Samiul 1

A BRIEF REVIEW ON
ADVANCES IN PHYTOCHEMICAL DELIVERY SYSTEMS

FOR IMPROVED ANTICANCER ACTIVITY
By
SAMIUL ALAM
B. PHARM, 4 YEAR, 8TH SEMESTER, ROLL NO: 36201921112
TH
REGISTRATRION NO: 213620201920003
Dissertation Submitted to the
Maulana Abul Kalam Azad University of Technology

(MAKAUT), West Bengal
In partial fulfillment of
the requirements for the degree of
BACHELOR OF PHARMACY
Under the Guidance of
MR. RUPAM ROY
Assistant Professor
Departmet Of Pharmaceutics
GITANJALI COLLEGE OF PHARMACY

Lohapur, Birbhum, West Bengal, India
2024
GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page i

DECLARATION
I hereby declare that this dissertation, entitled “ADVANCES IN PHYTOCHEMICAL

DELIVERY SYSTEMS FOR IMPROVED ANTICANCER ACTIVITY- A
REVIEW” is a bonafide and project work carried out by me under the guidance of Mr.
RUPAM ROY, Gitanjali College of Pharmacy, Lohapur, Birbhum, West Bengal, India.
Signature __________________________
NAME: SAMIUL AALAM
ROLL NO: 36201921112
Date :
Place :
GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page ii

GITANJALI COLLEGE OF PHARMACY
CERTIFICATE BY THE GUIDE
This is to certify that the dissertation, entitled “ADVANCES IN PHYTOCHEMICAL

DELIVERY SYSTEMS FOR IMPROVED ANTICANCER ACTIVITY” is a bonafide
project work done by SAMIUL ALAM, ROLL NO : 36201921112, REGISTRSTION
NO : 213620201920003 in partial fulfilment of the requirement for the degree of Bachelor
of Pharmacy.
Supervisor Name with Signature
Gitanjali College of Pharmacy
Date:
Place;
GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page iii
Gitanjali College of Pharmacy
CERTIFICATE
This is to certify that the dissertation, entitled “ADVANCES IN PHYTOCHEMICAL

DELIVERY SYSTEMS FOR IMPROVED ANTICANCER ACTIVITY” is a bonafide
project work done by SAMIUL ALAM under the guidance of Mr. RUPAM ROY (ASSISTANT
PROFESSOR)., Gitanjali College of Pharmacy, Lohapur, Birbhum, West Bengal, India.
Prof. (Dr.) Mrinmay Das

Principal,
GCP, Lohapur, Birbhum.
Evaluator’s Signature:
Date:
Place:
GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page iv

ACKNOWLEDGEMENT
I would like to express our sincere gratitude to all those who have contributed to the
successful completion of our project work on " ADVANCES IN PHYTOCHEMICAL
DELIVERY SYSTEMS FOR IMPROVED ANTICANCER ACTIVITY” Without
their support, guidance, and encouragement, this project would not have been possible.
First and foremost, I would like to thank our supervisor Mr. Rupam Roy (ASSISTANT
PROFESSOR) for his invaluable guidance throughout the project. His expertise, patience,
and constant support have been instrumental in shaping this project work and expanding
our knowledge in the field of drug delivery. I would also like to extend our heartfelt thanks
to all the faculty members of Gitanjali college of Pharmacy for their valuable insights and
suggestions. Their constructive feedback during project reviews and discussions greatly
enhanced the quality of our work. I am grateful to the staff members of the department of
pharmacy at Gitanjali college of Pharmacy for their assistance during the course of this
project. Their prompt responses and cooperation in providing necessary resources and
laboratory facilities were immensely helpful.
Furthermore, I am indebted to our fellow classmates and friends for their constant
encouragement and support throughout this journey. Their valuable inputs and discussions
have broadened our perspective and enriched our understanding of the subject. Last but not
least, I would like to thank our family for their unconditional love, understanding, and
unwavering support. Their encouragement and belief in our abilities have been the driving
force behind our success.
In conclusion, I would like to extend our heartfelt appreciation to all those who have played
a part, directly or indirectly, in the completion of this project. Your contributions have been
invaluable, and I am grateful for your support in making this endeavour a reality.
GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page v

TABLE OF CONTENTS
Sl. No. Title Page No.
1 INTRODUCTION 1-2
2 PHYTOCHEMICALS IN CANCER THERAPY 3-15
PHYTOCHEMICAL BASED NANOMEDICINE

3 FOR CANCER TREATMENT 15-26
NANO-DRUG DELIVERY OF
PHYTOCHEMICALS AGAINST DIFFERENT
4 26-56
TYPES OF CANCER:
CURRENT LIMITATIONS
5 57
FUTURE PERSPECTIVES
6 58-59
7 REFERENCES 60-64
GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page vi

ADVANCES IN PHYTOCHEMICAL DELIVERY SYSTEMS FOR IMPROVED
ANTICANCER ACTIVITY- A REVIEW
1. INTRODUCTION:
Gene alterations are one way that cancer is classified as a hereditary disease. Cancer is the
second most common cause of death in the world each year. Cancer is caused by unchecked
cell growth and extension, which causes cells to stop responding to checkpoints and
eventually build tumors and spread. It is a Non-Communicable Disease (NCD) that is well
known to pose a worldwide risk. It is concerning that cancer puts the lives of every fourth
person at danger. A person with a weakened immune system or one that is repressed is
more likely to develop cancer. The elements, which include advanced age, stressful
situations, debilitating chronic illnesses, prior chemotherapy, and medication resistance,
each of these elements could raise the chance of developing cancer even more.
In 2020, there will be roughly 10 million cancer-related deaths worldwide and 19.3 million
new cases. Men and women are said to be affected by over thirty different types of cancer,
including stomach, liver, lung, and breast cancer (Bray et al. 2018). According to Bray et
al. (2018), cervical cancer is one of the most common cancers and the primary cause of
mortality for women globally. Despite recent improvements in early identification and
advanced therapy options, the prevalence and fatality rate have increased. Gastric cancer
(GC) is the second most common cause of cancer-related deaths worldwide, accounting for
around 7,60,000 cases (Gurunathan et al. 2015). Ovarian cancer is the deadliest of all
female-specific reproductive cancers. It generally accounts for 6.7% of cancer-related
fatalities among women worldwide.
Among the many variables influencing the occurrence of cancer, lifestyle is important.
Research indicates that plant-based and bioactive diets can reduce the incidence and
progression of cancer. Natural resources have been utilized in medicine for many years;
since the 1990s, flavonoids have garnered particular interest. The secondary metabolites
called flavonoids are found in plants and are what give them their yellow, red, and orange
GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 1

colors. Flavonoids are mostly found in plants as glycosides, which are categorized into
different classes based on their chemical makeup.
WHAT IS CANCER:
Cancer is a disease in which some of the body’s cells grow uncontrollably and spread to
other parts of the body.
Cancer can start almost anywhere in the human body, which is made up of trillions of cells.
Normally, human cells grow and multiply (through a process called cell division) to form
new cells as the body needs them. When cells grow old or become damaged, they die, and
new cells take their place.
Sometimes this orderly process breaks down, and abnormal or damaged cells grow and
multiply when they shouldn’t. These cells may form tumors, which are lumps of tissue.
Tumors can be cancerous or not cancerous.
Cancerous tumors spread into, or invade, nearby tissues and can travel to distant places in
the body to form new tumors (a process called metastasis). Cancerous tumors may also be
called malignant tumors. Many cancers form solid tumors, but cancers of the blood, such
as leukemias, generally do not.
Benign tumors do not spread into, or invade, nearby tissues. When removed, benign tumors
usually don’t grow back, whereas cancerous tumours sometimes do. Benign tumors can
sometimes be quite large, however. Some can cause serious symptoms or be life
threatening, such as benign tumors in the brain.

2. PHYTOCHEMICALS IN CANCER THERAPY
Natural compounds are more widely available and less expensive than small molecule
inhibitors, which are created and produced in laboratories to target certain components in
cancer treatment. Furthermore, natural products have the capacity to target several routes
and biological mechanisms in cancer treatment, unlike small chemical inhibitors which are
exclusive to one pathway. In recent years, there has been interest in the use of nutrition and
food in the prevention and treatment of cancer. Many types of cancer in humans have been
treated using phytochemicals. A meta-analysis consisting of ninety-three studies revealed
a possible correlation between food and cancer risk andfurthermore, postmenopausal,
hormone receptor-negative women have shown a stronger correlation with this association
[1]. Important epidemiological studies have also demonstrated that fruits, vegetables, and
soy products can lower the chance of developing breast cancer. It's interesting to note that
using naturally occurring substances has helped lower the risk of breast cancer
development, relapse, and recurrence.
Natural compounds and their bioactive components have been analyzed, and the results
show that these compounds can suppress angiogenesis, reduce ER-α levels, inhibit
proliferation and metastasis, induce apoptosis and cell cycle arrest, and improve the
response of breast tumors to radiation and chemotherapy [2]. Nonetheless, natural products
are not limited to treating breast cancer as a tumor type. The FDA has validated the use of
complementary natural products and immunotherapeutic strategies in cancer patient’s
clinical studies. Remarkably, natural ingredients have sped up the process of finding new

Fig1: Various Type of Phytochemical for the treatment of cancer.
cancer drugs [1]. There is growing evidence that 47% of anti-tumor medicines may be
developed from natural compounds and separated. Increased consumption of fiber and
natural products can significantly lower the risk of developing cancer worldwide,
according to epidemiological research, which further supports the potential of dietary
components in cancer therapy. It has been demonstrated by researchers that natural
products can reduce liver carcinogenesis, improve immunomodulatory function, prevent
tumor cell growth and invasion, and enhance the effectiveness of chemotherapy
medications in the treatment of cancer. Certain dietary components have tumor-specific
anti-cancer action. There is ample evidence to suggest that phytochemicals are currently at
the forefront of the search for new cancer drugs. They vary from their synthetic equivalents
in that they possess a higher degree of stereochemistry and a distinct structure. Natural
products are said to occupy a greater area than synthetic molecules because they are
embedded into certain areas of the chemical space that is significant to biology [3]. Of all

the small molecule anti-cancer medications licensed for use in cancer therapy between
1940 and 2012, 48.6% are derived from natural substances. William C. Campbell, Satoshi
Omura, and Youyou Tu even received the Noble Prize in 2015 in recognition of their
research on the use of artemisinin and avermectins to treat parasitic disorders. A wide range
of phytochemicals, including phenolics, carotenoids, terpenoids, alkaloids, and
organosulfur compounds, are now leading as anticancer agents in preclinical and clinical
application. One or more aromatic rings with one or more hydroxyl groups may be seen in
the chemical structure of phenolics. The polyene chain shown in the carotenoid structure
has nine to eleven double bonds and may end in rings. Due to the conjugated double bond
arrangement, there is a large reduction potential, or the capacity to move electrons across
the molecule [4]. Terpenoids are a modified family of naturally occurring organic
compounds that are generated from isoprene, a 5-carbon substance, and have a methyl
group that has been oxidized and relocated or deleted at different places. These compounds
are known as terpenes. Organosulfur compounds are made up of sulfur atoms that are either
cyclically or noncyclically bonded to a carbon atom or a cyanate group. we are highlighting
a few phytochemicals that have demonstrated their anticancer potential. Of these, a few
phytochemicals have previously received FDA approval as anticancer medicines; the most
well-known phytochemicals in clinical use are paclitaxel (Taxol) and the vinca alkaloids
(vinblastine and vincristine) . Here, a few phytochemicals with stronger anticancer qualities
are mentioned along with a thorough explanation of how they work. Phytochemicals have
anticancer effects through many mechanisms, including the regulation of oncogenic
pathways linked to the development and advancement of cancer. They target aberrantly
expressed molecular factors, specifically destroy rapidly multiplying cancer cells, control
oxidative stress, alter cell growth factors, trigger cell cycle arrest, prevent metastasis, arrest
angiogenesis, decrease chemoresistance, EMT, and immunomodulation, and control
epigenetic alterations [5].

