of Applied Pharmaceutics, pp. 51–55, Feb.
2023, doi: 10.22159/ijap.2023.v15s1.47507.
[139] A. O. Elzoghby, S. A. El-Lakany, M. W. Helmy, M. M. Abu-Serie, and N. A. Elgindy,
“Shell-crosslinked zein nanocapsules for oral codelivery of exemestane and resveratrol
in breast cancer therapy,” Nanomedicine, vol. 12, no. 24, pp. 2785–2805, Dec. 2017,
doi: 10.2217/nnm-2017-0247.
[140] V. Mikušová and P. Mikuš, “Advances in Chitosan-Based Nanoparticles for Drug
Delivery.,” Int J Mol Sci, vol. 22, no. 17, Sep. 2021, doi: 10.3390/ijms22179652.
[141] M. S. Freag, W. M. Saleh, and O. Y. Abdallah, “Self-assembled phospholipid-based
phytosomal nanocarriers as promising platforms for improving oral bioavailability of
the anticancer celastrol,” Int J Pharm, vol. 535, no. 1–2, pp. 18–26, Jan. 2018, doi:
10.1016/j.ijpharm.2017.10.053.
[142] A. R. Gaikwad, K. D. Ahire, A. A. Gosavi, K. S. Salunkhe, and A. Khalkar, “Gaikwad
Abhijeet R. Phytosome as a Novel Drug Delivery System for Bioavailability
Enhancement of Phytoconstituents and its Applications: A Review,” Journal of Drug
Delivery and Therapeutics, vol. 11, no. 3, pp. 138–152, May 2021, doi:
10.22270/jddt.v11i3.4847.
[143] M. M. Abd Elwakil et al., “Inhalable lactoferrin–chondroitin nanocomposites for
combined delivery of doxorubicin and ellagic acid to lung carcinoma,” Nanomedicine,
vol. 13, no. 16, pp. 2015–2035, Aug. 2018, doi: 10.2217/nnm-2018-0039.
[144] T. Upadhyay, V. A. Ansari, U. Ahmad, N. Sultana, and J. Akhtar, “Exploring
Nanoemulsion for Liver Cancer Therapy,” Curr Cancer Ther Rev, vol. 16, no. 4, pp.
260–268, Nov. 2020, doi: 10.2174/1573394716666200302123336.
[145] A. Antignani, E. C. H. Ho, M. T. Bilotta, R. Qiu, R. Sarnvosky, and D. J. FitzGerald,
“Targeting Receptors on Cancer Cells with Protein Toxins,” Biomolecules, vol. 10, no.
9, p. 1331, Sep. 2020, doi: 10.3390/biom10091331.
[146] T. Jiang, K. Jin, X. Liu, and Z. Pang, “Nanoparticles for tumor targeting,” in
Biopolymer-Based Composites, Elsevier, 2017, pp. 221–267. doi: 10.1016/B978-0-08-
101914-6.00008-9.
[147] D. Ou, S. ‐Ja Tseng, I. M. Kempson, C. Hsu, P. Yang, and Z. Liao, “Enhanced
Targeting and Immune Activation of Tumor Microenvironment by Nanomodified
Anti‐PD1 in Liver Cancer,” Adv Ther (Weinh), vol. 4, no. 6, Jun. 2021, doi:
10.1002/adtp.202100048.
[148] K. Yuan et al., “Application and Mechanisms of Triptolide in the Treatment of
Inflammatory Diseases—A Review,” Front Pharmacol, vol. 10, Dec. 2019, doi:
10.3389/fphar.2019.01469.
[149] Y.-Q. Zhang et al., “Galactosylated chitosan triptolide nanoparticles for overcoming
hepatocellular carcinoma: Enhanced therapeutic efficacy, low toxicity, and validated
network regulatory mechanisms,” Nanomedicine, vol. 15, no. 1, pp. 86–97, Jan. 2019,
doi: 10.1016/j.nano.2018.09.002.
[150] Y. Liu et al., “Berberine diminishes cancer cell PD-L1 expression and facilitates
antitumor immunity via inhibiting the deubiquitination activity of CSN5,” Acta Pharm
Sin B, vol. 10, no. 12, pp. 2299–2312, Dec. 2020, doi: 10.1016/j.apsb.2020.06.014.
[151] K. R. Paudel et al., “Berberine-loaded liquid crystalline nanoparticles inhibit non-small
cell lung cancer proliferation and migration in vitro,” Environmental Science and
Pollution Research, vol. 29, no. 31, pp. 46830–46847, Jul. 2022, doi: 10.1007/s11356-
022-19158-2.
[152] N. Ahmad, R. Ahmad, S. Al Qatifi, M. Alessa, H. Al Hajji, and M. Sarafroz, “A
bioanalytical UHPLC based method used for the quantification of Thymoquinone-
loaded-PLGA-nanoparticles in the treatment of epilepsy,” BMC Chem, vol. 14, no. 1,
p. 10, Dec. 2020, doi: 10.1186/s13065-020-0664-x.
[153] N. Ahmad et al., “A Chitosan-PLGA based catechin hydrate nanoparticles used in
targeting of lungs and cancer treatment,” Saudi J Biol Sci, vol. 27, no. 9, pp. 2344–
2357, Sep. 2020, doi: 10.1016/j.sjbs.2020.05.023.
[154] S.-Y. Heo et al., “Anti-Cancer Effect of Chlorophyllin-Assisted Photodynamic
Therapy to Induce Apoptosis through Oxidative Stress on Human Cervical Cancer,”
Int J Mol Sci, vol. 24, no. 14, p. 11565, Jul. 2023, doi: 10.3390/ijms241411565.
[155] J. Das, A. Samadder, J. Mondal, S. K. Abraham, and A. R. Khuda-Bukhsh, “Nano-
encapsulated chlorophyllin significantly delays progression of lung cancer both in in
vitro and in vivo models through activation of mitochondrial signaling cascades and
drug-DNA interaction,” Environ Toxicol Pharmacol, vol. 46, pp. 147–157, Sep. 2016,
doi: 10.1016/j.etap.2016.07.006.
[156] H. Liao, Z. Wang, Z. Deng, H. Ren, and X. Li, “Curcumin inhibits lung cancer
invasion and metastasis by attenuating GLUT1/MT1-MMP/MMP2 pathway.,” Int J
Clin Exp Med, vol. 8, no. 6, pp. 8948–57, 2015.
[157] T. Zhang, Y. Chen, Y. Ge, Y. Hu, M. Li, and Y. Jin, “Inhalation treatment of primary
lung cancer using liposomal curcumin dry powder inhalers,” Acta Pharm Sin B, vol. 8,
no. 3, pp. 440–448, May 2018, doi: 10.1016/j.apsb.2018.03.004.
[158] L. Zhang et al., “Enhanced Chemotherapeutic Efficacy of PLGA-Encapsulated
Epigallocatechin Gallate (EGCG) Against Human Lung Cancer.,” Int J Nanomedicine,
vol. 15, pp. 4417–4429, 2020, doi: 10.2147/IJN.S243657.
[159] A. Granja, M. Pinheiro, and S. Reis, “Epigallocatechin Gallate Nanodelivery Systems
for Cancer Therapy.,” Nutrients, vol. 8, no. 5, May 2016, doi: 10.3390/nu8050307.
[160] J. Seguin et al., “Liposomal encapsulation of the natural flavonoid fisetin improves
bioavailability and antitumor efficacy,” Int J Pharm, vol. 444, no. 1–2, pp. 146–154,
Feb. 2013, doi: 10.1016/j.ijpharm.2013.01.050.
[161] R. M. Kumar et al., “Fisetin in Cancer: Attributes, Developmental Aspects, and
Nanotherapeutics,” Pharmaceuticals, vol. 16, no. 2, p. 196, Jan. 2023, doi:
10.3390/ph16020196.
[162] A. Aghebati‐Maleki et al., “Nanoparticles and cancer therapy: Perspectives for
application of nanoparticles in the treatment of cancers,” J Cell Physiol, vol. 235, no.
3, pp. 1962–1972, Mar. 2020, doi: 10.1002/jcp.29126.
[163] E. U. Stolarczyk et al., “Synthesis and characterization of genistein conjugated with
gold nanoparticles and the study of their cytotoxic properties,” European Journal of
Pharmaceutical Sciences, vol. 96, pp. 176–185, Jan. 2017, doi:
10.1016/j.ejps.2016.09.019.
[164] J. Pai, C. Hsu, Y. Hsieh, T. Tsai, K. Hua, and M. Weng, “Suppressing migration and
invasion of H1299 lung cancer cells by honokiol through disrupting expression of an
HDAC6‐mediated matrix metalloproteinase 9,” Food Sci Nutr, vol. 8, no. 3, pp. 1534–
1545, Mar. 2020, doi: 10.1002/fsn3.1439.
[165] L. Chen et al., “Honokiol Prodrug Nanoparticles Based on In Situ Albumin Binding
for Long Circulation and High Tumor Uptake,” ACS Med Chem Lett, vol. 12, no. 10,
pp. 1589–1595, Oct. 2021, doi: 10.1021/acsmedchemlett.1c00429.
[166] Y. Taheri et al., “Myricetin bioactive effects: moving from preclinical evidence to
potential clinical applications.,” BMC Complement Med Ther, vol. 20, no. 1, p. 241,
Aug. 2020, doi: 10.1186/s12906-020-03033-z.
[167] Y. Song et al., “Folic acid (FA)-conjugated mesoporous silica nanoparticles combined
with MRP-1 siRNA improves the suppressive effects of myricetin on non-small cell
lung cancer (NSCLC),” Biomedicine & Pharmacotherapy, vol. 125, p. 109561, May
2020, doi: 10.1016/j.biopha.2019.109561.
[168] S. Md et al., “Formulation Design, Statistical Optimization, and In Vitro Evaluation of
a Naringenin Nanoemulsion to Enhance Apoptotic Activity in A549 Lung Cancer
Cells,” Pharmaceuticals, vol. 13, no. 7, p. 152, Jul. 2020, doi: 10.3390/ph13070152.
[169] B. Salehi et al., “The Therapeutic Potential of Naringenin: A Review of Clinical
Trials,” Pharmaceuticals, vol. 12, no. 1, p. 11, Jan. 2019, doi: 10.3390/ph12010011.
[170] W. H. Talib and L. T. Al Kury, “Parthenolide inhibits tumor-promoting effects of
nicotine in lung cancer by inducing P53 - dependent apoptosis and inhibiting VEGF
expression,” Biomedicine & Pharmacotherapy, vol. 107, pp. 1488–1495, Nov. 2018,
doi: 10.1016/j.biopha.2018.08.139.
[171] K. K. Gill, A. Kaddoumi, and S. Nazzal, “Mixed micelles of PEG2000-DSPE and
vitamin-E TPGS for concurrent delivery of paclitaxel and parthenolide: Enhanced
chemosenstization and antitumor efficacy against non-small cell lung cancer (NSCLC)
cell lines,” European Journal of Pharmaceutical Sciences, vol. 46, no. 1–2, pp. 64–71,
May 2012, doi: 10.1016/j.ejps.2012.02.010.
[172] W.-C. Huang, M.-L. Chan, M.-J. Chen, T.-H. Tsai, and Y.-J. Chen, “Modulation of
macrophage polarization and lung cancer cell stemness by MUC1 and development of
a related small-molecule inhibitor pterostilbene,” Oncotarget, vol. 7, no. 26, pp.
39363–39375, Jun. 2016, doi: 10.18632/oncotarget.8101.
[173] N. A. N. Hanafy, R. H. Abdelbadea, A. E. Abdelaziz, and E. A. Mazyed, “Formulation
and optimization of folate-bovine serum albumin-coated ethoniosomes of pterostilbene
as a targeted drug delivery system for lung cancer: In vitro and in vivo
demonstrations,” Cancer Nanotechnol, vol. 14, no. 1, p. 49, Dec. 2023, doi:
10.1186/s12645-023-00197-4.
[174] A. Anand David, R. Arulmoli, and S. Parasuraman, “Overviews of biological
importance of quercetin: A bioactive flavonoid,” Pharmacogn Rev, vol. 10, no. 20, p.
84, 2016, doi: 10.4103/0973-7847.194044.
[175] X. Zhou, H.-Y. Liu, H. Zhao, and T. Wang, “RGD-modified nanoliposomes containing
quercetin for lung cancer targeted treatment,” Onco Targets Ther, vol. Volume 11, pp.
5397–5405, Sep. 2018, doi: 10.2147/OTT.S169555.
[176] Y. Zhao et al., “Resveratrol ameliorates Lewis lung carcinoma‐bearing mice
development, decreases granulocytic myeloid‐derived suppressor cell accumulation
and impairs its suppressive ability,” Cancer Sci, vol. 109, no. 9, pp. 2677–2686, Sep.
2018, doi: 10.1111/cas.13720.
[177] M. Annaji, I. Poudel, S. H. S. Boddu, R. D. Arnold, A. K. Tiwari, and R. J. Babu,
“Resveratrol‐loaded nanomedicines for cancer applications,” Cancer Rep, vol. 4, no. 3,
Jun. 2021, doi: 10.1002/cnr2.1353.
[178] T. Wu, W. Liu, W. Guo, and X. Zhu, “Silymarin suppressed lung cancer growth in
mice via inhibiting myeloid-derived suppressor cells,” Biomedicine &
Pharmacotherapy, vol. 81, pp. 460–467, Jul. 2016, doi: 10.1016/j.biopha.2016.04.039.
[179] Y. Wang, A.-J. Yuan, Y.-J. Wu, L.-M. Wu, and L. Zhang, “Silymarin in cancer
therapy: Mechanisms of action, protective roles in chemotherapy-induced toxicity, and
nanoformulations,” J Funct Foods, vol. 100, p. 105384, Jan. 2023, doi:
10.1016/j.jff.2022.105384.
[180] J. Xie et al., “The antitumor effect of tanshinone IIA on anti-proliferation and
decreasing VEGF/VEGFR2 expression on the human non-small cell lung cancer A549
cell line,” Acta Pharm Sin B, vol. 5, no. 6, pp. 554–563, Nov. 2015, doi:
10.1016/j.apsb.2015.07.008.
[181] R. M. El-Moslemany, A. H. El-Kamel, E. A. Allam, H. M. Khalifa, A. Hussein, and A.
A. Ashour, “Tanshinone IIA loaded bioactive nanoemulsion for alleviation of
lipopolysaccharide induced acute lung injury via inhibition of endothelial glycocalyx
shedding,” Biomedicine & Pharmacotherapy, vol. 155, p. 113666, Nov. 2022, doi:
10.1016/j.biopha.2022.113666.
[182] H. Xu et al., “An efficient Trojan delivery of tetrandrine by poly(N-vinylpyrrolidone)-
block-poly(ε-caprolactone) (PVP-b-PCL) nanoparticles shows enhanced apoptotic
induction of lung cancer cells and inhibition of its migration and invasion.,” Int J
Nanomedicine, vol. 9, pp. 231–42, 2014, doi: 10.2147/IJN.S55541.
[183] B. N. and C. K.R., “Tetrandrine and cancer – An overview on the molecular
approach,” Biomedicine & Pharmacotherapy, vol. 97, pp. 624–632, Jan. 2018, doi:
10.1016/j.biopha.2017.10.116.
[184] M. Sazuka, H. Imazawa, Y. Shoji, T. Mita, Y. Hara, and M. Isemura, “Inhibition of
Collagenases from Mouse Lung Carcinoma Cells by Green Tea Catechins and Black
Tea Theaflavins,” Biosci Biotechnol Biochem, vol. 61, no. 9, pp. 1504–1506, Jan.
1997, doi: 10.1271/bbb.61.1504.
[185] R. Maity et al., “Gold nanoparticle-assisted enhancement in the anti-cancer properties
of theaflavin against human ovarian cancer cells,” Materials Science and Engineering:
C, vol. 104, p. 109909, Nov. 2019, doi: 10.1016/j.msec.2019.109909.
[186] N. Kumar, R. K. Salar, M. Prasad, and K. Ranjan, “Synthesis, characterization and
anticancer activity of vincristine loaded folic acid-chitosan conjugated nanoparticles
on NCI-H460 non-small cell lung cancer cell line,” Egyptian Journal of Basic and
Applied Sciences, vol. 5, no. 1, pp. 87–99, Mar. 2018, doi:
10.1016/j.ejbas.2017.11.002.
[187] R. Shukla, A. Singh, and K. K. Singh, “Vincristine-based nanoformulations: a
preclinical and clinical studies overview,” Drug Deliv Transl Res, Aug. 2023, doi:
10.1007/s13346-023-01389-6.
[188] X. S. Wu and N. Wang, “Synthesis, characterization, biodegradation, and drug
delivery application of biodegradable lactic/glycolic acid polymers. Part II:
biodegradation.,” J Biomater Sci Polym Ed, vol. 12, no. 1, pp. 21–34, 2001, doi:
10.1163/156856201744425.
[189] E. A. Sykes et al., “Tailoring nanoparticle designs to target cancer based on tumor
pathophysiology.,” Proc Natl Acad Sci U S A, vol. 113, no. 9, pp. E1142-51, Mar.
2016, doi: 10.1073/pnas.1521265113.
[190] U. K. Sukumar, B. Bhushan, P. Dubey, I. Matai, A. Sachdev, and G. Packirisamy,
“Emerging applications of nanoparticles for lung cancer diagnosis and therapy,” Int
Nano Lett, vol. 3, no. 1, p. 45, Dec. 2013, doi: 10.1186/2228-5326-3-45.
[191] W. Mehnert, “Solid lipid nanoparticles Production, characterization and applications,”
Adv Drug Deliv Rev, vol. 47, no. 2–3, pp. 165–196, Apr. 2001, doi: 10.1016/S0169-
409X(01)00105-3.
[192] D. T. Baviskar, A. S. Amritkar, H. S. Chaudhari, and D. K. Jain, “Modulation of drug
release from nanocarriers loaded with a poorly water soluble drug (flurbiprofen)
comprising natural waxes.,” Pharmazie, vol. 67, no. 8, pp. 701–5, Aug. 2012.
[193] R. Müller, “Solid lipid nanoparticles (SLN) for controlled drug delivery
â&#128;&#147; a review of the state of the art,” European Journal of Pharmaceutics
and Biopharmaceutics, vol. 50, no. 1, pp. 161–177, Jul. 2000, doi: 10.1016/S0939-
6411(00)00087-4.
[194] P. Barthelemy, J. P. Laforêt, N. Farah, and J. Joachim, “Compritol® 888 ATO: an
innovative hot-melt coating agent for prolonged-release drug formulations,” European
Journal of Pharmaceutics and Biopharmaceutics, vol. 47, no. 1, pp. 87–90, Jan. 1999,
doi: 10.1016/S0939-6411(98)00088-5.
[195] S. S. M. et al., “A spotlight on alkaloid nanoformulations for the treatment of lung
cancer,” Front Oncol, vol. 12, Oct. 2022, doi: 10.3389/fonc.2022.994155.
[196] P. Ma et al., “Development of Idarubicin and Doxorubicin Solid Lipid Nanoparticles
to Overcome Pgp-Mediated Multiple Drug Resistance in Leukemia,” J Biomed
Nanotechnol, vol. 5, no. 2, pp. 151–161, Apr. 2009, doi: 10.1166/jbn.2009.1021.
[197] Y. Zou et al., “Effective Treatment of Early Endobronchial Cancer With Regional
Administration of Liposome-p53 Complexes,” JNCI Journal of the National Cancer
Institute, vol. 90, no. 15, pp. 1130–1137, Aug. 1998, doi: 10.1093/jnci/90.15.1130.
[198] M. Nassimi et al., “Low cytotoxicity of solid lipid nanoparticles in in vitro and ex vivo
lung models,” Inhal Toxicol, vol. 21, no. sup1, pp. 104–109, Jul. 2009, doi:
10.1080/08958370903005769.
[199] J. Madan, K. Dua, and P. Khude, “Development and evaluation of solid lipid
nanoparticles of mometasone furoate for topical delivery,” Int J Pharm Investig, vol. 4,
no. 2, p. 60, 2014, doi: 10.4103/2230-973X.133047.
[200] C. Chen et al., “Orally delivered salmon calcitonin-loaded solid lipid nanoparticles
prepared by micelle–double emulsion method via the combined use of different solid