2.1. Phenolics
Numerous epidemiological studies support the idea that naturally occurring phenolic
chemicals help prevent and cure cancer. Certain strategies against cancer are exhibited by
Fig 2: Chemical structure of phytochemicals that exhibit anticancer properties such as

phenolics, carotenoids, terpenoids, alkaloids, glycosides andorganosulfur compounds.
the simple and polyphenolic compounds. These mechanisms include anti-oxidant and anti-
inflammatory properties, as well as modification of several molecular pathways involved
in tumor development and progression. Here, we describe the mechanisms of action of
important polyphenol groups, including lignans, stilbenes, and flavonoids, in preclinical
and clinical research, and offer insights into their anticancer efficaciousness. A polyphenol
called curcumin, which comes from Curcuma longa, has anticancer properties while having
less harmful effects. Curcumin modulates p53, PI3K/Akt, Wnt-β catenin, NF-κB,
JAK/STAT, and TGF-β pathways to promote apoptosis, inhibit angiogenesis, and prevent
metastasis in breast, lung, hematological, gastric, colorectal, pancreatic, and hepatic
cancers. In a similar vein, quercetin is a flavonoid that may be found in many fruits, berries,

and brassica vegetables. Research findings indicate that quercetin has anticancer effects in
both in vitro and in vivo models of breast, lung, nasopharyngeal, kidney, colorectal,
prostate, pancreatic, and ovarian malignancies [6]. Through influencing the Wnt/β-catenin,
PI3K/Akt/mTOR, and MAPK/ERK pathways, quercetin promotes cell cycle arrest,
limiting cell proliferation, boosting apoptosis, altering autophagy, and lowering
angiogenesis and metastasis in cancer cells. Fruits, vegetables, and Chinese medicinal
herbs are the source of the flavonoid apigenin, which has been shown to have anticancer
activities against cancers of the breast, lung, liver, skin, blood, colon, prostate, pancreatic,
oral, and stomach [4]. Apigenin prevents cancer by influencing many signaling pathways
both in vivo and in vitro, including the Wnt/β-catenin, PI3K/Akt, NF-κB, MAPK/ERK,
and JAK/STAT pathways, resulting in the induction of autophagy, cell cycle arrest,
apoptosis (via the activation of both intrinsic and extrinsic pathways), a decrease in
migration and invasion, and an increase in the immune response. In vivo, in vitro, and
clinical studies, genistein—an additional phytochemical—isoflavone generated from
soybeans and soy products that has anticancer properties including inducing apoptosis, cell
cycle arrest, reducing metastasis, and inhibiting angiogenesis. In cancer cells, genistein
may control the NF-κB, PI3K/Akt, MAPK/ERK 1/2, and Wnt/β-catenin pathways. In
clinical trials, genistein was tested as a cancer treatment either alone or in conjunction with
additional chemotherapy drugs. According to research, cancer cells may become resistant
to the anticancer medications that are routinely prescribed in clinics, a significant clinical
challenge to the successful treatment of cancer patients. Polo-like kinase 1 (Plk1) has been
demonstrated to be involved in chemoresistance; hence, medicines that target Plk1 may be
able to lessen or completely eradicate cancer cells' ability to resist anticancer medications.
In this instance, genistein, a Plk1 inhibitor, was studied in phase II clinical trials and shown
to downregulate MDR in patients with prostate cancer (ClinicalTrials.gov:
NCT01126879). Shin et al. also showed that in paclitaxel-resistant prostate cancer cells,
genistein (a Plk1 inhibitor) decreased the expression of MDR1 and MRP1, which are key

components of chemoresistance. Green tea contains a polyphenolic flavonoid called

epigallocatechin-3-gallate (EGCG), which has anticancer properties by causing cell cycle
arrest, apoptosis, and inhibition of cancer cell migration, angiogenesis, and proliferation
[7]. EGCG has been shown in several preclinical investigations to alter a variety of
oncogenic pathways and prevent the development of tumors. To confirm the dose,
anticancer activity, and safety profile of EGCG in prostate, bladder, head and neck, breast,
ovarian, and lung cancer, several human clinical trials have been completed or are now
underway. IThe trial's breast cancer participants had undergone radiation following a
mastectomy. Additionally, for two weeks following the conclusion of radiation therapy,
EGCG solution was sprayed on the radiation region starting at the onset of Grade 1
radiation dermatitis. The EGCG concentration increased at seven levels, including three to
six individuals in each, from 40 to 660 μmol/liter. One patient experienced acute skin
redness as a result of receiving 140 μmol/liter of EGCG therapy. Other individuals in this
level, however, did not have EGCG toxicity. As a result, they concluded from this trial that
treating radiation dermatitis in patients with breast cancer following a mastectomy with
topical EGCG treatment was feasible and well tolerated [8].

Fig 3: Proposed mechanism of anticancer activities of phytochemicals.
2.2. Carotenoids
A class of naturally occurring pigments found in many fruits and vegetables are called
carotenoids. The body of research indicating carotenoids may have a role in carcinogenesis
has been increasing over the last twenty years. Numerous carotenoids, including lycopene,
β-carotene, and all-trans retinoic acid (ATRA), are significantly contributing to tumor
prevention and decrease in both in vitro and in vivo investigations. According to studies,
M2 macrophase and activated fibroblast are two important elements that control the
proliferation and survival of cancer cells in the tumor microenvironment. According to Lee
et al., phorbol-12-myristate-13-acetate and IL-4 were used to create the M2 macrophage
phenotype in U937 cells, whereas TGF-β1 was used to induce the activated fibroblast
phenotype in CCD-18Co cells. They discovered that in preclinical and clinical models,
phytochemicals with strong anticancer characteristics, including phenolics, carotenoids,
terpenoids, alkaloids, glycosides, and organosulfur compounds, were treated with β-
carotene. Preclinical and clinical research have demonstrated the strong anticancer effects
of ATRA, a metabolite of vitamin A. ATRA is a very promising compound that causes
cancer cells to undergo apoptosis and is known to decrease growth. In a recent study,
Kocher et al. reported that patients (n = 27) with advanced, incurable pancreatic ductal
adenocarcinoma received treatment with ATRA (45 mg/m2 orally, days 1–15/cycle)

combined with a dosage of gemcitabine-nab-paclitaxel that was authorized by the FDA and
the European Medicines Agency. Researchers discovered that using gemcitabine, nab-
paclitaxel, and ATRA as a pancreatic stromal-targeting drug to inhibit pancreatic ductal
adenocarcinoma is safe and well-tolerated for patients (ClinicalTrials.gov: NCT03307148)
[9]. A non-provitamin A carotenoid found in yellow and red fruits and plants, lycopene
effectively inhibits the growth and spread of cancer by inducing apoptosis.
Table 1. Phytochemicals that exhibit potent anticancer properties and their
mechanism of action in preclinical and clinical models.
S. Nanotechno Size Route Clinical /In-vivo results Refere
no logy tool of nce
adminis
tration
Phenolics based nanomedicine
Curcumin
1. Curcumin/ 27.3 Intrave Showed cytotoxicity to C-26 colon cancer 2

MPEG-PCL ± 1.3 nous cells and efficiently inhibited tumor growth
micelles nm through inhibiting angiogenesis in in vivo
mice model.
2. Lipocurc™ 117 Intrave Phase1 dose-escalation study on the safety, 6
(Liposomal nm nous tolerability and activity of Lipocurc ™ in
curcumin) patients with locally advanced or metastatic
cancer reported that 300 mg/m2 liposomal
curcumin over 6 h was the maximum
tolerated dose in patients. Significant tumor
marker responses and transient clinical
benefit were observed in two patients.
3. Curcumin 170 Intrave Enhanced anti-tumor activity on C26 colon 2

and nm nous carcinoma in vivo by enhancing intracellular
doxorubicin accumulation of both the drugs at the tumor
co-loaded site through passive targeting
PEGylated
liposomes
4. Curcumin 200 Intrave 5-10-fold more effective than free curcumin 4

loaded solid nm nous to overcome the Pgp-mediated
lipid chemoresistance in MDA-MB-231 human

nanoparticl triple negative breast cancer cell line and in

es (SLNPs) vivo mice model.
Epigallocatechin gallate (EGCG)
1. EGCG Oral High cytotoxicity towards MBT-2 bladder 7

adsorbed on Intra- cancer cells. Significant reduction in tumor
nanogold tumora volume in bladder cancer xenograft model.
particles l
(pNG)
S. Nanotechno Size Route of Clinical /In-vivo results Refere

no logy tool administ nce
ration
2. EGCG-pNG 64.7 Intratu Demonstrated 4.91 times high cytotoxicity 3

(EGCG/pN nm moral towards B16F10 murine melanoma cells in
G 50µM: comparison to native EGCG and were also
2.5 ppm) 1.66 times more potent than EGCG for
inhibition of tumor growth in a murine
melanoma model.
3. Methoxy 155. Peritu Significantly inhibited tumor growth in

poly 3± moral female BALB/c mice xenograft model.
(ethylene 3.2 TUNEL assay showed more occurrence of
glycol)-PLA nm apoptotic cells in MPEG-PLA-Qu treated
nanoparticl tumors compared to free quercetin at similar
es dose.
encapsulati
ng
quercetin
4. Quercetin 15.4 Perior Approximately 1.5-fold higher tumor 6
loaded – al growth inhibition than free quercetin control
DSPE- 18.5 group in lung cancer female Rag-2M mice
PEG2000 nm xenograft model.

S. Nanotechnolog size Route of Clinical /In-vivo results Reference

no y tool administratio
n
1. Dual drug 105 Intravenous +Preclinical tests in a nude mice 9

loaded ± 0.4 tumor xenograft model revealed
liposomal nm greater antitumoral activity via
formulation of passive targeting of liposomes.
5-Fluorouracil
and apigenin
2. Aptamer- 226 Intravenous +Distinctively enhanced 4

conjugated nm bioavailability of apigenin in
apigenin- colon tissue and plasma.
loaded Reduced tumor size
nanoparticle significantly in swiss albino
(apt-ANP) mice colorectal carcinoma
model.
3. Apigenin 101. Oral plus Potent inhibition of skin 9

loaded PLGA 3 ± Topical tumorigenesis in
nanoparticles 0.00 benzo[a]pyrene and
4 nm ultraviolet-B induced skin
cancer of mice based on the
suppression of epidermal
hyperplasia as well as on the
modulation of biomarkers of
cell proliferation, intracellular
ROS accumulation and
mitochondrial apoptosis.

2.3. Terpenoids
Terpenoids are structurally varied families of natural chemicals that have garnered
significant attention as anticancer agents and have a wide variety of medicinal uses. In both
in vitro and in vivo models, a number of terpenoids, including nimbolide, ursolic acid,
withaferin A, etc., exhibit potential anticancer properties. Nimbolide is a limnoid triterpene
that is extracted from Azadirachta indica leaves and flowers. According to recent research,
nimbolide inhibits the growth of various solid tumors, including pancreatic, breast, oral,
and non-small cell lung cancer, in both in vitro and in vivo systems. It also prevents EMT,
migration, and invasion. These effects are mediated by inducing ROS-mediated apoptosis
and inhibiting proliferation by downregulating PI3K/AKT/mTOR and ERK signaling [10].
Similar to this, the triterpenoid ursolic acid, which is obtained from fruits, vegetables, and
medicinal plants, has potent anticancer properties. It does this by preventing the growth,
migration, and apoptosis of various cancer cells while having no negative effects on healthy
cells. Furthermore, research conducted in vivo demonstrated that ursolic acid had
noteworthy anticancer properties and did not cause any harm to mice []. Withaniasomnifera
leaves and roots are the source of withaferin A, a terpenoid that effectively inhibits the
growth of cancer cells in vitro and in xenograft tumor models, including glioblastoma,
neuroblastoma, multiple myeloma, leukemia, breast, colon, ovarian, and head and neck
cancer cells [11].

Figure 4: Common routes of phytochemicals administration fromfoodandnano-carriers
2.4. Alkaloids
Alkaloids are naturally occurring substances derived from plants that have been separated
from medicinal plants and herbs. They have been shown to have anticancer and anti-
proliferative properties in a variety of in vitro and in vivo cancer models. Several alkaloids
such as vinca alkaloids (vinorelbine and vincristine) have already been successfully
attained in clinical trials, but others like berberine and piperine, etc. are under preclinical
investigations. Among them, vinblastine and vincristine are produced from Catharanthus
roseus and intensively explored as anticancer drugs. According to studies, the
aforementioned vinca alkaloids can be utilized in vivo and in vitro to treat diseases such as
leukemia, lymphoma, lung, breast, and Kaposi's sarcoma when combined with
chemotherapy drugs []. Since the 1960s, China has been using the natural alkaloid CBT-
01® (tetrandrine) as an antifibrotic medication. Recently, CBT-01®, an inhibitor of the P-
gp efflux pump in MDR cancer, advanced to the advanced stage of clinical trials. In clinical
trial phase I, CBT-01® was given in conjunction with paclitaxel and the favorable findings
obtained from this research were further encouraged for phase II/III testing][12].