lipids,” Nanomedicine, vol. 8, no. 7, pp. 1085–1100, Jul. 2013, doi:
10.2217/nnm.12.141.
[201] S. Cai, Q. Yang, T. R. Bagby, and M. L. Forrest, “Lymphatic drug delivery using
engineered liposomes and solid lipid nanoparticles,” Adv Drug Deliv Rev, vol. 63, no.
10–11, pp. 901–908, Sep. 2011, doi: 10.1016/j.addr.2011.05.017.
[202] G. Calixto, J. Bernegossi, L. de Freitas, C. Fontana, and M. Chorilli,
“Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer:
A Review,” Molecules, vol. 21, no. 3, p. 342, Mar. 2016, doi:
10.3390/molecules21030342.
[203] S. CHOI, “Novel cationic solid lipid nanoparticles enhanced p53 gene transfer to lung
cancer cells,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 68, no.
3, pp. 545–554, Mar. 2008, doi: 10.1016/j.ejpb.2007.07.011.
[204] Y. Yao et al., “Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in
Overcoming Drug Resistance,” Front Mol Biosci, vol. 7, Aug. 2020, doi:
10.3389/fmolb.2020.00193.
[205] L. Wang et al., “Enhancing the Antitumor Activity of Berberine Hydrochloride by
Solid Lipid Nanoparticle Encapsulation,” AAPS PharmSciTech, vol. 15, no. 4, pp.
834–844, Aug. 2014, doi: 10.1208/s12249-014-0112-0.
[206] S. J. Jow and L. C. Cha, “[Study on the physical and chemical properties of berberine
as related to the biological effects. I. Acid dissociation constant].,” Yao Xue Xue Bao,
vol. 12, no. 9, pp. 571–6, Sep. 1965.
[207] K. Fukuda, Y. Hibiya, M. Mutoh, M. Koshiji, S. Akao, and H. Fujiwara, “Inhibition by
berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells,” J
Ethnopharmacol, vol. 66, no. 2, pp. 227–233, Aug. 1999, doi: 10.1016/S0378-
8741(98)00162-7.
[208] Y.-J. Oh et al., “Aripiprazole Montmorillonite: A New Organic-Inorganic
Nanohybrid Material for Biomedical Applications,” Chemistry - A European Journal,
vol. 19, no. 15, pp. 4869–4875, Apr. 2013, doi: 10.1002/chem.201203384.
[209] D. S. Rawat, B. K. Thakur, M. Semalty, A. Semalty, P. Badoni, and M. S. M. Rawat,
“Baicalein-Phospholipid Complex: A Novel Drug Delivery Technology for
Phytotherapeutics,” Curr Drug Discov Technol, vol. 10, no. 3, pp. 224–232, May
2013, doi: 10.2174/1570163811310030005.
[210] W. K. Murphy et al., “Phase II Study of Taxol in Patients With Untreated Advanced
Non-Small-Cell Lung Cancer,” JNCI Journal of the National Cancer Institute, vol. 85,
no. 5, pp. 384–388, Mar. 1993, doi: 10.1093/jnci/85.5.384.
[211] S. J. Antonia et al., “Concurrent paclitaxel/cisplatin with thoracic radiation in patients
with stage IIIA/B non-small cell carcinoma of the lung.,” Semin Oncol, vol. 22, no. 4
Suppl 9, pp. 34–7, Aug. 1995.
[212] J. Crown, M. O’Leary, and W.-S. Ooi, “Docetaxel and Paclitaxel in the Treatment of
Breast Cancer: A Review of Clinical Experience,” Oncologist, vol. 9, no. S2, pp. 24–
32, Jun. 2004, doi: 10.1634/theoncologist.9-suppl_2-24.
[213] Y. Yang et al., “PLGA Porous Microspheres Dry Powders for Codelivery of
Afatinib‐Loaded Solid Lipid Nanoparticles and Paclitaxel: Novel Therapy for EGFR
Tyrosine Kinase Inhibitors Resistant Nonsmall Cell Lung Cancer,” Adv Healthc
Mater, vol. 8, no. 23, Dec. 2019, doi: 10.1002/adhm.201900965.
[214] C.-M. J. Hu et al., “Half-Antibody Functionalized Lipid−Polymer Hybrid
Nanoparticles for Targeted Drug Delivery to Carcinoembryonic Antigen Presenting
Pancreatic Cancer Cells,” Mol Pharm, vol. 7, no. 3, pp. 914–920, Jun. 2010, doi:
10.1021/mp900316a.
[215] K. Raza, B. Singh, A. Mahajan, P. Negi, A. Bhatia, and O. P. Katare, “Design and
evaluation of flexible membrane vesicles (FMVs) for enhanced topical delivery of
capsaicin,” J Drug Target, vol. 19, no. 4, pp. 293–302, May 2011, doi:
10.3109/1061186X.2010.499464.
[216] N. Aggarwal and S. Goindi, “Preparation and &lt;I&gt;In&lt;/I&gt;
&lt;I&gt;Vivo&lt;/I&gt; Evaluation of Solid Lipid Nanoparticles of Griseofulvin for
Dermal Use,” J Biomed Nanotechnol, vol. 9, no. 4, pp. 564–576, Apr. 2013, doi:
10.1166/jbn.2013.1569.
[217] S. D. Mandawgade and V. B. Patravale, “Development of SLNs from natural lipids:
Application to topical delivery of tretinoin,” Int J Pharm, vol. 363, no. 1–2, pp. 132–
138, Nov. 2008, doi: 10.1016/j.ijpharm.2008.06.028.
[218] S. Goindi, A. Guleria, and N. Aggarwal, “Development and Evaluation of Solid Lipid
Nanoparticles of N-6-Furfuryl Adenine for Prevention of Photoaging,” J Biomed
Nanotechnol, vol. 11, no. 10, pp. 1734–1746, Oct. 2015, doi: 10.1166/jbn.2015.2111.
[219] A. G. Muller, S. D. Sarker, I. Y. Saleem, and G. A. Hutcheon, “Delivery of natural
phenolic compounds for the potential treatment of lung cancer,” DARU Journal of
Pharmaceutical Sciences, vol. 27, no. 1, pp. 433–449, Jun. 2019, doi: 10.1007/s40199-
019-00267-2.
[220] C. Vasile, D. Pamfil, E. Stoleru, and M. Baican, “New Developments in Medical
Applications of Hybrid Hydrogels Containing Natural Polymers,” Molecules, vol. 25,
no. 7, p. 1539, Mar. 2020, doi: 10.3390/molecules25071539.
[221] A. Ulldemolins et al., “Perspectives of nano-carrier drug delivery systems to overcome
cancer drug resistance in the clinics,” Cancer Drug Resistance, 2021, doi:
10.20517/cdr.2020.59.
[222] T. T. Duong et al., “Nanoformulation and Evaluation of Oral Berberine-Loaded
Liposomes,” Molecules, vol. 26, no. 9, p. 2591, Apr. 2021, doi:
10.3390/molecules26092591.
[223] M. A. Macchione, D. Aristizabal Bedoya, F. N. Figueroa, M. Á. Muñoz-Fernández,
and M. C. Strumia, “Nanosystems Applied to HIV Infection: Prevention and
Treatments,” Int J Mol Sci, vol. 21, no. 22, p. 8647, Nov. 2020, doi:
10.3390/ijms21228647.
[224] O. Vittorio et al., “Polyphenols delivery by polymeric materials: challenges in cancer
treatment,” Drug Deliv, vol. 24, no. 1, pp. 162–180, Jan. 2017, doi:
10.1080/10717544.2016.1236846.
[225] C. Loira-Pastoriza, J. Todoroff, and R. Vanbever, “Delivery strategies for sustained
drug release in the lungs,” Adv Drug Deliv Rev, vol. 75, pp. 81–91, Aug. 2014, doi:
10.1016/j.addr.2014.05.017.
[226] A. Kumari, S. K. Yadav, and S. C. Yadav, “Biodegradable polymeric nanoparticles
based drug delivery systems,” Colloids Surf B Biointerfaces, vol. 75, no. 1, pp. 1–18,
Jan. 2010, doi: 10.1016/j.colsurfb.2009.09.001.
[227] I. A. Siddiqui et al., “Introducing Nanochemoprevention as a Novel Approach for
Cancer Control: Proof of Principle with Green Tea Polyphenol Epigallocatechin-3-
Gallate,” Cancer Res, vol. 69, no. 5, pp. 1712–1716, Mar. 2009, doi: 10.1158/0008-
5472.CAN-08-3978.
[228] L. Sanchez, Y. Yi, and Y. Yu, “Effect of partial PEGylation on particle uptake by
macrophages,” Nanoscale, vol. 9, no. 1, pp. 288–297, 2017, doi:
10.1039/C6NR07353K.
[229] R. Cheung, T. Ng, J. Wong, and W. Chan, “Chitosan: An Update on Potential
Biomedical and Pharmaceutical Applications,” Mar Drugs, vol. 13, no. 8, pp. 5156–
5186, Aug. 2015, doi: 10.3390/md13085156.
[230] S. Nitta and K. Numata, “Biopolymer-Based Nanoparticles for Drug/Gene Delivery
and Tissue Engineering,” Int J Mol Sci, vol. 14, no. 1, pp. 1629–1654, Jan. 2013, doi:
10.3390/ijms14011629.
[231] S. Gelperina, K. Kisich, M. D. Iseman, and L. Heifets, “The Potential Advantages of
Nanoparticle Drug Delivery Systems in Chemotherapy of Tuberculosis,” Am J Respir
Crit Care Med, vol. 172, no. 12, pp. 1487–1490, Dec. 2005, doi:
10.1164/rccm.200504-613PP.
[232] C. S. Yah, G. S. Simate, and S. E. Iyuke, “Nanoparticles toxicity and their routes of [244] S. Karthikeyan, N. Rajendra Prasad, A. Ganamani, and E. Balamurugan, “Anticancer
exposures.,” Pak J Pharm Sci, vol. 25, no. 2, pp. 477–91, Apr. 2012. activity of resveratrol-loaded gelatin nanoparticles on NCI-H460 non-small cell lung
cancer cells,” Biomedicine & Preventive Nutrition, vol. 3, no. 1, pp. 64–73, Jan. 2013,
[233] A. Kumar et al., “Innovative pharmaceutical development based on unique properties
doi: 10.1016/j.bionut.2012.10.009.
of nanoscale delivery formulation,” Nanoscale, vol. 5, no. 18, p. 8307, 2013, doi:
10.1039/c3nr01525d. [245] M. Singh, P. Bhatnagar, S. Mishra, P. Kumar, Y. Shukla, and K. C. Gupta, “PLGA-
encapsulated tea polyphenols enhance the&amp;nbsp;chemotherapeutic efficacy of
[234] S. R. Jhawar et al., “Oncolytic Viruses—Natural and Genetically Engineered Cancer
cisplatin against human cancer cells and mice bearing Ehrlich ascites carcinoma,” Int J
Immunotherapies,” Front Oncol, vol. 7, Sep. 2017, doi: 10.3389/fonc.2017.00202.
Nanomedicine, p. 6789, Oct. 2015, doi: 10.2147/IJN.S79489.
[235] O. Barash, N. Peled, U. Tisch, P. A. Bunn, F. R. Hirsch, and H. Haick, “Classification
[246] J. Duan et al., “Reversion of multidrug resistance by co-encapsulation of doxorubicin
of lung cancer histology by gold nanoparticle sensors,” Nanomedicine, vol. 8, no. 5,
and curcumin in chitosan/poly(butyl cyanoacrylate) nanoparticles,” Int J Pharm, vol.
pp. 580–589, Jul. 2012, doi: 10.1016/j.nano.2011.10.001.
426, no. 1–2, pp. 193–201, Apr. 2012, doi: 10.1016/j.ijpharm.2012.01.020.
[236] S. Karthikeyan, S. L. Hoti, and N. R. Prasad, “Resveratrol loaded gelatin nanoparticles
[247] Y. Sadzuka, M. Nagamine, T. Toyooka, Y. Ibuki, and T. Sonobe, “Beneficial effects
synergistically inhibits cell cycle progression and constitutive NF-kappaB activation,
of curcumin on antitumor activity and adverse reactions of doxorubicin,” Int J Pharm,
and induces apoptosis in non-small cell lung cancer cells,” Biomedicine &
vol. 432, no. 1–2, pp. 42–49, Aug. 2012, doi: 10.1016/j.ijpharm.2012.04.062.
Pharmacotherapy, vol. 70, pp. 274–282, Mar. 2015, doi:
10.1016/j.biopha.2015.02.006. [248] E. Sánchez‐López et al., “Memantine‐Loaded PEGylated Biodegradable Nanoparticles
for the Treatment of Glaucoma,” Small, vol. 14, no. 2, Jan. 2018, doi:
[237] C.-M. J. Hu, S. Aryal, and L. Zhang, “Nanoparticle-assisted combination therapies for
10.1002/smll.201701808.
effective cancer treatment,” Ther Deliv, vol. 1, no. 2, pp. 323–334, Aug. 2010, doi:
10.4155/tde.10.13. [249] E. Sánchez-López et al., “PEGylated PLGA nanospheres optimized by design of
experiments for ocular administration of dexibuprofen—in vitro, ex vivo and in vivo
[238] D. K. Jensen et al., “Design of an inhalable dry powder formulation of DOTAP-
characterization,” Colloids Surf B Biointerfaces, vol. 145, pp. 241–250, Sep. 2016, doi:
modified PLGA nanoparticles loaded with siRNA,” Journal of Controlled Release,
10.1016/j.colsurfb.2016.04.054.
vol. 157, no. 1, pp. 141–148, Jan. 2012, doi: 10.1016/j.jconrel.2011.08.011.
[250] C. Cañadas et al., “In vitro , ex vivo and in vivo characterization of PLGA
[239] K. Tahara, T. Sakai, H. Yamamoto, H. Takeuchi, N. Hirashima, and Y. Kawashima,
nanoparticles loading pranoprofen for ocular administration,” Int J Pharm, vol. 511,
“Improved cellular uptake of chitosan-modified PLGA nanospheres by A549 cells,”
no. 2, pp. 719–727, Sep. 2016, doi: 10.1016/j.ijpharm.2016.07.055.
Int J Pharm, vol. 382, no. 1–2, pp. 198–204, Dec. 2009, doi:
10.1016/j.ijpharm.2009.07.023. [251] J. Araújo, E. Vega, C. Lopes, M. A. Egea, M. L. Garcia, and E. B. Souto, “Effect of
polymer viscosity on physicochemical properties and ocular tolerance of FB-loaded
[240] N. M. Khalil et al., “Pharmacokinetics of curcumin-loaded PLGA and PLGA–PEG
PLGA nanospheres,” Colloids Surf B Biointerfaces, vol. 72, no. 1, pp. 48–56, Aug.
blend nanoparticles after oral administration in rats,” Colloids Surf B Biointerfaces,
2009, doi: 10.1016/j.colsurfb.2009.03.028.
vol. 101, pp. 353–360, Jan. 2013, doi: 10.1016/j.colsurfb.2012.06.024.
[252] Y. Wang, P. Li, T. Truong-Dinh Tran, J. Zhang, and L. Kong, “Manufacturing
[241] B. Teong et al., “Enhanced anti-cancer activity by curcumin-loaded hydrogel
Techniques and Surface Engineering of Polymer Based Nanoparticles for Targeted
nanoparticle derived aggregates on A549 lung adenocarcinoma cells,” J Mater Sci
Drug Delivery to Cancer,” Nanomaterials, vol. 6, no. 2, p. 26, Feb. 2016, doi:
Mater Med, vol. 26, no. 1, p. 49, Jan. 2015, doi: 10.1007/s10856-014-5357-3.
10.3390/nano6020026.
[242] Y.-M. Tsai, C.-F. Chien, L.-C. Lin, and T.-H. Tsai, “Curcumin and its nano-
[253] E. B. Souto et al., “Nanoparticle Delivery Systems in the Treatment of Diabetes
formulation: The kinetics of tissue distribution and blood–brain barrier penetration,”
Complications,” Molecules, vol. 24, no. 23, p. 4209, Nov. 2019, doi:
Int J Pharm, vol. 416, no. 1, pp. 331–338, Sep. 2011, doi:
10.3390/molecules24234209.
10.1016/j.ijpharm.2011.06.030.
[254] Vieira et al., “Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic
[243] S. P. Kumar, K. Birundha, K. Kaveri, and K. T. R. Devi, “Antioxidant studies of
Syndrome—Review of Classical and New Compounds: Part-I,” Pharmaceuticals, vol.
chitosan nanoparticles containing naringenin and their cytotoxicity effects in lung
12, no. 4, p. 152, Oct. 2019, doi: 10.3390/ph12040152.
cancer cells,” Int J Biol Macromol, vol. 78, pp. 87–95, Jul. 2015, doi:
10.1016/j.ijbiomac.2015.03.045. [255] E. Sánchez-López et al., “Memantine loaded PLGA PEGylated nanoparticles for
Alzheimer’s disease: in vitro and in vivo characterization,” J Nanobiotechnology, vol.
16, no. 1, p. 32, Dec. 2018, doi: 10.1186/s12951-018-0356-z.
[256] K. Madaan, S. Kumar, N. Poonia, V. Lather, and D. Pandita, “Dendrimers in drug
delivery and targeting: Drug-dendrimer interactions and toxicity issues,” J Pharm
Bioallied Sci, vol. 6, no. 3, p. 139, 2014, doi: 10.4103/0975-7406.130965.
[257] Z. Lyu, L. Ding, A. Y.-T. Huang, C.-L. Kao, and L. Peng, “Poly(amidoamine)
dendrimers: covalent and supramolecular synthesis,” Mater Today Chem, vol. 13, pp.
34–48, Sep. 2019, doi: 10.1016/j.mtchem.2019.04.004.
[258] I. Sohail et al., “Polyamidoamine (PAMAM) dendrimers synthesis, characterization
and adsorptive removal of nickel ions from aqueous solution,” Journal of Materials
Research and Technology, vol. 9, no. 1, pp. 498–506, Jan. 2020, doi:
10.1016/j.jmrt.2019.10.079.
[259] T. E. Parry, “Folate responsive neuropathy.,” Presse Med, vol. 23, no. 3, pp. 131–7,
Jan. 1994.
[260] N. Chaniotakis, K. Thermos, and M. Kalomiraki, “Dendrimers as tunable vectors of
drug delivery systems and biomedical and ocular applications,” Int J Nanomedicine, p.
1, Dec. 2015, doi: 10.2147/IJN.S93069.
[261] S. Mignani and J.-P. Majoral, “Dendrimers as macromolecular tools to tackle from
colon to brain tumor types: a concise overview,” New Journal of Chemistry, vol. 37,
no. 11, p. 3337, 2013, doi: 10.1039/c3nj00300k.
[262] A. P. Sherje, M. Jadhav, B. R. Dravyakar, and D. Kadam, “Dendrimers: A versatile
nanocarrier for drug delivery and targeting,” Int J Pharm, vol. 548, no. 1, pp. 707–720,
Sep. 2018, doi: 10.1016/j.ijpharm.2018.07.030.
[263] R. I. CASTRO, O. FORERO-DORIA, and L. GUZMÁN, “Perspectives of Dendrimer-
based Nanoparticles in Cancer Therapy,” An Acad Bras Cienc, vol. 90, no. 2 suppl 1,
pp. 2331–2346, Aug. 2018, doi: 10.1590/0001-3765201820170387.
[264] A. A. Kale and V. P. Torchilin, “Design, Synthesis, and Characterization of pH-
Sensitive PEG−PE Conjugates for Stimuli-Sensitive Pharmaceutical Nanocarriers:
The Effect of Substitutes at the Hydrazone Linkage on the pH Stability of PEG−PE
Conjugates,” Bioconjug Chem, vol. 18, no. 2, pp. 363–370, Mar. 2007, doi:
10.1021/bc060228x.
[265] Q. Zhong and S. R. P. da Rocha, “Poly(amidoamine) Dendrimer–Doxorubicin
Conjugates: In Vitro Characteristics and Pseudosolution Formulation in Pressurized
Metered-Dose Inhalers,” Mol Pharm, vol. 13, no. 3, pp. 1058–1072, Mar. 2016, doi:
10.1021/acs.molpharmaceut.5b00876.
[266] M. Markowicz, P. Szymański, M. Ciszewski, A. Kłys, and E. Mikiciuk-Olasik,
“Evaluation of poly(amidoamine) dendrimers as potential carriers of iminodiacetic