2.5. Organosulfur compounds
Organosulfur compounds, such as sulforaphane, which is derived from cruciferous

vegetables, have been extensively studied recently as anticancer agents in both in vitro and
in vivo models. Sulforaphane exhibits chemopreventive activity, cell cycle arrest, and
induces apoptosis by modulating Nrf2-Keap1 and NF-κBsignaling pathways. Recent
studies have reported that sulforaphane affects epigenetic genes that primarily regulate
tumor initiation and progression. In this regard, Castro et al. have shown that sulforaphane
significantly inhibited cell proliferation and mammosphere formation in triple negative
breast cancer stem-like cells in both in vitro and in vivo by regulating [13].
3. Phytochemical based nanomedicine for cancer treatment

Preclinical research on many cancer types has demonstrated the potential of
phytochemicals as an anticancer drug; nevertheless, its clinical applicability is limited by
its inherent characteristics, which include poor aqueous solubility, low bioavailability, poor
stability, and poor circulation time. Consequently, a great deal of effort has been focused
on developing phytochemical-based nanoformulation, or phytonanomedicine, which can
improve the aqueous solubility, extended pharmacokinetics with higher bioavailability (a
steady state therapeutic level of phytochemicals over an extended period of time), and
targeted tumor uptake with higher cellular uptake in order to mitigate the intrinsic
properties of phytochemicals. Some of the phytonanomedicines that are FDA-approved or
being studied in clinical trials for the treatment of cancer are available here. A number of
extremely effective nanocarriers, including lipid- and polymer-based and inorganic
nanoparticles, have been employed extensively to boost the anti-cancer therapeutic
effectiveness of phytochemicals. Due to improved phytochemical transport to the tumor
site through passive or active targeting, recent advances in therapeutic efficiency through
the use of nanomedicines have drawn a lot of attention [14]. We have also spoken about

the function and mode of action of several phytonanomedicines for tumor targeting.
Phytonanomedicine provides improved solubility, cellular absorption, drug internalization,
dispersion in tumor tissue, less toxicity, and less non-specific binding in addition to
protecting encapsulated phytochemicals from degradation. Additionally, by triggering
apoptosis, cell cycle arrest, blocking EMT, metastasis, angiogenesis, drug resistance, and
controlling autophagy and epigenetic alterations, this enhances the anticancer effectiveness
of phytonanomedicine [15].
3.1. Phenolics based nanomedicine
Plant secondary metabolites known as polyphenols are widely distributed and have
attracted a lot of scientific interest because of their special physiochemical characteristics.
The in-vitro and in-vivo antioxidant activity of these compounds, which primarily explains
their anticancer effect, is attributed to their phenolic hydroxyl groups. Many phenolic-
based nanoparticle kinds have been developed in recent decades with the goal of improving
their biocompatibility, effectiveness, and adaptability. These phenolic nanomedicines
include a broad range of nanoformulations, including those based on lipids, polymers, and
inorganic substances. Here, we give a summary of latest advancements in cancer treatment
using phenolic-based nanomedicine. Although curcumin has demonstrated strong
anticancer properties, its limited absorption, low bioavailability, fast systemic clearance,
and high metabolism impede its practical use. Its aqueous solubility is a very low ~11
ng/ml. In addition, it degrades in an alkaline environment. Due to its limited lipid solubility
of 0.6 μg/ml, native curcumin has great promise in vitro but very little or no action in vivo.
Different kinds of curcumin nanoformulations have been created to get around these
restrictions. To investigate the safety, tolerability, and anti-tumor efficaciousness of
escalating liposomal curcumin (LipocurcTM) dosages in patients with metastatic
cancer. The highest acceptable dose of liposomal curcumin over a period of 6 hours was

reported in a phase I study including 32 patients. This dosage is indicated as a starting point
for anticancer studies. In a different investigation, Sesarman et al. found that co-loading
PEGylated liposomes with curcumin and doxorubicin improved anti-tumor action on C26
colon cancer in vivo by boosting intracellular accumulation of both medications at the
tumor site by passive targeting. Gou and colleagues created curcumin-loaded
monomethoxy poly (ethylene glycol) - poly (ε-caprolactone) (MPEG-PCL) micelles,
which had better pharmacokinetics in an in vivo setting since curcumin is a hydrophobic
medication. When administered intravenously, curcumin demonstrated cytotoxicity to C-
26 colon cancer cells when loaded into MPEG-PCL micelles. Excellent anti-cancer
efficacy has been shown by EGCG in both in vitro and in vivo models, as well as in a few
clinical and epidemiological investigations. Its poor bioavailability and stability have
prevented it from being used in clinical settings, despite its strong anticancer potential [16].
To get around these restrictions, EGCG has been created on a variety of nano delivery
platforms, including metallic, polymeric, gold, carbohydrate-based, and liposomal delivery
systems. Solid lipid nanoparticles (SLNPs) coupled with gastrin releasing peptide receptors
(GRPR), which are overexpressed in breast cancer, have been produced recently by
Radhakrishnan et al. It was discovered that, in comparison to free EGCG, peptide linked
EGCG SLNPs showed increased cytotoxicity in the mouse melanoma cell line B16F10 and
the human breast cancer cell line MDA-MB-231. Furthermore, as compared to an
equivalent dose of non-conjugated formulation or free EGCG, peptide-conjugated
nanoformulation demonstrated improved reduction in tumor volume in C57/BL6 mice
following intraperitoneal injection of 50 mg/kg. Additionally, hardly many liposomal
formulations for EGCG have been created. For the treatment of basal cell carcinoma (BCC)
in female nude mice, Fang et al. created liposomal formulations of EGCG and other
catechins to be administered topically and intratumorally. They came to the conclusion that
intra-tumoral injection, which increased EGCG deposition in tumor tissues, was a more
efficient way to target cancer cells. The same group reported using EGCG liposomal

formulations for BCC therapy in vivo in another investigation. They found that by shielding
EGCG from oxidation and degradation, liposomal formulation considerably increased its
stability when compared to the medication in free form. Compared to the non-encapsulated
EGCG therapy at lower dosages, it also allowed for larger EGCG accumulation at the
tumor site and increased BCC cell death [17].
Because quercetin modulates many carcinogenic signaling pathways linked to

proliferation, migration, and apoptosis, it has great medical potential, particularly in the
treatment of cancer. However, its quick gastrointestinal digestion, limited oral
bioavailability, and poor water solubility limit its therapeutic potential. Thus, a variety of
nanoparticle forms have been created in an effort to enhance its pharmacokinetics (Table
3). In one such work, Rezaei et al. found that the hyperbranched polyamidoamine-b-
polyethylene glycol-modified Fe3O4 nanoparticles (Fe3O4@PAMAM-b-PEG-FA) loaded
with quercetin exhibited more cytotoxicity than quercetin alone. In addition, they noticed
that, in contrast to non-folate conjugated nanoparticles, the nanoparticles readily
aggregated in tumor tissue. Well-known for its anti-inflammatory and anti-cancer qualities
is the phytochemical apigenin. On the other hand, low oral bioavailability and water
solubility hinder its actions. Thus, in an effort to improve its solubility and bioavailability,
it has been created in several nanoformulations (Table 3). Sen et al. created liposomes
loaded with a dual medication combination of apigenin and 5-fluorouracil by a modified
thin film hydration process. In contrast to solo and combination free medicines, they found
that dual-drug liposomes were more cytotoxic to human colorectal cancer cell lines, HCT-
15 and HT-29. Additionally, it was discovered that the dual-drug liposomes were more
effective in preventing angiogenesis and cell division. The aforementioned findings were
in good agreement with preclinical research conducted in a tumor xenograft model on
naked mice, where nanoformulation was revealed to have superior anti-neoplastic and anti-
tumorigenic effects than individual and combination free medicines. The scientists came

to the conclusion that the liposomal drug-loaded nano-carrier's passive targeting was what
allowed for the enhanced chemotherapeutic potential in vivo.
A pleiotropic phytochemical with proven anti-cancer properties is resveratrol. Despite

having stronger anti-cancer properties, its clinical use is still far off because of a number
of issues, including low bioavailability, quick metabolism, brief half-life, and quick
elimination [91]. Meng et al. created PEGylated liposomes loaded with both paclitaxel and
resveratrol in this setting, and they found that the liposomes significantly cytotoxicated the
cancer cell line MCF-7/Adr. Additionally, they discovered that, in contrast to liposomes
that were loaded with a single medication, such as paclitaxel and resveratrol, these
liposomes significantly reduced drug resistance in tumor-bearing animals [18].
Fig5. Targeting inflammatory signaling pathways by phytochemicals and small molecules

3.2. Carotenoids based nanomedicine

Numerous epidemiological studies have demonstrated the potential anticarcinogenic
properties of carotenoids, demonstrating an inverse relationship between cancer risk and
the consumption of green and yellow fruits and vegetables. However, this class of
phytochemical also has low bioavailability and poor water solubility. One such carotenoid
is beta-carotene (βC), which has good antitumor activity but is not well soluble in water,
has low oral bioavailability, is chemically unstable, etc. These factors prevent it from being
used in commercially viable products that aim to improve human health. To enhance the
biopharmaceutical properties of βC, Jain et al. created βC-loaded zein nanoparticles (βC-
NPs). They discovered that the maximum serum concentration (Cmax) increased by
approximately 2.3 times, the area under the curve (AUCtotal) increased by approximately
2.7 times, the half-life (t1/2) increased by approximately 1.5 times, and the mean residence
time (MRT) increased by approximately 1.5 times. These findings suggest a significant
increase in the oral bioavailability of βC following its incorporation into zein nanoparticles.
Furthermore, they found that in a rat model of breast cancer, the aforementioned
nanoparticles dramatically reduced the hepatotoxicity associated with methotrexate (MTX)
and enhanced its anti-tumor activity.
Of all the carotenoids, lycopene has the highest capacity to quench singlet oxygen, which
gives it strong antioxidant and anticarcinogenic properties. However, it also has low
bioavailability and water solubility. Jain et al. produced lycopene loaded whey protein
isolate nanoparticles (LYC-WPI-NPs) to improve its pharmacokinetics. By regulating the
release from the nanoformulation and promoting its absorption through lymphatic routes,
LYC-WPI-NPs improved the oral bioavailability of lycopene. Additionally, NPs were
found to be more effective than natural lycopene in reducing tumor development and
increasing survival rate in an animal model of breast cancer, according to in vivo studies.
[19]

Fig 6: Illustration of versatile drug delivery vehicles for anticancer phytochemicals and
targeting strategies of phytonanomedicine for complete tumor regression.
3.3. Terpenoids based nanomedicine
Another carotenoid with strong anti-cancer potential is All-trans Retinoic Acid (ATRA),
yet its pharmacokinetics are not well-established. Han et al. conducted a study whereby
they created gold nanoparticles coated with PEGylated polyethylenimine for the purpose
of co-delivering ATRA and siRNA that targets heat shock protein 47 (HSP47). They
noticed that the extracellular matrix (ECM) synthesis was decreased both in vitro and in
vivo, and that the active pancreatic stellate cells (PSCs) were changed into quiescent PSCs
via nanoformulation, which may be attributed to ATRA. In two desmoplastic pancreatic
tumor models, they successfully stopped the growth of the tumor. The biggest family of
phytochemicals, terpenoids, have a great deal of promise as lead molecules in drug
development. Many terpenoids exhibit strong anti-cancer effects by blocking the growth

and spread of cancer cells as well as a variety of other mechanisms [7]. Terpenoid ursolic
acid (UA) has strong anti-cancer properties, but like other phytochemicals, it has poor
water solubility, which results in limited bioavailability, a short half-life, and poor oral
medication absorption in the body. Numerous nanoformulations have been created to
improve its therapeutic benefits and get around its pharmacological restrictions. Zhou et al.
created one such nanoformulation by contrasting polymeric micelles that have a propensity
to self-assemble and form the distinctive core-shell structure, which consists of a
hydrophilic corona outside and a hydrophobic inner core, using amphiphilic block
copolymers. Another terpenoid produced from Azadirachta indica, nimbolide, has attracted
a lot of interest in the last 10 years due to its strong and versatile anti-cancer properties.
Recently, a nimbolide-encapsulated PLGA nanoformulation was created, and both an in
vitro and an in-silico model were used to assess the therapeutic effectiveness of the
material. This work has shown that, in comparison to native nimbolide, nimbolide
nanoparticles significantly suppress proliferative activity and trigger the Mesenchymal-to-
Epithelial Transition (MET) by combined inhibition of AKT and mTOR signaling.
Additionally, induction of apoptosis, chemosensitization, and loss of tumor-initiating
potential were seen in pancreatic CSCs with MET activation [20].