derivatives using solubility studies and 2D-NOESY NMR spectroscopy,” J Biol Phys,
vol. 38, no. 4, pp. 637–656, Sep. 2012, doi: 10.1007/s10867-012-9277-5.
[267] A. A. Chis et al., “Applications and Limitations of Dendrimers in Biomedicine,”
Molecules, vol. 25, no. 17, p. 3982, Sep. 2020, doi: 10.3390/molecules25173982.
[268] P. R. Dvornic and D. A. Tomalia, “Recent advances in dendritic polymers,” Curr Opin
Colloid Interface Sci, vol. 1, no. 2, pp. 221–235, Apr. 1996, doi: 10.1016/S1359-
0294(96)80008-2.
[269] M. Murakami et al., “Improving Drug Potency and Efficacy by Nanocarrier-Mediated
Subcellular Targeting,” Sci Transl Med, vol. 3, no. 64, Jan. 2011, doi:
10.1126/scitranslmed.3001385.
[270] D.-W. Kim et al., “Multicenter phase II trial of Genexol-PM, a novel Cremophor-free,
polymeric micelle formulation of paclitaxel, with cisplatin in patients with advanced
non-small-cell lung cancer,” Annals of Oncology, vol. 18, no. 12, pp. 2009–2014, Dec.
2007, doi: 10.1093/annonc/mdm374.
[271] L.-P. Li, “Cisplatin‐Loaded Polymeric Micelles with Aggregation‐Induced Emission
Feature for Cellular Imaging and Chemotherapy,” ChemistrySelect, vol. 3, no. 48, pp.
13682–13691, Dec. 2018, doi: 10.1002/slct.201802542.
[272] L. Zhang et al., “Improving Drug Delivery of Micellar Paclitaxel against Non‐Small
Cell Lung Cancer by Coloading Itraconazole as a Micelle Stabilizer and a Tumor
Vascular Manipulator,” Small, vol. 14, no. 51, Dec. 2018, doi:
10.1002/smll.201802112.
[273] D. Mei et al., “α-Conotoxin ImI-modified polymeric micelles as potential nanocarriers
for targeted docetaxel delivery to α7-nAChR overexpressed non-small cell lung
cancer,” Drug Deliv, vol. 25, no. 1, pp. 493–503, Jan. 2018, doi:
10.1080/10717544.2018.1436097.
[274] P. L. Reshma et al., “Overcoming drug-resistance in lung cancer cells by paclitaxel
loaded galactoxyloglucan nanoparticles,” Int J Biol Macromol, vol. 136, pp. 266–274,
Sep. 2019, doi: 10.1016/j.ijbiomac.2019.06.075.
[275] G. M. Mekhail, A. O. Kamel, G. A. S. Awad, and N. D. Mortada, “Anticancer effect of
atorvastatin nanostructured polymeric micelles based on stearyl-grafted chitosan,” Int J
Biol Macromol, vol. 51, no. 4, pp. 351–363, Nov. 2012, doi:
10.1016/j.ijbiomac.2012.05.026.
[276] T. Zhang, Y. Chen, Y. Ge, Y. Hu, M. Li, and Y. Jin, “Inhalation treatment of primary
lung cancer using liposomal curcumin dry powder inhalers,” Acta Pharm Sin B, vol. 8,
no. 3, pp. 440–448, May 2018, doi: 10.1016/j.apsb.2018.03.004.
[277] J. C. Sung, B. L. Pulliam, and D. A. Edwards, “Nanoparticles for drug delivery to the
lungs,” Trends Biotechnol, vol. 25, no. 12, pp. 563–570, Dec. 2007, doi:
10.1016/j.tibtech.2007.09.005.
[278] A. Mahmud and D. E. Discher, “Lung vascular targeting through inhalation delivery:
Insight from filamentous viruses and other shapes,” IUBMB Life, vol. 63, no. 8, pp.
607–612, Aug. 2011, doi: 10.1002/iub.481.
[279] A. J. Thorley and T. D. Tetley, “New perspectives in nanomedicine,” Pharmacol Ther,
vol. 140, no. 2, pp. 176–185, Nov. 2013, doi: 10.1016/j.pharmthera.2013.06.008.
[280] C. Alexiou et al., “Locoregional cancer treatment with magnetic drug targeting.,”
Cancer Res, vol. 60, no. 23, pp. 6641–8, Dec. 2000.
[281] G. Pilcer and K. Amighi, “Formulation strategy and use of excipients in pulmonary
drug delivery,” Int J Pharm, vol. 392, no. 1–2, pp. 1–19, Jun. 2010, doi:
10.1016/j.ijpharm.2010.03.017.
[282] I. M. El-Sherbiny and H. D. C. Smyth, “Controlled Release Pulmonary Administration
of Curcumin Using Swellable Biocompatible Microparticles,” Mol Pharm, vol. 9, no.
2, pp. 269–280, Feb. 2012, doi: 10.1021/mp200351y.
[283] F. Ungaro et al., “Dry powders based on PLGA nanoparticles for pulmonary delivery
of antibiotics: Modulation of encapsulation efficiency, release rate and lung deposition
pattern by hydrophilic polymers,” Journal of Controlled Release, vol. 157, no. 1, pp.
149–159, Jan. 2012, doi: 10.1016/j.jconrel.2011.08.010.
[284] J. S. Patton and P. R. Byron, “Inhaling medicines: delivering drugs to the body through
the lungs,” Nat Rev Drug Discov, vol. 6, no. 1, pp. 67–74, Jan. 2007, doi:
10.1038/nrd2153.
[285] T. C. Rodrigues et al., “Mucosal immunization with PspA (Pneumococcal surface
protein A)-adsorbed nanoparticles targeting the lungs for protection against
pneumococcal infection,” PLoS One, vol. 13, no. 1, p. e0191692, Jan. 2018, doi:
10.1371/journal.pone.0191692.
[286] J. U. Menon, P. Ravikumar, A. Pise, D. Gyawali, C. C. W. Hsia, and K. T. Nguyen,
“Polymeric nanoparticles for pulmonary protein and DNA delivery,” Acta Biomater,
vol. 10, no. 6, pp. 2643–2652, Jun. 2014, doi: 10.1016/j.actbio.2014.01.033.
[287] R. Gaul, J. M. Ramsey, A. Heise, S.-A. Cryan, and C. M. Greene, “Nanotechnology
approaches to pulmonary drug delivery,” in Design of Nanostructures for Versatile
Therapeutic Applications, Elsevier, 2018, pp. 221–253. doi: 10.1016/B978-0-12-
813667-6.00006-1.
[288] A. Nieto-Orellana et al., “Dry-powder formulations of non-covalent protein complexes
with linear or miktoarm copolymers for pulmonary delivery,” Int J Pharm, vol. 540,
no. 1–2, pp. 78–88, Apr. 2018, doi: 10.1016/j.ijpharm.2018.02.008.
[289] H. Yamamoto, Y. Kuno, S. Sugimoto, H. Takeuchi, and Y. Kawashima, “Surface-
modified PLGA nanosphere with chitosan improved pulmonary delivery of calcitonin
by mucoadhesion and opening of the intercellular tight junctions,” Journal of
Controlled Release, vol. 102, no. 2, pp. 373–381, Feb. 2005, doi:
10.1016/j.jconrel.2004.10.010.
[290] H. Mansour, Haemosu, and X. Wu, “Nanomedicine in pulmonary delivery,” Int J
Nanomedicine, p. 299, Dec. 2009, doi: 10.2147/IJN.S4937.
[291] S. Azarmi, W. H. Roa, and R. Löbenberg, “Targeted delivery of nanoparticles for the
treatment of lung diseases,” Adv Drug Deliv Rev, vol. 60, no. 8, pp. 863–875, May
2008, doi: 10.1016/j.addr.2007.11.006.
[292] X.-B. Liu et al., “Pulmonary delivery of scutellarin solution and mucoadhesive
particles in rats,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 70,
no. 3, pp. 845–852, Nov. 2008, doi: 10.1016/j.ejpb.2008.07.004.
[293] R. Vehring, “Pharmaceutical Particle Engineering via Spray Drying,” Pharm Res, vol.
25, no. 5, pp. 999–1022, May 2008, doi: 10.1007/s11095-007-9475-1.
[294] P. C. Seville, H. Li, and T. P. Learoyd, “Spray-Dried Powders for Pulmonary Drug
Delivery,” Crit Rev Ther Drug Carrier Syst, vol. 24, no. 4, pp. 307–360, 2007, doi:
10.1615/CritRevTherDrugCarrierSyst.v24.i4.10.
[295] X. Chen, L. Cui, X. Duan, B. Ma, and D. Zhong, “PHARMACOKINETICS AND
METABOLISM OF THE FLAVONOID SCUTELLARIN IN HUMANS AFTER A
SINGLE ORAL ADMINISTRATION,” Drug Metabolism and Disposition, vol. 34,
no. 8, pp. 1345–1352, Aug. 2006, doi: 10.1124/dmd.106.009779.
[296] K. Liu et al., “Paclitaxel and quercetin nanoparticles co-loaded in microspheres to
prolong retention time for pulmonary drug delivery,” Int J Nanomedicine, vol. Volume
12, pp. 8239–8255, Nov. 2017, doi: 10.2147/IJN.S147028.
[297] J. H. Schiller et al., “Comparison of Four Chemotherapy Regimens for Advanced
Non–Small-Cell Lung Cancer,” New England Journal of Medicine, vol. 346, no. 2, pp.
92–98, Jan. 2002, doi: 10.1056/NEJMoa011954.
[298] J. Ho and M. Cheung, “Combination of Phytochemicals as Adjuvants for Cancer
Therapy,” Recent Pat Anticancer Drug Discov, vol. 9, no. 3, pp. 297–302, Jul. 2014,
doi: 10.2174/1574892809666140619154838.
[299] B. Rizeq, I. Gupta, J. Ilesanmi, M. AlSafran, M. M. Rahman, and A. Ouhtit, “The
Power of Phytochemicals Combination in Cancer Chemoprevention.,” J Cancer, vol.
11, no. 15, pp. 4521–4533, 2020, doi: 10.7150/jca.34374.
[300] Y. Yang, N. Li, T.-M. Wang, and L. Di, “Natural Products with Activity against Lung
Cancer: A Review Focusing on the Tumor Microenvironment,” Int J Mol Sci, vol. 22,
no. 19, p. 10827, Oct. 2021, doi: 10.3390/ijms221910827.
[301] J. Liu et al., “pH-Sensitive nano-systems for drug delivery in cancer therapy,”
Biotechnol Adv, vol. 32, no. 4, pp. 693–710, Jul. 2014, doi:
10.1016/j.biotechadv.2013.11.009.
[302] M. Cai et al., “Metal Organic Frameworks as Drug Targeting Delivery Vehicles in the
Treatment of Cancer,” Pharmaceutics, vol. 12, no. 3, p. 232, Mar. 2020, doi:
10.3390/pharmaceutics12030232.
[303] P. Huang et al., “Nano-, micro-, and macroscale drug delivery systems for cancer
immunotherapy,” Acta Biomater, vol. 85, pp. 1–26, Feb. 2019, doi:
10.1016/j.actbio.2018.12.028.
[304] S. Wang, Y. Meng, J. Li, J. Liu, Z. Liu, and D. Li, “A novel and simple oral colon-
specific drug delivery system based on the pectin/modified nano-carbon sphere
nanocomposite gel films,” Int J Biol Macromol, vol. 157, pp. 170–176, Aug. 2020,
doi: 10.1016/j.ijbiomac.2020.04.197.
[305] P. Sriamornsak, “Application of pectin in oral drug delivery,” Expert Opin Drug Deliv,
vol. 8, no. 8, pp. 1009–1023, Aug. 2011, doi: 10.1517/17425247.2011.584867.
[306] S.-L. Zhang et al., “Pectin supplement significantly enhanced the anti-PD-1 efficacy in
tumor-bearing mice humanized with gut microbiota from patients with colorectal
cancer,” Theranostics, vol. 11, no. 9, pp. 4155–4170, 2021, doi: 10.7150/thno.54476.
[307] T. Fang et al., “Modified citrus pectin inhibited bladder tumor growth through
downregulation of galectin-3,” Acta Pharmacol Sin, vol. 39, no. 12, pp. 1885–1893,
Dec. 2018, doi: 10.1038/s41401-018-0004-z.
[308] S. PENG et al., “Traditional Chinese Medicine Brucea Javanica Oil Enhances the
Efficacy of Anlotinib in a Mouse Model of Liver-Metastasis of Small-cell Lung
Cancer,” In Vivo (Brooklyn), vol. 35, no. 3, pp. 1437–1441, Apr. 2021, doi:
10.21873/invivo.12395.
[309] W. Li et al., “Fei-Liu-Ping ointment inhibits lung cancer growth and invasion by
suppressing tumor inflammatory microenvironment,” BMC Complement Altern Med,
vol. 14, no. 1, p. 153, Dec. 2014, doi: 10.1186/1472-6882-14-153.
[310] R. Liu et al., “Anti-tumor enhancement of Fei-Liu-Ping ointment in combination with
celecoxib via cyclooxygenase-2-mediated lung metastatic inflammatory
microenvironment in Lewis lung carcinoma xenograft mouse model,” J Transl Med,
vol. 13, no. 1, p. 366, Dec. 2015, doi: 10.1186/s12967-015-0728-1.
[311] A. Mazzocca et al., “A Secreted Form of ADAM9 Promotes Carcinoma Invasion
through Tumor-Stromal Interactions,” Cancer Res, vol. 65, no. 11, pp. 4728–4738,
Jun. 2005, doi: 10.1158/0008-5472.CAN-04-4449.
[312] R. Zhou et al., “ADAM9 Mediates Triple-Negative Breast Cancer Progression via
AKT/NF-κB Pathway,” Front Med (Lausanne), vol. 7, Jun. 2020, doi:
10.3389/fmed.2020.00214.
[313] J. ZHANG, J. QI, N. CHEN, W. FU, B. ZHOU, and A. HE, “High expression of a
disintegrin and metalloproteinase-9 predicts a shortened survival time in completely
resected stage I non-small cell lung cancer,” Oncol Lett, vol. 5, no. 5, pp. 1461–1466,
May 2013, doi: 10.3892/ol.2013.1209.
[314] J. Liu et al., “pH-Sensitive nano-systems for drug delivery in cancer therapy,”
Biotechnol Adv, vol. 32, no. 4, pp. 693–710, Jul. 2014, doi:
10.1016/j.biotechadv.2013.11.009.
[315] Y.-S. Lin, C.-Y. Hsieh, T.-T. Kuo, C.-C. Lin, C.-Y. Lin, and Y.-P. Sher, “Resveratrol-
mediated ADAM9 degradation decreases cancer progression and provides synergistic
effects in combination with chemotherapy.,” Am J Cancer Res, vol. 10, no. 11, pp.
3828–3837, 2020.
[316] W. LIU et al., “Carnosic acid enhances the anti-lung cancer effect of cisplatin by
inhibiting myeloid-derived suppressor cells,” Chin J Nat Med, vol. 16, no. 12, pp. 907–
915, Dec. 2018, doi: 10.1016/S1875-5364(18)30132-8.
[317] Y. Chen et al., “Water extract of ginseng and astragalus regulates macrophage
polarization and synergistically enhances DDP’s anticancer effect,” J Ethnopharmacol,
vol. 232, pp. 11–20, Mar. 2019, doi: 10.1016/j.jep.2018.12.003.
[318] N. S. Srivastava and R. A. K. Srivastava, “Curcumin and quercetin synergistically
inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/β-catenin
signaling and apoptotic pathways in A375 cells,” Phytomedicine, vol. 52, pp. 117–128,
Jan. 2019, doi: 10.1016/j.phymed.2018.09.224.
[319] W.-W. Chao, Y.-W. Cheng, Y.-R. Chen, S.-H. Lee, C.-Y. Chiou, and L.-F. Shyur,
“Phyto-sesquiterpene lactone deoxyelephantopin and cisplatin synergistically suppress
lung metastasis of B16 melanoma in mice with reduced nephrotoxicity,”
Phytomedicine, vol. 56, pp. 194–206, Mar. 2019, doi: 10.1016/j.phymed.2018.11.005.
[320] X. Jin, Q. Yang, and Y. Zhang, “Synergistic apoptotic effects of apigenin TPGS
liposomes and tyroservatide: implications for effective treatment of lung cancer,” Int J
Nanomedicine, vol. Volume 12, pp. 5109–5118, Jul. 2017, doi: 10.2147/IJN.S140096.
[321] B. Rizeq, I. Gupta, J. Ilesanmi, M. AlSafran, M. M. Rahman, and A. Ouhtit, “The
Power of Phytochemicals Combination in Cancer Chemoprevention.,” J Cancer, vol.
11, no. 15, pp. 4521–4533, 2020, doi: 10.7150/jca.34374.
[322] W. Zhuo, L. Zhang, Y. Zhu, B. Zhu, and Z. Chen, “Fisetin, a dietary bioflavonoid,
reverses acquired Cisplatin-resistance of lung adenocarcinoma cells through
MAPK/Survivin/Caspase pathway.,” Am J Transl Res, vol. 7, no. 10, pp. 2045–52,
2015.
[323] J. Ho and M. Cheung, “Combination of Phytochemicals as Adjuvants for Cancer
Therapy,” Recent Pat Anticancer Drug Discov, vol. 9, no. 3, pp. 297–302, Jul. 2014,
doi: 10.2174/1574892809666140619154838.
[324] S. H. Jafri, J. Glass, R. Shi, S. Zhang, M. Prince, and H. Kleiner-Hancock,
“Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and
in vivo,” Journal of Experimental & Clinical Cancer Research, vol. 29, no. 1, p. 87,
Dec. 2010, doi: 10.1186/1756-9966-29-87.
[325] I. Rahat et al., “Thymoquinone-entrapped chitosan-modified nanoparticles:
formulation optimization to preclinical bioavailability assessments,” Drug Deliv, vol.
28, no. 1, pp. 973–984, Jan. 2021, doi: 10.1080/10717544.2021.1927245.
[326] W. Liu et al., “Tetrandrine combined with gemcitabine and Cisplatin for patients with
advanced non-small cell lung cancer improve efficacy.,” Int J Biomed Sci, vol. 8, no.
1, pp. 28–35, Mar. 2012.
[327] Y.-M. Chen, R.-P. Perng, C.-M. Tsai, and J. Whang-Peng, “A Phase II randomized
study of paclitaxel plus carboplatin or cisplatin against chemo-naive inoperable non-
small cell lung cancer in the elderly.,” J Thorac Oncol, vol. 1, no. 2, pp. 141–5, Feb.
2006.
[328] P. F. Yumuk et al., “Results of paclitaxel (day 1 and 8) and carboplatin given on every
three weeks in advanced (stage III-IV) non-small cell lung cancer,” BMC Cancer, vol.
5, no. 1, p. 10, Dec. 2005, doi: 10.1186/1471-2407-5-10.
[329] S. Banerjee, Y. Li, Z. Wang, and F. H. Sarkar, “Multi-targeted therapy of cancer by
genistein,” Cancer Lett, vol. 269, no. 2, pp. 226–242, Oct. 2008, doi:
10.1016/j.canlet.2008.03.052.
[330] S. Sen, H. Sharma, and N. Singh, “Curcumin enhances Vinorelbine mediated apoptosis
in NSCLC cells by the mitochondrial pathway,” Biochem Biophys Res Commun, vol.
331, no. 4, pp. 1245–1252, Jun. 2005, doi: 10.1016/j.bbrc.2005.04.044.
[331] P. K. Teja, J. Mithiya, A. S. Kate, K. Bairwa, and S. K. Chauthe, “Herbal
nanomedicines: Recent advancements, challenges, opportunities and regulatory
overview,” Phytomedicine, vol. 96, p. 153890, Feb. 2022, doi:
10.1016/j.phymed.2021.153890.
[332] N. Joudeh and D. Linke, “Nanoparticle classification, physicochemical properties,
characterization, and applications: a comprehensive review for biologists,” J
Nanobiotechnology, vol. 20, no. 1, p. 262, Jun. 2022, doi: 10.1186/s12951-022-01477-
8.
[333] L. A. Kolahalam, I. V. Kasi Viswanath, B. S. Diwakar, B. Govindh, V. Reddy, and Y.
L. N. Murthy, “Review on nanomaterials: Synthesis and applications,” Mater Today