Fig.7 Schematic representation illustrating the mechanism of phytochemicals-based

nanomedicine for cancer therapy.
3.4. Alkaloids based nanomedicine
Numerous screens for the identification of anticancer medicines have demonstrated the
richness of alkaloids, which are secondary metabolites of plants and a rich source of
effective antiproliferative and anticancer agents. Vinblastine, vindesine, vinorelbine, and
vincristine are examples of alkaloids that have shown promise as anticancer medications
in clinical settings. A number of alkaloids have low bioavailability and water solubility,
similar to other phytochemicals. Clinics utilize vincristine, a vinca alkaloid, to treat small
cell lung cancer, acute myeloid leukemia, neuroblastoma, and Hodgkin's disease; but,
because to its limited absorption, greater dosages are required, which has a number of
negative effects. In order to avoid these adverse effects, a nanoformulation known as
Marqibo (liposomal non-PEGylated nanoparticle encapsulating vincristine sulfate) was

created, and the FDA has authorized it for the treatment of Philadelphia chromosome-
negative lymphoblastic leukemia. [21]
Although berberine has strong anticancer effects and helps prevent cancer from spreading,
its short plasma half-life makes it less effective as a pharmaceutical agent because of its
low bioavailability at the tumor site [102]. Parhi et al. created one such nanoformulation in
which berbamine was encapsulated in lipid-based nanoparticles (NPs). In highly metastatic
cancer cell lines, the formulation was found to limit growth, proliferation, and metastasis
more than native berbamine did. Furthermore, in the C57BL/6 mouse model, NPs
demonstrated improved inhibition of primary B16F10 melanoma tumor development when
compared to free berbamine. Additionally, at a dosage that was somewhat cytotoxic, they
prevented the lung metastasis of B16F10 cells in vivo [22].
Another alkaloid that has attracted a lot of interest in the last 10 years is piperlongumine,
which possesses strong and targeted anti-cancer properties. However, because of its low
bioavailability and water solubility, its translation in clinical settings is hindered [103].
Table 3 lists the many nanoformulations that have been created to maximize its
pharmacokinetic prolife. One such formulation that has been created recently is total serum
nanoparticles (TSN-PL) loaded with piperlongumine. Compared to total serum
nanoparticles (TSN) loaded with paclitaxel and the therapeutically utilized combination of
gemcitabine and nano-PTX, these nanoparticles demonstrated greater cytotoxic activity in
two pancreatic cell lines. Furthermore, in the pancreatic xenograft model, (TSN-PL)
demonstrated strong antitumor activity. In comparison to natural piperlongumine, another
piperlongumine-loaded PLGA nanoparticle has been produced that greatly suppresses
breast cancer stem-like cells by inhibiting STAT3 signalling [23].

3.5. Glycoside based nanomedicine

Plant secondary metabolites known as glycosides have exceptional medicinal potential and
practical applications. Anthraquinone glycoside emodin inhibits the growth, invasion, and
metastasis of tumor cells, hence demonstrating anti-cancer effects. It exhibits cancer cell-
specific toxicity while protecting healthy cells. Despite having a high level of biological
activity, the inclusion of anthraquinone is thought to be the cause of its poor water
solubility, which hinders its clinical translation. Consequently, a number of
nanoformulations have been created in an effort to improve its pharmacokinetic
characteristics. To address this, Jiang et al. created emodin-loaded stearic acid-g-chitosan
oligosaccharide (CSO-SA/EMO) nanomicelles, which demonstrated increased
cytotoxicity when compared to free emodin in MGC803 and BGC823 gastric cancer cells.
Another glycoside with anti-cancer potential is thymoquinone, although it has poor oral
bioavailability and poor water solubility [108]. El-far et al. developed thymoquinone
PLGA nanoparticles (TQ-NPs) to improve the drug's water solubility in order to solve this
problem. Additionally, they discovered that using TQ-NPs in conjunction with doxorubicin
(DOX) greatly decreased both the amount of tumor in colon and breast cancer xenograft
models as well as the amount of cardiotoxicity caused by doxorubicin [14].
3.6. Organosulfur compounds-based nanomedicine
Because they induce carcinogen detoxification, reduce tumor cell growth, scavenge free
radicals, inhibit DNA adduct formation, induce cell cycle arrest, and induce apoptosis,
organosulfur compounds have good chemopreventive activity in cancer. The organosulfur
chemical sulforaphane has garnered significant interest lately due to its potential anticancer
effects [4]. Despite having an 82% oral bioavailability. Its use in the pharmaceutical
industry is limited due to its instability and susceptibility to heat, oxygen, and alkaline
conditions. A limited number of nanoformulations have been created to address the

aforementioned problems and improve its anti-cancer characteristics. To address this,

Mangla et al. created nanostructured lipid carriers (NLCs) loaded with tamoxifen (TAM)
and sulforaphane (SFN). These NLCs improved intestinal permeability and raised the oral
bioavailability of TAM and SFN by 5.2 and 4.8 times, respectively. Sulforaphane was
found to lessen TAM-associated toxicity in in vivo experiments. Huang et al. demonstrated
in different research that PLGA/hyaluronic acid (PLGA-b-HA) nanoparticles co-loaded
with docetaxel and sulforaphane effectively triggered cytotoxicity and decreased the
population of breast CSCs by downregulating β-catenin expression in vitro [24]
4. NANO-DRUG DELIVERY OF PHYTOCHEMICALS AGAINST

DIFFERENT TYPES OF CANCER:
There is no one cure for cancer, even with the wide range of cutting-edge treatments
accessible to patients. This encourages scientists to carry out further research on anticancer
medications and efficient delivery systems. Above this, a vast array of phytochemicals have
been demonstrated to have anticancer properties against various cancer types. Scientists
use nanotechnology, a freshly invented tool, to improve their minor backlogs. This
technique is able to work with matter that has at least one dimension measured in
nanometers. Numerous scientific domains, such as organic chemistry, surface science,
semiconductor physics, molecular biology, microfabrication, medicine, and biotechnology,
have benefited from the comprehensive character of nanotechnology. These applications
virtually always require the use of nanomaterials. Specifically, the nanomaterial is utilized
to construct nano-systems, which range in size from 1 to 100 nm and are used as transport
modules to deliver drugs or other substances in nanomedicine. Another name for this
nanosystem is a nanocarrier. Various types of nanocarriers are employed for the delivery
of drugs in fatal illnesses like cancer. Since nanocarriers are essential to both vision and

treatment, their participation in cancer is unavoidable. This is because it is simple to build

these nanocarriers to specifically target cancer cells while excluding normal cells .Carbon
nanotubes, liposomes, dendrimers, nanoshells, nanocages, and micelles are a few of the
primary nanocarriers employed in cancer research.The micelle is a collection of molecules
that has a hydrophilic tail area in the center and an outside hydrophobic head region. The
dendrimer is a star-shaped, highly branching macromolecule that has symmetrical
dimensions around its center at the nanoscale . Similar to a micelle, a liposome is a
spherical vesicle that forms a lipid bilayer by the arrangement of hydrophilic and
hydrophobic groups. However, the components that make up the nanocomposite are
multiphase, with at least one of them being in nanoscale [9].Drugs that are both
hydrophobic and hydrophilic can be delivered throughout the body with the help of these
nanocarriers. Given that water makes up the majority of the human body, the ability of the
nanocarrier to transport drugs specifically to the intended location is a significant
therapeutic efficiency . The medications carried are detrimental to the body's natural cells.
The reduced size and site-specificity of the nanocarriers allow them to carefully transport
the medications to the intended location. The four targeting features of a nanocarrier are
temperature sensitivity, pH sensitivity, active, and passive. The delivery of the nanocarrier
is targeted by pH and temperature variations in cancer cells; however, it may also be
covered with coating materials such as PEG to correlate with the duration of circulation. A
cell-specific ligand is supplied to the nanocarrier in the event of active targeting [16].
Chemotherapy for cancer patients is the primary use of these nanocarriers. The
hydrophobic nature of anticancer medications, the greater temperature, the lower pH, and
the possible requirement for particular target ability might all be contributing factors . The
increased permeability and retention (EPR) effect of nanocarriers is a significant benefit in
the treatment of cancer. During angiogenesis, or the creation of new blood vessels, it
includes the aggregation of macromolecules or nanoparticles during their extravasation in
the tumor tissue. The use of nanotechnology in cancer treatment is unquestionable due to

the aforementioned criteria . Nonetheless, the important research on the administration of

different phytochemicals by nanomedicine against major tumors is included in the
following subsections [25].
4.1. LUNG CANCER:
Pulmonary carcinoma, another name for lung cancer, is typified by unchecked cell
proliferation in the lungs. It is among the leading causes of cancer-related mortality in both
genders. Small-cell lung carcinoma, non-small-cell lung carcinoma, and lung carcinoid
tumor are the three main forms of lung cancer . It has been discovered that the small-
molecule polyphenol honokiol has a preventive impact on lung cancer. Based on the
poly(ἐ-caprolactone)-poly(ethylene glycol)-poly(ἐ-caprolactone) copolymer, the honokiol
was added to the micelles (PCEC). The resulting honokiol-loaded PCEC micelles were
around 61 nm in size. But when the temperature rose, the particle size shrank, making it
better suited for blood injection as a medication delivery method. Comparable dose-
dependent antiprolierative effects were observed by the free and loaded honokiol micelles
on the human lung adenocarcinoma cells A549. In the in vitro setting, the produced
micelles displayed a standard two-phase-release characteristic . Using a non-small cell lung
carcinoma cell line, Merlin et al. investigated the anticancer potential of poly-d,l-lactide-
coglycolide (PLGA) nanoparticles loaded with the phenolic phytonutrient ferulic acid. The
double emulsion approach was used to create the ferulic acid loaded PLGA nanoparticles,
which had a particle size of around 483 nm. Ferulic acid-loaded PLGA nanoparticles and
ferulic acid alone were both used to treat NCI-H460 cells. The outcomes showed that the
ferulic acid-loaded nanoparticle had a stronger anticancer impact. Additionally, increased
reactive oxygen species (ROS) levels, DNA damage, modified mitochondrial
transmembrane potential (MMP), and apoptotic morphological alterations were all
implicated in the nanoparticle-induced cytotoxicity. These elements imply that FERULAC
acid-loaded PLGA nanoparticles are a viable treatment option for lung cancer [5].

Nanoparticles were used to deliver the new anticancer medication β-Lapachone (β-lap),
which is bioactivated by NAD(P)H:quinone oxidoreductase-1 (NQO1), an enzyme that has
been identified to be selectively overexpressed in non-small cell lung cancer (NSCLC).
Using a film sonication process, the β-Lap was integrated into poly(ethylene glycol)-co-
poly(D,L-lactic acid) (PEG-PLA) polymer microcapsules. The prepared micelles were
around 30 nm in size and included a core-shell design. Mice with subcutaneous A549 lung
tumors received an injection of β-Lap microgels via the caudal or tail veins, and the
biodistribution was examined. The findings indicated that there was an increase in β-Lap
accumulation and extended blood circulation. Moreover, PARP-1 hyperactivation and
DNA damage were caused by the in vitro delivery of micelles LLC malignancies [17].
The fundamental idea behind the production of polymeric micelles. Zhang and colleagues
investigated the synergistic impact of paclitaxel and β-Lapachone micelles on A549 non-
small cell lung cancer (NSCLC) cells. The PEG-PLA micelles exhibited an encapsulation
efficiency of 100.7 ± 2.2% and a drug loading efficiency of around 100.3 ± 3.0% when β-
lapachone and paclitaxel were co-encapsulated. The combined β-Lapachone and Paclitaxel
micelle was seen to have a higher enhanced effect compared to the individual β-Lapachone
and Paclitaxel micelle. The combined micelle had a noteworthy antiproliferative impact at
an IC50 of 0.16 μM, whereas the respective IC50s for the β-Lapachone and Paclitaxel
micelles were 4.5 μM and 0.32 μM, respectively. Therefore, it was anticipated that both
substances would work in concert to prevent lung cancer. [26]
The flavonoid luteolin was tested against H292 lung cancer cells after being encapsulated
in a nanocarrier. The polymeric basis of the nanocarrier consisted of polyethylene glycol
(PLA-PEG) and polylactic acid. The average size of the generated nanoparticle was around
115 nm. Both free and loaded luteolin exhibited antiproliferative effect against H292 cells.
The fact that the IC50 of nanoluteolin was notably lower than that of free luteolin indicates
that the nanosystem enhances bioavailability. Similar outcomes in the colony formation
experiment were noted [8].

Fig8: Lung Cancer.