Proc, vol. 18, pp. 2182–2190, 2019, doi: 10.1016/j.matpr.2019.07.371.
[334] J. D. Clogston, V. A. Hackley, A. Prina-Mello, S. Puri, S. Sonzini, and P. L. Soo,
“Sizing up the Next Generation of Nanomedicines,” Pharm Res, vol. 37, no. 1, p. 6,
Jan. 2020, doi: 10.1007/s11095-019-2736-y.
[335] J. D. Clogston, “The importance of nanoparticle physicochemical characterization for
immunology research: What we learned and what we still need to understand,” Adv
Drug Deliv Rev, vol. 176, p. 113897, Sep. 2021, doi: 10.1016/j.addr.2021.113897.
[336] F. S. H. Lu, N. S. Nielsen, C. P. Baron, L. H. S. Jensen, and C. Jacobsen,
“Physico‐chemical Properties of Marine Phospholipid Emulsions,” J Am Oil Chem
Soc, vol. 89, no. 11, pp. 2011–2024, Nov. 2012, doi: 10.1007/s11746-012-2105-z.
[337] M. Sheikhpour et al., “Co-Administration of Curcumin and Bromocriptine Nano-
liposomes for Induction of Apoptosis in Lung Cancer Cells,” Iran Biomed J, vol. 24,
no. 1, pp. 24–29, Jan. 2020, doi: 10.29252/ibj.24.1.24.
[338] J. Singh, Y. Hussain, S. Luqman, and A. Meena, “Targeting Ca2+ signalling through
phytomolecules to combat cancer,” Pharmacol Res, vol. 146, p. 104282, Aug. 2019,
doi: 10.1016/j.phrs.2019.104282.
[339] M. C. Fadus, C. Lau, J. Bikhchandani, and H. T. Lynch, “Curcumin: An age-old anti-
inflammatory and anti-neoplastic agent,” J Tradit Complement Med, vol. 7, no. 3, pp.
339–346, Jul. 2017, doi: 10.1016/j.jtcme.2016.08.002.
[340] J. Tomé-Carneiro, M. Larrosa, A. González-Sarrías, F. Tomás-Barberán, M. García-
Conesa, and J. Espín, “Resveratrol and Clinical Trials: The Crossroad from In Vitro
Studies to Human Evidence,” Curr Pharm Des, vol. 19, no. 34, pp. 6064–6093, Sep.
2013, doi: 10.2174/13816128113199990407.
[341] F. Chen and W. Cai, “Nanomedicine for targeted photothermal cancer therapy: where
are we now?,” Nanomedicine, vol. 10, no. 1, pp. 1–3, Jan. 2015, doi:
10.2217/nnm.14.186.
[342] K. Lubelska, K. Wiktorska, L. Mielczarek, M. Milczarek, I. Zbroińska-Bregisz, and Z.
Chilmonczyk, “Sulforaphane Regulates NFE2L2/Nrf2-Dependent Xenobiotic
Metabolism Phase II and Phase III Enzymes Differently in Human Colorectal Cancer
and Untransformed Epithelial Colon Cells,” Nutr Cancer, vol. 68, no. 8, pp. 1338–
1348, Nov. 2016, doi: 10.1080/01635581.2016.1224369.
[343] S. Paul et al., “Targeting cellular microtubule by phytochemical apocynin exhibits
autophagy-mediated apoptosis to inhibit lung carcinoma progression and
tumorigenesis,” Phytomedicine, vol. 67, p. 153152, Feb. 2020, doi:
10.1016/j.phymed.2019.153152.
[344] J. Singh, S. Luqman, and A. Meena, “Emerging role of phytochemicals in targeting
predictive, prognostic, and diagnostic biomarkers of lung cancer,” Food and Chemical
Toxicology, vol. 144, p. 111592, Oct. 2020, doi: 10.1016/j.fct.2020.111592.
[345] J. H. Lee and Y. Yeo, “Controlled drug release from pharmaceutical nanocarriers,”
Chem Eng Sci, vol. 125, pp. 75–84, Mar. 2015, doi: 10.1016/j.ces.2014.08.046.
[346] J. K. Patra et al., “Nano based drug delivery systems: recent developments and future
prospects,” J Nanobiotechnology, vol. 16, no. 1, p. 71, Dec. 2018, doi:
10.1186/s12951-018-0392-8.
[347] P. Aggarwal, J. B. Hall, C. B. McLeland, M. A. Dobrovolskaia, and S. E. McNeil,
“Nanoparticle interaction with plasma proteins as it relates to particle biodistribution,
biocompatibility and therapeutic efficacy,” Adv Drug Deliv Rev, vol. 61, no. 6, pp.
428–437, Jun. 2009, doi: 10.1016/j.addr.2009.03.009.
[348] P. Somu and S. Paul, “Supramolecular nanoassembly of lysozyme and α-lactalbumin
(apo α-LA) exhibits selective cytotoxicity and enhanced bioavailability of curcumin to
cancer cells,” Colloids Surf B Biointerfaces, vol. 178, pp. 297–306, Jun. 2019, doi:
10.1016/j.colsurfb.2019.03.016.
[349] R. Staud, “Effectiveness of CAM Therapy: Understanding the Evidence,” Rheumatic
Disease Clinics of North America, vol. 37, no. 1, pp. 9–17, Feb. 2011, doi:
10.1016/j.rdc.2010.11.009.
[350] Y. Liu, K. Xu, J. Bai, L. Li, and X. Yang, “[Qualitative evaluation on literatures
related with treatment of lung cancer with combined use of chemotherapy and Chinese
herbs].,” Zhongguo Zhong Xi Yi Jie He Za Zhi, vol. 25, no. 2, pp. 123–5, Feb. 2005.
[351] S. Chen et al., “Oral Chinese herbal medicine (CHM) as an adjuvant treatment during
chemotherapy for non-small cell lung cancer: A systematic review,” Lung Cancer, vol.
68, no. 2, pp. 137–145, May 2010, doi: 10.1016/j.lungcan.2009.11.008.
[352] C. C. L. Xue, A. L. Zhang, K. M. Greenwood, V. Lin, and D. F. Story, “Traditional
Chinese Medicine: An Update on Clinical Evidence,” The Journal of Alternative and
Complementary Medicine, vol. 16, no. 3, pp. 301–312, Mar. 2010, doi:
10.1089/acm.2009.0293.
[353] M.-X. Luo, S. Hua, and Q.-Y. Shang, “Application of nanotechnology in drug delivery Oncology, vol. 6, no. 10, pp. 1757–1760, Oct. 2011, doi:
systems for respiratory diseases (Review),” Mol Med Rep, vol. 23, no. 5, p. 325, Mar. 10.1097/JTO.0b013e31822e2941.
2021, doi: 10.3892/mmr.2021.11964.
[354] S. Sharifi, S. Behzadi, S. Laurent, M. Laird Forrest, P. Stroeve, and M. Mahmoudi,
“Toxicity of nanomaterials,” Chem. Soc. Rev., vol. 41, no. 6, pp. 2323–2343, 2012,
doi: 10.1039/C1CS15188F.
[355] S. Y. Madani, A. Mandel, and A. M. Seifalian, “A concise review of carbon
nanotube’s toxicology,” Nano Rev, vol. 4, no. 1, p. 21521, Jan. 2013, doi:
10.3402/nano.v4i0.21521.
[356] R. Singh et al., “Tissue biodistribution and blood clearance rates of intravenously
administered carbon nanotube radiotracers,” Proceedings of the National Academy of
Sciences, vol. 103, no. 9, pp. 3357–3362, Feb. 2006, doi: 10.1073/pnas.0509009103.
[357] R. Rastegar et al., “Evaluation of a novel biocompatible magnetic nanomedicine based
on beta-cyclodextrin, loaded doxorubicin-curcumin for overcoming chemoresistance in
breast cancer,” Artif Cells Nanomed Biotechnol, vol. 46, no. sup2, pp. 207–216, Nov.
2018, doi: 10.1080/21691401.2018.1453829.
[358] D. M. Anwar, M. El-Sayed, A. Reda, J.-Y. Fang, S. N. Khattab, and A. O. Elzoghby,
“Recent advances in herbal combination nanomedicine for cancer: delivery technology
and therapeutic outcomes,” Expert Opin Drug Deliv, vol. 18, no. 11, pp. 1609–1625,
Nov. 2021, doi: 10.1080/17425247.2021.1955853.
[359] A. Lakshmanan et al., “Nanocurcumin-Loaded UCNPs for Cancer Theranostics:
Physicochemical Properties, In Vitro Toxicity, and In Vivo Imaging Studies,”
Nanomaterials, vol. 11, no. 9, p. 2234, Aug. 2021, doi: 10.3390/nano11092234.
[360] X. Huang, L. He, X. Luo, H. Yin, and D. Yang, “Deformation and coalescence of
water droplets in viscous fluid under a direct current electric field,” International
Journal of Multiphase Flow, vol. 118, pp. 1–9, Sep. 2019, doi:
10.1016/j.ijmultiphaseflow.2019.05.013.
[361] L. Zou et al., “Current Approaches of Photothermal Therapy in Treating Cancer
Metastasis with Nanotherapeutics,” Theranostics, vol. 6, no. 6, pp. 762–772, 2016, doi:
10.7150/thno.14988.
[362] A. Weiss and P. Nowak-Sliwinska, “Current Trends in Multidrug Optimization: An
Alley of Future Successful Treatment of Complex Disorders,” SLAS Technol, vol. 22,
no. 3, pp. 254–275, Jun. 2017, doi: 10.1177/2472630316682338.
[363] R. B. Mokhtari et al., “Combination therapy in combating cancer,” Oncotarget, vol. 8,
no. 23, pp. 38022–38043, Jun. 2017, doi: 10.18632/oncotarget.16723.
[364] K. Kesarwani and R. Gupta, “Bioavailability enhancers of herbal origin: An
overview,” Asian Pac J Trop Biomed, vol. 3, no. 4, pp. 253–266, Apr. 2013, doi:
10.1016/S2221-1691(13)60060-X.
[365] M. Q. Baggstrom et al., “A Phase II Study of AT-101 (Gossypol) in Chemotherapy-
Sensitive Recurrent Extensive-Stage Small Cell Lung Cancer,” Journal of Thoracic
 Similarity Report Similarity Report

22% Overall Similarity

science.gov
Top sources found in the following databases: 10 <1%
Internet
15% Internet database 16% Publications database
Crossref database Crossref Posted Content database Vivek P Chavda, Disha Vihol, Bhavya Mehta, Dhruvil Shah et al. "Phytoc...
11 <1%
Crossref

TOP SOURCES
Jeffrey D. Clogston. "The importance of nanoparticle physicochemical ...
The sources with the highest number of matches within the submission. Overlapping sources will not be 12 <1%
displayed. Crossref

journal-uamd.org dokumen.pub
1 2%
13 <1%
Internet
Internet

mdpi.com Shaimaa Ibrahim, Tatsuaki Tagami, Toshihiro Kishi, Tetsuya Ozeki. "Cu...
2 1%
14 <1%
Crossref
Internet

frontiersin.org Jyoti Singh, Suaib Luqman, Abha Meena. "Emerging role of phytochemi...
3 1%
15 <1%
Crossref
Internet

Mahak Fatima, Mohammad Kashif Iqubal, Ashif Iqubal, Harsimran Kaur... ibj.pasteur.ac.ir
4 1%
16 <1%
Internet
Crossref

tandfonline.com S. H. van Rijt, T. Bein, S. Meiners. "Medical nanoparticles for next gene...
5 1%
17 <1%
Crossref
Internet

link.springer.com Phatsapong Yingchoncharoen, Danuta S. Kalinowski, Des R. Richardso...

6 <1%
18 <1%
Crossref
Internet

Balsam Rizeq, Ishita Gupta, Josephine Ilesanmi, Mohammed AlSafran, ... pure.unamur.be
7 <1%
19 <1%
Internet
Crossref

dspace.daffodilvarsity.edu.bd:8080 Ashitha Jose, Sreekanth K., Radhakrishnan E.K.. "Advancements in nan...

8 <1%
20 <1%
Crossref
Internet

pureadmin.qub.ac.uk ebin.pub
9 <1%
21 <1%
Internet
Internet

Sources overview Sources overview

 Similarity Report Similarity Report

researchgate.net worldwidescience.org
22 <1% 34 <1%
Internet Internet

hindawi.com Marisol Huerta, Susana Roselló, Luis Sabater, Ana Ferrer et al. "Circulat...
23 <1% 35 <1%
Internet Crossref

"Cutting-Edge Enabling Technologies for Regenerative Medicine", Sprin... Yan Du, Xue Cai. "Therapeutic potential of natural compounds from her...
24 <1% 36 <1%
Crossref Crossref

coek.info roderic.uv.es
25 <1% 37 <1%
Internet Internet

jnanobiotechnology.biomedcentral.com pharmaexcipients.com
26 <1% 38 <1%
Internet Internet

"INVITED ABSTRACTS", Journal of Thoracic Oncology, 2013 thesesups.ups-tlse.fr

27 <1% 39 <1%
Crossref Internet

"Natural Products for Cancer Chemoprevention", Springer Science and ... wjgnet.com
28 <1% 40 <1%
Crossref Internet

vdoc.pub "Advanced Drug Delivery Strategies for Targeting Chronic Inflammator...

29 <1% 41 <1%
Internet Crossref

Akhileshwar Kumar Srivastava, Divya Singh, Rajesh Kumar Singh. "Deli... Cristina Pérez-Ramírez, Marisa Cañadas-Garre, Miguel Ángel Molina, ...
30 <1% 42 <1%
Crossref Crossref

amsdottorato.unibo.it Parusu Kavya Teja, Jinal Mithiya, Abhijeet S. Kate, Khemraj Bairwa, Sid...
31 <1% 43 <1%
Internet Crossref

jctres.com Zhenglin He, Yihan Wang, Liang Han, Yue Hu, Xianling Cong. "The mec...
32 <1% 44 <1%
Internet Crossref

Kyu H. Shin. "Induction Therapy (IT) of non small cell lung cancer (NSC... dovepress.com
33 <1% 45 <1%
Crossref Internet

Sources overview Sources overview

 Similarity Report Similarity Report

eurekaselect.com Sabya Sachi Das, Srushti Tambe, Priya Ranjan Prasad Verma, Purnima ...
46 <1% 58 <1%
Internet Crossref

Kang Liu, Weijuan Chen, Tingting Yang, Baofang Wen, Dejun Ding, Mich... event.eortc.org
47 <1% 59 <1%
Crossref Internet

journal.frontiersin.org jbiomedsci.biomedcentral.com
48 <1% 60 <1%
Internet Internet

Nanocosmetics and Nanomedicines, 2011. "Nanomaterials and Nanotechnology", Springer Science and Business ...
49 <1% 61 <1%
Crossref Crossref

etd.uwc.ac.za Advances in Experimental Medicine and Biology, 2016.

50 <1% 62 <1%
Internet Crossref

pdfs.semanticscholar.org Biswas, Swati, Onkar S. Vaze, Sara Movassaghian, and Vladimir P. Tor...
51 <1% 63 <1%
Internet Crossref

Marina Gallarate, Luigi Battaglia, E. Peira, Michele Trotta. "Peptide-Loa... Diana Sousa, Débora Ferreira, Joana L. Rodrigues, Lígia R. Rodrigues. "...
52 <1% 64 <1%
Crossref Crossref

Md Sohel, Habiba Sultana, Tayeba Sultana, Md. Al Amin et al. "Chemot... Jing Cheng, Ziqin Yan, Kailong Jiang, Chen Liu, Dehua Xu, Xilin Lyu, Xia...
53 <1% 65 <1%
Crossref Crossref

Cancer Targeted Drug Delivery, 2013. M. López Rodríguez. "Toxicity associated to radiotherapy treatment in l...
54 <1% 66 <1%
Crossref Crossref

Eldar-Boock, Anat, Dina Polyak, Anna Scomparin, and Ronit Satchi-Fain... Rodriguez Luccioni, Hector Luis. "Studies of ferrite based magnetic na...
55 <1% 67 <1%
Crossref Publication

Mitochondria as Targets for Phytochemicals in Cancer Prevention and ... Vasilii F. Otvagin, Natalia S. Kuzmina, Ekaterina S. Kudriashova, Alexan...
56 <1% 68 <1%
Crossref Crossref

Raj Kumar. "Lipid-Based Nanoparticles for Drug-Delivery Systems", Els... Ying Lv, Wenqing Li, Wei Liao, Haibo Jiang, Yuwei Liu, Jiansheng Cao, ...
57 <1% 69 <1%
Crossref Crossref

Sources overview Sources overview

 Similarity Report Similarity Report

Yutong Sui, Yanqun Yang, Jing Zhang, Ziwei Wang, Xue Geng, Jiakang ... Ibrahim M. Abdulbaqi, Reem Abou Assi, Anan Yaghmur, Yusrida Darwis...
70 <1% 82 <1%
Crossref Crossref

en.wikipedia.org Jyotsana Dwivedi, Pranjal Sachan, Pranay Wal, Sumeet Dwivedi, Mukes...
71 <1% 83 <1%
Internet Crossref

pubs.rsc.org Kim, Sungwon, and Kinam Park. "Polymer Micelles for Drug Delivery", T...
72 <1% 84 <1%
Internet Crossref

smartech.gatech.edu Mahmoud Nasrollahzadeh, Nayyereh Sadat Soheili Bidgoli, Fahimeh So...

73 <1% 85 <1%
Internet Crossref

nice.org.uk Mariana Neves Amaral, Jacinta O. Pinho, M. Manuela Gaspar, Catarina ...
74 <1% 86 <1%
Internet Crossref

"Medicinal Plants for Lung Diseases", Springer Science and Business ... Mayada M. Elgohary, Maged W. Helmy, Elsayeda-Zeinab A. Abdelfattah...
75 <1% 87 <1%
Crossref Crossref

"Pharmacogenomic Precision Medicine: Best Practice Toolkit for Impr... NA. "Supplement 2, Proceedings of the 14th World Conference on Lun...
76 <1% 88 <1%
Crossref posted content Crossref

Amit K. Jain, Kaushik Thanki, Sanyog Jain. "Co-encapsulation of Tamo... Patenting Nanomedicines, 2012.
77 <1% 89 <1%
Crossref Crossref

Armer, Jessica S.. "Risk and Resilience in Ovarian Cancer Survivorship:... Rachel Gaul, Joanne M. Ramsey, Andreas Heise, Sally-Ann Cryan, Cath...
78 <1% 90 <1%
Publication Crossref

Asma Ismail Mahmod, Wamidh H. Talib. "Anticancer activity of Mandra... Sheersha Pramanik, Sourav Mohanto, Ravi Manne, Rahul R. Rajendran, ...
79 <1% 91 <1%
Crossref Crossref

Baabur-Cohen, Hemda, Liora Omer, and Ronit Satchi-Fainaro. "Recent ... Shengjun Peng, Yizhou Wang, Zhifang Sun, Laien Zhao et al. "Nanopart...
80 <1% 92 <1%
Crossref Crossref

Handbook of Nanoparticles, 2016. Timothy C. Johnstone, Kogularamanan Suntharalingam, Stephen J. Lip...

81 <1% 93 <1%
Crossref Crossref

Sources overview Sources overview

 Similarity Report Similarity Report

Xinyi Zhang, Mengya Zhang, Hengqing Cui, Tinglin Zhang, Lili Wu, Can ... wunboundmedicine.com
94 <1% 106 <1%
Crossref Internet

biblio.ugent.be
95 <1%
Internet

buescholar.bue.edu.eg
96 <1%
Internet

cris.brighton.ac.uk
97 <1%
Internet

downloads.hindawi.com
98 <1%
Internet

edepositireland.ie
99 <1%
Internet

era.library.ualberta.ca
100 <1%
Internet

library.ndsu.edu
101 <1%
Internet

mdpi-res.com
102 <1%
Internet

publica-rest.fraunhofer.de
103 <1%
Internet

researchonline.ljmu.ac.uk
104 <1%
Internet

physiology.org
105 <1%
Internet

Sources overview Sources overview