4.2. Breast Cancer
Breast cancer is a malignant tumor that mostly affects women. It originates in the breast
cells. Women between the ages of 40 and 70 are most vulnerable to breast cancer. It is the
second most prevalent cause of mortality globally and can quickly spread to other sections
of the body if treatment is not received. Lung cancer is frequently discovered to be caused
in many cases by the metastasis of breast cancer . The MCF-7 and MDA-MB-453 breast
cancer cell lines received the diarylheptanoid chemical curcumin via a biologically
produced nanoparticle, and the molecule's therapeutic benefits were noted. Using the
capillary-microdot approach, the nanoparticle was created from silk fibrin polymer alone
or covalently mixed with chitosan (SFCS) polymers. Every produced nanoparticle weighed
less than 100 nm and was examined using cell lines from breast cancer. Remarkably, in
both breast cancer cell lines, silk fibroin exhibited more absorption and effectiveness than
SFCS nanoparticle. When compared to the SFCS nanoparticle, the silk fibroin nanoparticle
reduced the cell viability of both breast cancer cell lines . Sebak et al. synthesized a
noscapine-targeted nanoparticle using human serum albumin (HSA) and assessed the effect
on SK-BR-3 breast cancer cells. Noscapine is an alkaloid of the benzylisoquinoline class
that is extracted from plants of the poppy family. The HAS nanoparticle and noscapine-
loaded nanoparticle were created using the pH-coacervation process. The size of the

nanoparticles varied from 150 to 300 nm, and their drug loading effectiveness was between
85 and 96%. Following the nanoparticle's first burst, a prolonged drug release discharged
around 10% of the drug. Both the HAS and the noscapine-loaded HAS nanoparticles were
used to treat the SK-BR-3 breast cancer cells. The vitality of breast cancer cells was
decreased by both drug-loaded and drug-free nanoparticles, although the impact of
noscapine-loaded nanoparticles was noticeably greater when compared [27].
Fig9:Phytochemicals for the treatment of breast cancer.
A pH-sensitive liposomes was used to deliver ursolic acid, a triterpenoid compound to the
MDA-MB-231 breast cancer cells.

The pH-sensitive liposomes was prepared by the lipid hydration method. The liposomes
had a mean
diameter of 191.1 ± 6.4 nm and a long term stability. The liposomes were predominantly
of vesicle size less than 100 nm promising good drug loading efficiency. The MDA-MB
cells were exposed to the pH-sensitive ursolic acid liposomes. The IC50 value of the ursolic
acid liposomes were much lower than the free ursolic acid indicating the improved
anticancer activity of the nano-liposomes . Odeh et al., prepared two different kinds of
liposomes, one thymoquinone-loaded liposomes (TQ-LP) and other thymoquinone loaded
in liposomes modified with Triton X-100 (XLP).Thymoquinone is a phytochemical
obtained from herbs that has strong chemopreventive properties and is hydrophobic by
nature. The diameter of both nanoparticles was around 100 nm, and for TQ-LP and XLP,
respectively, the entrapment effectiveness was above 90% and 49.6%. They were
investigated biologically both with fibroblasts and with MCF-7 cancer cells. However, the
TQLP exhibited very little toxicity on normal periodontal ligament fibroblasts and
successfully suppressed the growth of MCF-7 cells [23].

Fig10: Phytochemical in Colorectal cancer therapy.
It was shown that silibinin and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)
had an inhibiting impact on the cells that cause breast cancer. The lipid nanoparticles
loaded with silibinin and containing phosphatidylcholine and TPGS were created using a
thin-film hydrolysis technique. The encapsulation effectiveness of silibinin in the
nanoparticle was 98.63±0.30%, with an average size of 45 nm. According to cellular uptake
experiments, the drug concentration in MDA-MB-231 breast cancer cells was almost twice
as high following a 24-hour treatment with silibinin nanoparticles as it was following a
treatment with free silibinin. In the tests for cell viability, invasion, and migration,
corresponding outcomes were noted. Nevertheless, at a dose of 20 µg/mL, the silicin-
loaded nanoparticle significantly reduced the invasive and migrating potential of MDA-

MB-231 cells via downregulating MMP-9 and Snail pathways. As a result, it was
determined that the TPGS nanoparticle loaded with silibinin was a unique therapeutic agent
against breast cancer . Gallic acid, a phenolic phytochemical, was delivered using
dendrimers to inhibit breast cancer cells by Sharma et al. The Polyamidoamine (PAMAM)
dendrimers were assembled utilizing Tomalia's divergent growth methodology. For the
gallic acid that was placed into them, the dendrimers offered a high degree of surface
functionality and adaptability. The MCF-7 human breast cancer cells were used to test the
cytotoxicity of the gallic acid-loaded PAMAM nanoparticle. Gallic acid, gallic acid-loaded
PAMAM nanoparticles, and PAMAM dendrimer were used to treat MCF-7 cells. The
gallic acid-loaded PAMAM nanoparticles exhibited a synergistic antiproliferative impact
on MCF-7 cell growth, as demonstrated by the IC50 values [28].
4.3. Colorectal cancer
Colon or rectal cancer is referred to as colorectal cancer. According to the American Cancer
Society, colorectal cancer is the third most frequent kind of cancer in the US, accounting
for 50,310 cancer-related deaths and 136,830 new cases in 2016. Because our food has
direct touch with the intestinal epithelial cells, it is more vulnerable to it . Triptolide and
triptolide-loaded polymeric micelles were shown to be cytotoxic to HT29 human
adenocarcinoma cells, according to Zheng et al. Purified from the Chinese plant
Tripterygium wilfordii, triptolide is a diterpenoid tri-epoxide with anticancer properties,
although it also has certain adverse effects.Using a solvent evaporation technique, the
methoxypoly(ethylene glycol)-poly lactic acid (MePEG-PLA) copolymer was used to
create the triptolide loaded polymeric micelles (TP-PM). Both TP-PM and free triptolide
exhibited dose- and time-dependent effects on HT-29 cells; however, at all doses and
incubation durations, TP-PM's inhibitory effects on the proliferation of tumor cells were
more pronounced. Furthermore, the HT29 cells that were incubated with triptolide and TP-
PM showed an increase in caspase 3/7 activity, which is indicative of apoptosis. The

greatest apoptosis index was seen after 48 hours of incubation with 10 ng/ml TP-PM, at
6.96. As a result, TP was effectively transported by the polymeric micelles, which also
reduced its toxicity [29]. The biodegradable polymeric micelles was made up of the
monomethoxy poly (ethylene glycol) (MPEG) and poly (ἐ-caprolactone) (PCL) and loaded
with the honokiol by direct dissolution method assisted by ultrasonication. The average
particle size of obtained honokiol micelle was about 40nm and was treated to CT26 murine
colon carcinoma cells. The release rate of honokiol from the star-shaped polymeric micelles
was slower. Nevertheless, they exhibited antiproliferative effect against the CT26 cells in
a dose dependent fashion. Therefore, this star-shaped honokiol micelle may be used to
design a new dosage form [30].
Using human colon cancer HCT 116, Ravindran et al. investigated the anti-proliferative
properties of the bioactive phytochemical Nigella sativa, thymoquinone loaded in poly
(lactideco-glycolide) (TQ-PLGA) nanoparticles. The TQ-PLGA nanoparticle varied in size
from 150 to 200 nm and exhibited an encapsulation effectiveness of about 94%. When
applied to HCT116 cells, the TQPLGA nanoparticle demonstrated potent anticancer
properties.In addition, as compared to free thymoquinone, the nanoparticles demonstrated
activity in blocking NFkB activation and in reducing the production of cyclin D1, matrix
metalloproteinase (MMP)-9, and vascular endothelial growth factor (VEGF). Overall, the
findings show that TQ's anti-proliferative properties are enhanced when it is encapsulated
in nanoparticles [31]. A flavonoid with anticancer properties called luteolin (Lu) is
reportedly poorly soluble in water. The monomethoxy poly(ethylene glycol)-poly(ε-
caprolactone) (MPEG-PCL) micelles were utilized to administer it to C-26 colon
carcinoma cells in order to assess its anticancer properties and to assess its biodistribution
in vivo. Lu was enveloped by the MPEG-PCL micelles using a self-assembly technique.
The Lu/MPEGPCL micelle that was created had an encapsulation effectiveness of around
98.32% and a dimension of approximately 38.6 nm. It was also water soluble. The
pharmacokinetics of both free luteolin and Lu/MPEG-PCL micelles in rats indicate that the
usage of the latter resulted in a higher bioavailable concentration of luteolin. Furthermore,

at an IC50 of 12.62 ± 2.17 μg/mL, the Lu/MPEG-PCL micelles suppressed the proliferation
of C-26 colon cancer cells. Therefore, the study suggests that Lu be encapsulated into
MPEG-PCL micelles to produce an aqueous formulation of Lu that may have anticancer
properties [15].
Fig11 : Phytochemicals on colorectal cancer.
The benefits of self-carried curcumin nanoparticles for both in vitro and in vivo colon
cancer treatment were investigated by Zhang et al. Re-precipitation was used to create the
curcumin nanoparticles, which were subsequently ultrasonically attached to the
poly(maleic anhydride-alt-1-octadecene)-polyethylene glyco (C18PMH-PEG) surface to
increase the nanoparticles' biocompatibility. The nanoparticles showed a continuous
release behavior without an initial burst and exhibited loading and encapsulation
efficiencies of around 78.5% and 95.8%, respectively. The CT-26 colon cancer cells were
used to investigate the anticancer properties of the curcumin nanoparticles. The findings
demonstrated that the half-maximal inhibitory concentration (IC50) values of the free
curcumin (IC50 = 33.4 μM) were eight times lower in the curcumin nanoparticles (IC50 =
4.2 μM) than in the free curcumin. In vivo tests yielded similar outcomes. Tumor volumes
were 87% and 32%, respectively, in the CT-26 tumor-bearing nude mice following the
injection of curcumin and curcumin nanoparticles. This demonstrates that curcumin
nanoparticles have a greater impact on tumor cells than does free curcumin. When the
curcumin nanoparticle was examined for in vivo systemic toxicity, however, no negative
effects or toxicity were observed [32].
4.4. Skin cancer
Skin cancer is the most prevalent type of cancer worldwide, making up at least 40% of
cases. People with light skin are more susceptible to skin cancer. The cancer that develops
in melanoma, or cells containing melanocyte pigments, is the most deadly kind. It is
believed that one of the main causes of cancer is exposure to UV radiation from the sun
[10]. Poly (lactic-co-glycolide) nanoparticle-based delivery of the flavone apigenin against
melanoma was the subject of a thorough investigation by Das et al. The solvent
displacement approach was usedtocreate the poly (lactic-co-glycolide) nanoparticles
loaded with apigenin. The produced nanoparticle had a biphasic release profile, with a
three-day regulated release following an initial burst. The anti-proliferative impact of the
nanoparticle was investigated using HaCaT keratinocytes and A375 cutaneous melanoma.
When apigenin alone had an IC50 of 25 µM, it was found that the nanoparticle had a dose-
dependent impact on the A375 cells with an IC50 of 15 µM. On the other hand, normal
HaCaT cells did not experience any harmful effects. Double-stranded DNA (dsDNA)
intercalation, an increase in reactive oxygen species (ROS) buildup, and a decrease in
antioxidant enzyme activity were all brought on by the nanoparticle, which mediated death
through mitochondrial malfunction [33].

Fig12: Advanced phyto nanomedicine for treatment of skin carcinoma.
Subsequently, a study was conducted on the potential anti-carcinogenic properties of

poly(lactic glycolide) nanoparticles loaded with apigenin, against skin tumors generated in
mice by UVB and benzo(a)pyrene (BaP). After apigenin delivery, research was done on
the alterations in the mitochondria in addition to the anti-carcinogenic impact. The
apigenin-loaded nanoparticle performed better against UVB-BaP-induced melanoma,
which might be attributed to its quicker mobility and compact size. The frequency of
chromosomal abnormality and tissue damage were both reduced by the nanoparticles. In
addition, there was an increase in the production of reactive oxygen species (ROS),
swelling of the mitochondrial matrix, and modification of apoptotic markers as Apaf-1,
bax, bcl-2, and cyt c. Therefore, the poly (lactic-co-glycolide) nanoparticles loaded with
apigenin have the potential to be used therapeutically to treat skin cancer . Another study
examined the anticancer properties of combretastatin A-4, a dihydrostilbenoid, co-
encapsulated with doxorubicin, both in vitro and in vivo. The RGD-modified liposomes
were then filled with the chemicals. The disruptive agentcombretastatin A-4 enhanced the
integrin-overexpressing B16 and B16F10 melanoma cells' cellular absorption of
doxorubicin. Furthermore, compared to liposomes loaded with doxorubicin, the co-
encapsulated liposomes exhibited greater toxicity towards melanoma cells. Similarly, in
the male C57BL/6 mice that were implanted with melanoma B16F10 cells, the liposomes
loaded with combretastatin A-4 and doxorubicin showed the most effect on tumor
regression. As a result, the combretastatin A-4 encapsulation increased the doxorubicin's
effectiveness. Epigallocatechin 3-gallate (EGCG) encapsulated in chitosan nanoparticles
has been shown by Siddiqui et al. to have anti-proliferative and proapoptotic effects on
human melanoma cell development in both vitro and in vivo settings. To increase its
bioavailability to melanoma cells, the EGCG was loaded onto polylactic acid-polyethylene
glycol nanoparticles within the nanoparticle. We investigated the effects of both free and
loaded EGCG in Mel 928 cells. The outcomes demonstrated that this nano-formulation
outperformed native EGCG by an approximate 8-fold dosage advantage in terms of
inhibiting the proliferation of melanoma cells. Furthermore, when EGCG-loaded
nanoparticles were administered, the development of the Mel 928 tumor xenograft in the
mouse model was noted. This suppression involved alterations in the expression of the
proteins cyclins D1 and D3, as well as cell cycle phase arrest [34].

4.5. Prostate Cancer
Prostate cancer is caused by the formation of cancerous cells in the prostate gland, a male
reproductive organ. Medical terminology refers to the cancer as an adenocarcinoma since
it is developing in the glands. The American Cancer Society estimates that there will be
180,890 new cases of prostate cancer in 2016, which indicates that 1 in 7 American males
will receive a prostate cancer diagnosis .A biodegradable nanoparticle was used to transfer
the gallic acid ester derivative epigallocatechin 3-gallate (EGCG) to the prostate cancer
cells. Here, EGCG was coupled with ligands that target the prostate-specific membrane
antigen (PSMA) and the polylactic acid-polyethylene glycol polymeric profiles. The
PSMA targeting ligand was the pseudomimetic dipeptide N-[N-[(S)-1,3-
dicarboxypropyl]carbamoyl]-(S)-lysine (DCL). The impact of both targeted and
nontargeted nanoparticles on the LNCaP androgen-sensitive human prostate cancer cells'
ability to proliferate. Prostate cancer cells from PCa were subjected to both nanoparticle
experiments. The EGCG-loaded nanoparticle demonstrated growth inhibition that was both
highly effective and target-specific. In addition, it was discovered that the EGCG-loaded
nanoparticle had no effect in halting the growth of HUVECs. Consequently, it was shown
that the produced nanoparticles have specific toxicity against prostate cancer [35].
The increased targeting capacity of the folate-mediated EGCG bovine serum albumin
nanoparticles (FA-EGCG-BSANP) against PC-3 prostate cancer cells was assessed by Zu
et al. The nanoparticle had an entrapment efficacy of around 81.5% and a mean particle
size of approximately 200 nm. It was manufactured using the desolvation process. It was
discovered that the concentration-dependent targeting of the folate-mediated nanoparticle
to the PC-3 cells. The absorption of FAEGGCG-BSANP by PC-3 cells was 23.65 times
more than that of EGCG-BSANP. Because of FA-EGCG-BSANP, it was discovered that
the folate in the nanoparticle enhanced the lethality of PC-3 cells .

Fig13: Phyto nanomedicine to control skin cancer.

Another experiment was conducted wherein a nanocarrier was used to transfer gallate
EGCG to the prostate cancer cells, and the outcomes were documented. The nanocarrier,
composed of polylactic acid and polyethylene glycol (PLA-PEG), underwent both in vitro
and in vivo testing. When administered to PCa prostate cancer cells, the impact of nano-
trapped EGCG was ten times greater than that of free EGCG. The EGCG-loaded
nanoparticle's IC50 was found to be 3.74 μmol/L, and in the PCa cells, pro-apoptotic Bax
significantly increased while anti-apoptotic Bcl-2 decreased concurrently. Following the
injection of 22Rv1 cells into the mice, both free and loaded EGCG were administered. The
tumor size was greatly decreased, and the result was comparable to the in vitro settings
[36]. In addition to gallate, curcumin, a yellow polyphenol, was also investigated for
potential anticancer effects. Mukerjee and associates created a loaded nanoparticle with
curcumin and examined its anticancer properties property against the PC3, DU145, and
LNCaP prostate cancer cell lines. The poly (lactic-coglycolic acid) (PLGA) was loaded
with curcumin. emulsion solvent for solid, oil, and water to create nanospheres technique
of evaporation. Itwas discovered that the manufactured nanospheres feature a biphasic drug
release and a mean size of around 45 nm. in a way. The PLGA nanospheres coated with
curcumin were discovered to be more than the free curcumin's effectiveness. This was
represented in the inhibitory half-maximum. The curcumin IC50 loading The range of
PLGA nanospheres was 20 μM-22.5 μM, whereas the range of free curcumin was 32 μM–
34 μM. In addition, compared to free curcumin, the NF-κB function was significantly
suppressed by the curcumin-loaded PLGA nanospheres. An further investigation into the
anticancer properties of curcumin nanoemulsion in conjunction with resveratrol was
conducted, focusing on the natural phenol present in the nanoparticle. PTEN-CaP8 cancer
cells and PTEN-knockout animals with prostate cancer were given different liposome-
loaded nanoemulsions containing curcumin and resveratrol and administered together.
Studies conducted in vitro shown that curcumin and resveratrol together efficiently
inhibited cell proliferation and promoted apoptosis. Furthermore, in PTENCap8 cells that
had lost PTEN, the combination significantly suppressed the levels of p-Akt, AR, cyclin
D1, and mTOR proteins[37].
4.6. Ovarian Caner

When ovarian cells develop out of control, it can lead to ovarian cancer. Women who have
never given birth and those who have ovulated more frequently throughout their lives are
more susceptible to ovarian cancer. Statistics show that 14,240 women in the US alone will
lose their lives to ovarian cancer, with North America and Europe seeing higher rates of
ovarian cancer-related deaths than Asia and Africa . The ovarian cancer cells were treated
in a lab setting with a nanoparticle containing the small chemical polyphenol honokiol.The
monomethoxy poly(ethylene glycol)–poly(lactic acid) (MPEG–PLA) nanocarrier was

created using the ring-opening polymerization process, and the honokiol chemical was then
added to it using the solvent extraction method. The average particle size of the honokiol-
loaded MPEGPLA nanoparticle was around 80 nm, giving it a spherical shape. In the lab,
it was discovered that the nanoparticle released 53% of its charge in less than 24 hours. As
concentrations of the free honokiol and honokiol-loaded MPEG-PLA increased, the A2780
human ovarian cancer cells' viability reduced. Nonetheless, with an IC50 of 8.45µg/ml, the
honokiol-loaded MPEG-PLA nanoparticle may have reduced the proliferation of A2780
cells. This exceeded the impact of the free honokiol [32]. Yallapu et al. investigated the
anti-tumor properties of curcumin incorporated into poly(lactic-co-glycolide) (PLGA)
nanoparticles and their ability to treat cisplatin-resistant A2780CP ovarian cancer cells. In
the in vitro setting, it was discovered that the fabricated nanoparticles had an average size
of 560.4 nm and released curcumin in a steady and regulated manner. When compared to
the effects of free curcumin, the curcumin-loaded PLGA nanoparticle reduced the
proliferation of the A2780CP cells at an IC50 of around 13.9l M. The long-term impact
analysis revealed similar outcomes, with the PLGA nanoparticle laden with curcumin
reducing the colony's cancer cell count. These findings point to PLGA nanoparticles coated
with curcumin as one of the best therapeutic agents [26].

Fig 14: Phytochemical in ovarian cancer.
In recent years, researchers have investigated the anticancer effect and molecular
mechanism of resveratrol bovine serum albumin nanoparticles (RES-BSANP) on human
primary ovarian carcinoma cells that were subcutaneously implanted in nude mice. The
SKOV ovarian cancer cells were injected into the naked mice to create the tumor, and they
were also administered 200, 100, and 50 mg/kg RES-BSANP or 0.5 mL RES once a week.
According to the tumor progression observation, starting in the third week, RES-BSANP
effectively slowed the growth of carcinomas in nude mice, and the inhibition rate was much
greater than in animals receiving RES treatment. It was discovered that the RES-BSNAP
induced apoptosis by releasing cytochrome c, controlling caspase-3 and 9, and so
identifying the mitochondrial apoptotic pathway . The hydrophilic polymeric core of the
hydrophobic medication curcumin was used to transport it to the SKOV-3 ovarian cancer
cells. The hydrophilic polymeric core consisted of nanoparticles of poly(2-hydroxyethyl
methacrylate) [PHEMA]. Following the loading of the curcumin, the nanoparticle's size
was around 300 nm. According to the in vitro studies, the curcumin-loaded nanoparticle
exhibited superior tumor cell regression activity than curcumin that was free. Additionally,
they demonstrated a discernible decline in G0/G1 phase cells. When these nanosystems

delivering curcumin were investigated using an embryo model of zebrafish, they

demonstrated good biocompatibility [38].
4.7. Cervical Cancer

Cancer of the cervix, a portion of the uterus, is known as cervical cancer. Human
papillomavirus (HPV) infection is determined to be the cause of cervical cancer in 90% of
instances. It comes in at number four on the worldwide cancer death toll list for women.
But compared to invasive cervical cancer, cervical pre-cancers are identified considerably
more frequently . Sahu et al. conducted a fluorescence investigation on the curcumin-casein
micelle complex and its use as a drug nanocarrier to cancer cells. The curcumin was added
to the bovine casein micelles, resulting in micelles that were about spherical in form and
fewer than 200 nm in size. The hydrophobic interactions between the curcumin and casein
micelles resulted in the formation of these curcumin-micelles. We investigated the cellular
absorption and toxicity of free curcumin and curcumin-casein micelles using HeLa cervical
cancer cells. The green fluorescence released following the treatment demonstrated that the
casein micelles had enhanced the curcumin's absorption. There was an increase in cellular
absorption that was dependent on concentration. The cytotoxicity experiments yielded
similar results, with IC50 values of 14.85 and 12.69 μM for pure curcumin and the CM-
curcumin complex, respectively. This demonstrated that casein micelles functioned well as
a drug carrier . In order to deliver the yellow phytochemical curcumin to HeLa cancer cells,
Das et al. placed the phytochemical onto alginate-chitosan-pluronic composite
nanoparticles. Using ionotropic pre-gelation and polycationic cross-linking, the alginate,
chitosan, and pluronic were combined to generate the nanocomposite particles. This
pluronic was utilized to increase curcumin's solubility, as evidenced by the encapsulation
efficiency investigations. The average size of the nanoparticles was around 100 nm. The
HeLa cells exhibited a decent cellular uptake and a regulated release of the medication
from the nanoparticle. In addition, the composite nanoparticle loaded with curcumin at a
500 μg/mL dosage dramatically reduced the viability of HeLa cells [39].
Fig15:Phytochemicals on treatment of Cervical Cancer.
4.8. Liver cancer
Hepatic cancer, often known as liver cancer, is a kind of cancer that starts in the liver. It is
typically discovered by mistake and is mostly brought on by cirrhosis, which is brought on
by alcohol, hepatitis B, or hepatitis C. The American Cancer Society estimates that 39,230
new cases of liver cancer will be detected in 2016 . The impact of liposomal berberine, an
isoquinoline alkaloids form, on hepatoma was studied by Lin et al. The thin-film
hydration/extrusion process was used to create the berberine liposome, which contains 5%
mol of polyethenyl glycol (PEG). The HepG2 liver hepatocellular carcinoma cells were
exposed to berberine liposomes, which exhibited a 14% encapsulation efficiency. At 1.67
µg berberine/mL, the berberine liposome dramatically reduced the proliferation of HepG2
cells and, via a caspase/mitochondria-dependent mechanism, triggered apoptosis.
Additionally, the liposome was examined in vivo in mice with HepG2 tumors that were
not clothed. The outcomes demonstrated that the berberine liposomes successfully lowered

the weight and size of tumor development in addition to lowering the pace at which
berberine was eliminated from tissues and plasma. As a result, the research showed that
the liposome was an effective vehicle for berberine .However, HepG2 and Huh7 human
hepatocyte cells received the identical phytochemical in the form of a nanosuspension. The
nanosuspension was composed of D-α-tocopheryl polyethylene glycol 1000 succinate
(TPGS) and berberine phytochemical, with an average size of 73.1 ± 3.7 nm. At
concentrations of 8.1 and 4.7 μg/ml, the nanosuspension significantly affected the
proliferation of Huh7 and HepG2 cells, respectively. On the other hand, the proliferation
of hepatoma cells was suppressed by free berberine at concentrations of 18.3 and 6.5 μg/ml
(corresponding to HepG2 and Huh7 cells). In the in vivo study using mice having solid
tumors, the inhibition rate of berberine nanosuspensions was 63.7%, but that of free
berberine was just 41.4%. Consequently, the phytochemical's availability to cancer cells
has enhanced due to the nanosuspension [40].
Research was conducted to document the anti-cancer impact of a gambogic acid, which is
xanthonoid, loaded into lactoferrine nanoparticles. The gambogic acid-lactoferrin
nanoparticles (GL-NPs) were created using the nanoparticle albumin-bound (NAB)
technique. Lactoferrine is a cationic iron-binding glycoprotein. The gambogic acid from
the GL-NPs was well absorbed by the in situ intestinal perfusion, and the GL-NPs had a
mean size of around 150 nm and an encapsulation effectiveness of 7.2%. The gambogic
acid arginine solution and the GL-NPs had nearly the same antiproliferative impact on
HepG2 liver cancer cells. Aside from this, the GL-NPs inhibited the development of the
tumor and showed a high rate of inhibition when given orally to the S180 tumor mice. This
was almost 1.39 times more than the gambogic acid arginine solution's impact. The
preliminary path for the investigation of lactoferrine as an oral drug delivery vehicle has
also been cleared by these completed research projects . Zhai and colleagues synthesized
polymeric micelles loaded with apigenin and evaluated their antiproliferative potential
against HepG2 liver cancer cells. The Pluronic P123 and Solutol HS 15 polymeric micelles

have an average diameter of 16.9 nm. Their drug loading and entrapment efficiencies were
1.32% and 96.36%, respectively. With a prolonged drug release behavior, the polymeric
micelles supplied around 84% of the apigenin. The apigenin-loaded polymeric micelles
and free apigenin solution had IC50 values of 5.57 µg/mL and 20.19 µg/mL, respectively,
on HepG2 cells. The apigenin micelles dramatically inhibited the development of HepG2
cells at reduced amounts compared to the free apigenein, which could be explained by its
enhanced hydrophilicity [19].
When combined with gum Arabic, the diarylheptanoid molecule curcumin proved effective
against hepatoma cell lines. A highly polysaccharide material called Arabic gum is
employed to increase curcumin's solubility. The mean size of the self-assembled conjugates
was 270 nm, and they had a spherical shape. Tests revealed that the generated curcumin
conjugate was more stable and soluble in physiological pH. In addition, the conjugated
curcumin inhibited the proliferation of the HepG2 hepatocellular carcinoma cells. Owing
to the gum Arabic's galactose groups, they also demonstrated improved cell targeting
capabilities. Recently, resveratrol nanosuspensions were also made in addition to berberine
nanosuspensions[22]
High pressure homogenization was used in the production of the resveratrol
nanosuspension, which included poloxamer 188 and resveratrol. The nanosuspension was
assessed for its impact on HepG2 cells in addition to free resveratrol; its average size was
159 nm. Resveratrol decreased HepG2 cell growth with an IC50 of 2.91 μg/mL, according
to the MTT test data. Conversely, only at 7.13 μg/mL did free resveratrol have a
comparable impact. These findings thus point to resveratrol nanosuspension administration
as a potential tumor treatment strategy [42].

Fig 16: Liver cancer
4.9. Pancreatic cancer

Usually referred to as pancreatic adenocarcinoma, pancreatic cancer originates from cells
in the pancreas, a glandular organ located beneath the stomach. It is estimated to be the
seventh most prevalent cause of mortality, accounting for around 40,560 fatalities in 2016
alone. Obesity and tobacco use are typically to blame . The potential of the polyphenol
curcumin as an anticancer agent against pancreatic cancer has been investigated. Using
micellar aggregates of cross-linked and random copolymers of N-isopropylacrylamide
(NIPAAM), N-vinyl-2-pyrrolidone (VP) and poly(ethyleneglycol)monoacrylate (PEG-A),
the nanocurcumin or curcumin encapsulated nanoparticle was created. It was discovered
that the produced nanocurcumin was hydrophilic, dispersing easily in the aqueous media.
Nevertheless, curcumin and nanocurcumin were used to cure the MiaPaca pancreatic
cancer cell line. At 10 and 15 μM, respectively, they both markedly inhibited the
development of pancreatic cancer cells. Additionally, the nanocurcumin inhibited the
nuclear factor kappa B (NFκB) activation and downregulated the cytokines TNFα, IL-6,
and IL-8, which led to the induction of cellular death. As a result, it was discovered that
the nanocurcumin had greater solubility and all the characteristics of curcumin . Wei et al.
used cholesteryl-hyaluronic acid (CHA) nanogel to entrap the phytochemical curcumin as
an ester, which was then used for targeted administration to drug-resistant CD44-
expressing MiaPaca cancer cells. The spherical-shaped conjugated nanoparticle of
curcumin has a diameter of 20 nm. Therefore, it was determined that the oral delivery of

the curcumin-containing nanoparticle would result in a 2-5% loss. In addition, the

nanoparticle caused cancer cells to undergo apoptosis while reducing the expression of
biological targets for TNF-α, NF-κB, and COX-2, much like free curcumin does.
Furthermore, in the 4T1 mouse model injected with the MiaPaca cells, the tumor
development was suppressed by the curcumin-loaded nanoparticle up to a 13-fold increase.
Therefore, it is discovered that one of the best cancer therapies is curcumin delivered via
nanodrug delivery .In order to cure pancreatic cancer. created parenterally administrable
nanomicelles of 3,4-difluorobenzylidene curcumin (CDF). When compared to curcumin,
the nontoxic counterpart of 3,4-difluorobenzylidene curcumin is well-known for its
enhanced pancreatic specific accumulation in vivo and strong anti-cancer action. Using
non-covalent hydrophobic interactions, the styrene-maleic acid copolymer (SMA) with
CDF was self-assembled to create the nano-micelle. They were discovered to have a
prolonged drug release response to pancreatic cancer cell lines AsPC-1 and MiaPaCa-2.
Both the SMA-CDF nanomicelle and the free CDF demonstrated toxicity against the two
cell lines, with the nano-micelle's impact being greater than the free CDF's. For MiaPaCa-
2 cells, the IC50 was determined to be 230 ± 4.68 nM, whereas AsPC-1 cells had an IC50
of 710 ± 3.81 nM . Furthermore, the CDF loaded to the hyaluronic acid-conjugated
polyamidoamine dendrimers administered to the CD44 overexpressing MiaPaCa-2
pancreatic cancer cells was assessed by the same study team. Hyaluronic acid (HA) was
used as a targeted ligand in the construction of the nanocarrier, which was subsequently
loaded with the CDF (HA-PAMAM-CDF). The total particle size of the dendimer system
was 9.3 ± 1.5 nm. They demonstrated cytotoxicity against human pancreatic cancer cells,
AsPC-1 and MiaPaCa-2, in a dose-dependent manner. It was discovered that the half-
maximal value increased 1.71 times when HA-ligand was present [43].

Fig 17: Pancreatic cancer
4.10. Oral cancer

mouth cancer is the broad term for any malignant development seen in the mouth cavity.
It often begins as a primary lesion in any of the oral tissues and progresses over time.
According to the American Cancer Society, 9,450 people died from oral cancer in 2016.
Men are twice as likely to have oral cancer as women.
The active metabolite of artemisinin, dihydroartemisinin (DHA), was introduced to oral

cancer cells in a lab setting by loading a co-polymeric micelle with it. Using the modified
solvent evaporation process, the DHA was loaded into co-polymeric micelles composed of
methoxy poly(ethylene glycol)/poly(L-lactic acid) (mPEG). The physicochemical
investigations demonstrated the stability, spherical form, and around 130 nm mean size of
the nanoparticles. DHA was released from the co-polymeric micelles in a pH-dependent
manner using a biphasic drug release pattern, consisting of an initial burst and a subsequent
somewhat faster drug release. The DHA given via the micelle exhibited a higher anticancer
impact on the KB human oral cancer cells, as demonstrated by the MTT experiment, where
the IC50 was determined to be 18.70 µM compared to 24.55 µM for the free DHA. This
demonstrated how the drug's availability was increased by the nano-drug delivery method.
In addition, cells treated with DHAmicelles had some outward manifestations of apoptosis.
The KB human oral cancer cell line was given the polyphenolic component ellagic acid in
a chitosan nanoparticle form earlier this year.Ionic gelation was used to ensnare the ellagic
acid within the chitosan nanoparticle. It was discovered that the nanoparticles were
spherical in form and weighed on average 176 nm. Furthermore, it was discovered that the
nanoparticle exhibited a sustained drug release behavior and that the drug encapsulation
efficiency was around 94%, although the loading efficiency was only 33%. When ellagic
acid was administered via chitosan nanoparticle against KB cells, it was discovered to have
a higher therapeutic competence. They had an IC50 value of 0.953 µg/ml, showed a dose-
dependent impact, and caused observable DNA breakage in the KB cells [44].
Fig18 : Phytochemical to prevent Oral cancer
4.11. Leukemia
A class of malignancies known as leukemia often starts in the bone marrow and produces
an excessive amount of aberrant white blood cells. among affluent nations, it is prevalent
among children, and the American Cancer Society reported that 24,450 people died from
it in 2010 and 48. Anand et al. looked at the enhanced bioavailability of this approach
through in vivo testing, as well as the antiproliferative effectiveness of curcumin-loaded

PLGA nanoparticles in a lab setting. With a 97.5% encapsulation efficiency, the curcumin
medication was loaded onto a polymeric-based nanoparticle composed of poly (lactide-co-
glycolide) (PLGA) and a stabilizing polyethylene glycol (PEG). After that, the PLGA-PEG
loaded with curcumin was introduced to the human chronic myeloid leukemia cells KBM-
5.The results showed that the curcumin-loaded nanoparticles exhibited better cellular
uptake, inhibited TNF-induced NF-κB activation, suppressed NF-κB-regulated proteins
involved in invasion (MMP-9), angiogenesis (VEGF), and cell proliferation (cyclin D1),
and triggered apoptosis as compared to free curcumin. The mice received an intravenous
injection of 2.5 mg/kg of curcumin nanoparticle. The curcumin nanoparticle was shown to
be more bioavailable and to have a longer half-life than free curcumin, according to the
HPLC study [45]. In a different investigation, the co-formulation of curcumin and
doxorubicin in poly-(D,L-lactide-co-glycolide) nanoparticles inhibits the growth of
multidrug resistance in K562 Chronic Myeloid Leukemia Cells. The single emulsion
solvent evaporation method was used to create the doxorubicin and curcumin loaded PLGA
nanoparticle, which had an encapsulation effectiveness of 46% and 86%, respectively. The
dual drug loaded NPs' cellular absorption in K562 cells was about eight times more than
that of the dual drug in solution. In addition, when the nanoparticles were supplied at equal
dosages, they showed considerable growth inhibition with an IC50 value of 0.1 μg/mL,
accompanied by a progressive reduction in the mRNA expression of MDR1 and BCL-2.
Overall, compared to the medications alone, this combinational approach shows
considerable potential [46].
The multipurpose Chinese traditional medication Emodin, when coupled to D-α-tocopheryl

polyethylene glycol 1000 succinate (TPGS) to produce liposomes, inhibits leukemia. With
a particle size of 121.1 ± 44.9 nm and a high encapsulation effectiveness of around 95.2%
± 3.0%, the liposomes were observed. It was discovered that the emodin-TPGS liposomes
exhibited heightened cytotoxicity against the leukemia cell lines L1210 and K562. The
control of myeloid cell leukemia 1 (Mcl-1), B-cell lymphoma-2 (Bcl-2), and Bcl2-

associated X (Bax) protein levels was one aspect of this cytotoxicity. According to the bio-
distribution investigation, emodin-TPGS liposomes increased emodin's bioavailability in
the kidney and lungs by 1.7 times more than that of free emodin [94].Chitosan
nanoparticles loaded with a citrus polymethoxylated flavone nanobiletant were observed
to have antiproliferative action concurrently. The chitosan nanoparticles loaded with
nobiletin exhibited a loading effectiveness of 7.0% and were produced by Schiffbase
formation. The RAW264.7 Abelson murine leukemia virus-induced tumor cell lines and
L-929 normal subcutaneous connective tissue were used in the in vitro experiment at
different time points. The proliferation of RAW264.7 cells was shown to be inhibited by
both raw nobiletin and nobiletin-loaded chitosan nanoparticles, however L-929 growth was
not affected. Furthermore, the chitosan nanoparticles loaded with nobiletin demonstrated
significant suppression of malignant cells at an IC50 of 8 μg/mL, indicating their enormous
potential for use in cancer treatment [47].
The natural dietary lipophilic compound's antileukemic action when loaded onto
nanostructured lipid carriers. Using a high-pressure homogenization process, the
zerumbone-loaded nanostructured lipid carriers were created. The ZER-NLC particles that
were obtained exhibited a drug loading efficiency of around 7.92% and an average size of
52.68 ± 0.1 nm.Over a 48-hour period, zerumbone's drug release from ZER-NLC was
around 46.7%. ZER-NLC exhibited a considerable growth inhibition against Jurkat acute
lymphoblastic leukemia cells, with an IC50 of 5.64 ± 0.38 μg/mL. As a result, the study
recommends using ZER-NLC as a sustained-release medication carrier system to treat
leukemia [48].

Fig19: Lukemia.
4.12. Cancer in nervous system

Neurological cancers, including brain cancer and nerve sarcomas, are extremely
uncommon conditions that impact the neurological system . Shao et al. investigated the
growth-inhibiting impact of resveratrol when it was administered via a biodegradable
nanoparticle. The resultant biodegradable nanoparticle had a smooth, spherical form and
was composed of mPEG-PCL. For the mPEG-PCL nanoparticles, the encapsulation
efficiency was 91% and the drug loading efficiency was around 19%. They were put to the
test using C6 glioma cells. A tumor called a glioma originates from the glial cells in the
brain or spinal cord. The cytotoxicity of the resveratrol-loaded nanoparticle was higher
than that of the free resveratrol. Additionally, when the C6 cells were exposed to the
resveratrol-loaded nanoparticle, they produced a significantly higher quantity of ROS.
Thus, the results of this investigation imply that Res-loaded nanoparticles may be a viable
chemotherapeutic formulation for the treatment of malignant gliomas . The potential of the
phytochemical curcumin to suppress beta amyloid is being studied in relation to its ability
to impede the development of SH-SY5Y neuroblastoma cells. A solid extracranial cancer

growth made of neutrophils, neuroblastoma typically develops in the adrenal gland. The
poly(butyl)cyanoacrylate nanoparticles mediated by apolipoprotein E3 included curcumin,
with a particle size of around 195 nm. Additionally, research on the viability of the
neuroblastoma cells shown improved therapeutic impact with a prolonged drug release
effect. Thus, they came to the conclusion that the SH-SY5Y cells underwent apoptosis as
a result of the curcumin-loaded nanoparticles [49].The myeloma cells that self-organized
assemblies of curcumin micelles cytotoxically attacked. A malignant tumor called
myeloma develops in the bone marrow's plasma cells. Micelles were formed by loading
the lipophilic chemical curcumin onto the amphiphatic poly(oxyethylene) cholesteryl ether
(PEG-Chol). The PEG-Chol nanoparticle loaded with curcumin was more cytotoxic to
myeloma cells. The curcumin-loaded PEG-Chol nanoparticle at 1 µM dramatically reduced
the viability of the myeloma cells, although free curcumin at 5 µM had a substantial impact.
Thus, it appears that curcumin may be delivered as a stable drug carrier via the PEG-Chol
nanosystem [50]. When applied by nanoparticle to the SGC7901 gastric cancer cells, the
hydrophobic ursolic acid can cause cell death. the myeloma cells that self-organized
assemblies of curcumin micelles cytotoxically attacked. A malignant tumor called
myeloma develops in the bone marrow's plasma cells. Micelles were formed by loading
the lipophilic chemical curcumin onto the amphiphatic poly(oxyethylene) cholesteryl ether
(PEG-Chol). The PEG-Chol nanoparticle loaded with curcumin was more cytotoxic to
myeloma cells. The curcumin-loaded PEG-Chol nanoparticle at 1 µM dramatically reduced
the viability of the myeloma cells, although free curcumin at 5 µM had a substantial impact.
Thus, it appears that curcumin may be delivered as a stable drug carrier via the PEG-Chol
nanosystem [51]. When applied by nanoparticle to the SGC7901 gastric cancer cells, the
hydrophobic ursolic acid can cause cell death. The cells that make up the stomach's inner
lining are the source of gastric cancer, which primarily affects the elderly. Using the nano-
precipitation approach, methoxy poly(ethylene glycol)–polycaprolactone (mPEG–PCL)
block copolymers were used to create the ursolic acid nanoparticles as drug carriers. The

resultant nanoparticle has an encapsulation effectiveness of around 80%, is almost

spherical, and averages 144 nm in size. It was discovered that ursolic acid, both free and
loaded in nanoparticle form, had an impact on SGC7901 cells, although the nanocarrier by
itself did not have any harmful effects. Furthermore, the nanoparticles laden with ursolic
acid produced greater cell death and had a stronger impact. The inhibition of COX-2 and
the activation of caspase-3 were implicated in the cell death. As a result, the work provides
a useful method for enhancing UA's anticancer efficacy via a nanodrug delivery technology
[52].
Fig20: Cancer in nervous system.

5. Current limitations
Although significant efforts have been performed to introduce stimuli-responsive

nanocarriers for treatment of cancer, there are still some issues to be considered. The
phytochemicals have rapid metabolism, mainly in liver and their bioavailability and blood
circulation are low. Hence, it is highly suggested to load phytochemicals on nanocarriers
for cancer therapy. However, the question is that how much of drug is loaded and
encapsulated by nanocarriers? The studies have revealed that the encapsulation efficiency
of nanocarriers is low and therefore, this may cause problems related to therapeutic index
of phytochemicals. As a result, it is suggested to change the composition of nanoparticles
in a way to increase drug loading efficiency or develop layer-by-layer nanoparticles for
loading more phytochemicals in cancer therapy. Another issue is related to lack of specific
control of nanocarriers after distribution in the body. There are several factors that can
affect the fate of nanocarriers in the tumor cells.For instance, when nanoparticles enter into
bloodstream, they interact with proteins in the blood and protein corona is formed that can
change the fate of nanoparticles and their biodistribution. However, there is no specific tool
currently for evaluating protein corona impact and final fate of nanoparticles. In this case,
it is suggested to coat nanocarriers or at least modify them with ligands to increase
accumulation of nanoparticles in cancer site. Even in this case, protein corona can affect
the fate of nanoparticles and their next biodistribution. Another concern is that there is no
much investigation regarding potential of stimuli-responsive nanocarriers in crossing over
biological barriers such as blood-brain barrier and especially, blood-tumor barrier. In this
case, the tumorpenetrating peptides can be utilized to modify nanoparticles and increase
their potential in crossing over biological barriers. If the future studies focus on application
of theranostic nanoparticles, it can be understood that nanoparticles accumulate in which
tissues and this can broaden understanding regarding the biodistribution of nanoparticles

in the cancer tissues. Another limitation is that for improving nanoparticle potential in drug
delivery.
6. Future Prospects
Research in the past few decades has provided extensive evidence that phytochemicals
possess versatile anticancer activity. However, its clinical application is limited due to
poor aqueous solubility and low retention in body. In this regard, phytochemical based
nanomedicine i.e., phytonanomedicine can overcome these drawbacks and improve the
therapeutics efficacy by modulating pharmacokinetics and pharmacodynamics of
phytochemicals. It has been already established that nanoparticle based drug delivery
vehicles reach the tumor site due to passive targeting through EPR effect. The ultimate
goal for delivery of nanomedicine is to design a specific phytochemical-nanocarrier that
improves the drug delivery or uptake in cancer cells to get a higher therapeutic effect and
lower side effects in clinical settings. To enhance the tumor targeting capability of
phytonanomedicine, the nanoformulation can be conjugated to some targeting ligands so
that active targeting can be achieved. Additionally, the prospect of site-specific drug
release through nanomedicine prevents nonspecific delivery of drug that contributes in
regulating toxicity. Therefore, development of phytonanomedicine that can specifically
deliver drug to the tumor site could be an emerging area of research. The clinical impact
of phytonanomedicine can be improved by smart, realistic and rational prospective.In this
aspect, we have discussed some strategic directions to boost phytonanomedicine
performance, translation and exploitation for cancer treatment. Tissue specific targeting
and half-life of phytonanomedicine is the major concern upon systemic administration.
In this direction, PEGylation of nanomedicine can be beneficial as the stealth property of
PEG helps the nanoparticles to escape from immune macrophage and increase circulatory
half-life of phytochemicals. Recent studies have reported that currently available cancer
immunotherapies exhibits certain pathophysiological constrains in cancer patients. In this

context, developing immunomodulatory phytonanomedicines or combined treatment of

the current immunotherapy with phytonanomedicine or DNA insert encapsulated
nanoformulation for CART therapy inside patient body may help to improve the immuno-
oncological intervention outcomes and increase the number of long term survivors.
Several research have demonstrated that conventional therapies are able to target highly
proliferating cancer cells, leaving quiescent CSCs in tumor mass unharmed[56].Research
suggests that phytochemicals exhibit strong anti-CSCs properties. Therefore,
combination of conventional chemotherapeutics with phytochemicals could be an
effective approach to target both cancer cells and CSCs respectively for complete tumor
regression. Additionally, co-delivery of phytochemicals with miRNA or siRNA through
nanomedicine can modulate the cancer cells, CSCs and their microenvironment
simultaneously, which may offer a better therapeutic index. Besides this, nanoformulation
of a phytochemical with a fluorescent dye, further conjugated to an antibody or peptide
can achieve targeted therapy and diagnosis simultaneously. Therefore, developing such
novel combinational nanoformulation can help to improve patient compliance by
reducing side effects. Currently, a large number of studies focus on different types of
phytochemical loaded nanocarriers for effective tumor targeting, but cost, safety, chronic
toxicity, large scale manufacturing and batch-to-batch variability is the major concern for
clinical translation. Hence, further research is required to understand and improve the
design, complexity, manufacturing and biological interaction of phytonanomedicine to
develop next-generation cancer therapeutics. Further, establishment of smart strategies
are required to shift the phytonamomedicine to as many patients as possible by cumulative
efforts of consortia comprising academics/ researchers, clinicians, pharmaceutical
companies and regulatory authorities. This manuscript aim to streamline the role of
nanomedicine in translational cancer research that may help to promote the clinical
impact and patient performance of phytonanomedicine as anticancer drugs.

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A BRIEF REVIEW ON

ADVANCES IN PHYTOCHEMICAL DELIVERY SYSTEMS

REGISTRATRION NO: 213620201920003

Dissertation Submitted to the

Maulana Abul Kalam Azad University of Technology

GITANJALI COLLEGE OF PHARMACY

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page i

I hereby declare that this dissertation, entitled “ADVANCES IN PHYTOCHEMICAL

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page ii

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation, entitled “ADVANCES IN PHYTOCHEMICAL

Supervisor Name with Signature

Gitanjali College of Pharmacy

This is to certify that the dissertation, entitled “ADVANCES IN PHYTOCHEMICAL

Prof. (Dr.) Mrinmay Das

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page iv

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page v

Sl. No. Title Page No.

2 PHYTOCHEMICALS IN CANCER THERAPY 3-15

PHYTOCHEMICAL BASED NANOMEDICINE

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page vi

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 1

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 2

2. PHYTOCHEMICALS IN CANCER THERAPY

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 3

Fig1: Various Type of Phytochemical for the treatment of cancer.

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 4

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 5

Fig 2: Chemical structure of phytochemicals that exhibit anticancer properties such as

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 6

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 7

components of chemoresistance. Green tea contains a polyphenolic flavonoid called

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 8

Fig 3: Proposed mechanism of anticancer activities of phytochemicals.

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 9

1. Curcumin/ 27.3 Intrave Showed cytotoxicity to C-26 colon cancer 2

3. Curcumin 170 Intrave Enhanced anti-tumor activity on C26 colon 2

4. Curcumin 200 Intrave 5-10-fold more effective than free curcumin 4

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 10

nanoparticl triple negative breast cancer cell line and in

Epigallocatechin gallate (EGCG)

1. EGCG Oral High cytotoxicity towards MBT-2 bladder 7

S. Nanotechno Size Route of Clinical /In-vivo results Refere

2. EGCG-pNG 64.7 Intratu Demonstrated 4.91 times high cytotoxicity 3

3. Methoxy 155. Peritu Significantly inhibited tumor growth in

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 11

S. Nanotechnolog size Route of Clinical /In-vivo results Reference

1. Dual drug 105 Intravenous +Preclinical tests in a nude mice 9

2. Aptamer- 226 Intravenous +Distinctively enhanced 4

3. Apigenin 101. Oral plus Potent inhibition of skin 9

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 12

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 13

Figure 4: Common routes of phytochemicals administration fromfoodandnano-carriers

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 14

2.5. Organosulfur compounds

Organosulfur compounds, such as sulforaphane, which is derived from cruciferous

3. Phytochemical based nanomedicine for cancer treatment

GITANJALI COLLEGE OF PHARMACY, LOHAPUR, NALHATI, BIRBHUM, West Bengal Page 15