Journal of Drug Delivery Science and Technology 64 (2021) 102681

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst

Insight of nanomedicine strategies for a targeted delivery of

nanotherapeutic cues to cope with the resistant types of cancer stem cells
Yangyong Mao a, Mahpara Qamar b, Sarmad Ahmad Qamar b, Muhammad Imran Khan c,
Muhammad Bilal a, *, Hafiz M.N. Iqbal d, **
a
School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian, 223003, China
b
Department of Biochemistry, University of Agriculture, Faisalabad, Pakistan
c
Hefei National Lab for Physical Sciences at the Microscale and the Centers for Biomedical Engineering, University of Science and Technology of China, Hefei City, Anhui
Province, 230026, China
d
Tecnologico de Monterrey, School of Engineering and Sciences, Monterrey, 64849, Mexico

A R T I C L E I N F O A B S T R A C T

Keywords: Characteristics of small group of cancerous cells known as cancer stem cells (CSCs) or tumor initiating cells
Cancer stem cells involve relapse, metastasis, and drug resistant which highly influence the available therapeutic processes. Tu­
Nanomedicines moral drug resistance appears closely related to various acquire or intrinsic characteristics of CSCs e.g., detox­
Nanotherapeutics
ifying enzymes, drug efflux transporters, antiapoptotic protein overexpression, DNA repairability, specific
Drug resistance
Combinatorial therapeutics
morphology, and quiescence. The specific hypoxic stability and niche impart additional shield against anti-
cancer therapeutic approaches for CSCs. Therefore, CSC-based therapeutics are intended to form the core of
efficient anticancer strategies. Nanostructured constructs have demonstrated to possess promising applications e.
g., targeted drug release, controlled delivery, CSC-targeting drugs, and the development of novel gene-specific
diagnostic and treatment modalities. This review describes various drug resistant-related characteristics of
CSCs and aim to summarize recent therapeutic and biomedical approaches using nanostructures (nano­
medicines). The modification of components presents in extracellular matrix with the nanostructured constructs
is considered as one of the promising strategies to upgrade the intra-tumoral drug delivery. Different CSCs-
targeting therapies including photothermal therapy (PTT), photodynamic therapy (PDT), hyperthermia, and
radiotherapy-based methodologies, which could serve as the novel combination of therapeutic approaches to
eliminate CSCs and metastasis have also been described.

1. Introduction unknown, various mechanisms are responsible for the heterogeneity of

Cancer is characterized by an uncontrolled growth and metastasis,
and this uncontrolled spread can cause death in patients. In accordance
with International Agency for Research on Cancer, approximately 9.5
million deaths and 17 million new cases were reported during 2018,
excluding non-melanoma skin cancers [1]. Studies estimated around 7.6
million and 6.4 million new cases from high and medium human
development indexed (HDI) countries, respectively. Four million
cancer-associated deaths were reported among high, and 1.8 million
among medium HDI during 2018 [2]. According to an estimation, new
cancer cases will reach 27.5 million with 16.3 million deaths due to
cancer till 2020 [2]. Although, the principal causes behind cancer are
tumor milieu such as genetic mutations, dysregulated signaling path­
ways, and tumor microenvironment (TME), result in abruptly uncon­
trolled cell divisions are well established facts about cancers [3–5].
Surgery, radiotherapy, and Chemotherapy are common therapeutic
approaches being used in the treatment of cancerous cells from several
decades.
Surgery is the most commonly performed in almost every case of
solid tumor. Surgery is useful only when the tumor is localized and has
not been metastasized [6]. To possibly overcome the limitations of
surgery, almost every cancer patient receive chemotherapy after surgi­
cal removal of solid tumors or directly treated by radio- and/or che­
moradiotherapy [7,8]. It has been reported that 50% of cancer patients

* Corresponding author.
** Corresponding author.
E-mail addresses: bilaluaf@hyit.edu.cn (M. Bilal), hafiz.iqbal@tec.mx (H.M.N. Iqbal).

https://doi.org/10.1016/j.jddst.2021.102681
Received 16 May 2021; Received in revised form 15 June 2021; Accepted 25 June 2021
Available online 26 June 2021
1773-2247/© 2021 Elsevier B.V. All rights reserved.
Y. Mao et al.
receive radiotherapy as a major treatment option. Both chemotherapy
and radiotherapy principally focus on tumor burden reduction, and
hence, hitting the limitations of the treatment [9]. Although, there have
been significant advancements in cancer therapeutics, and various
modified therapeutics e.g., targeted biological agents, palliative care,
and others approaches, which have optimized the effects of conven­
tional therapies [10–13]. The persisting CSCs, their sub-populations,
plasticity, and other functional properties cause the disease prognosis
after partial recovery [9,14]. CSCs use common signaling pathways and
supply a progeny of cells for tumor [15]. CSCs have become important
concern for the scientists working in oncology due to their therapeutic
resistance issues.
Moore et al. [16] had put forward the theory of CSCs. The exact time
of observation of CSCs is contradictory. Lapidot et al. [17] witnessed
CSCs in acute myeloid leukemia patients. Authors reported that plas­
ticity behavior of cancerous and normal stem cells was pretty similar to
the ordinary stem cells [18]. This contradiction may be due to limited
browsing access of various search engines or lack of electronic version of
articles by that time. Later research lightened the role of CSCs very
brightly and confirmed the presence of stem cells in various types of
solid tumors. Evidences are accumulating that tumors are genetically
and phenotypically composed of diverse population of cells including
Fig. 1. Overview of scope of cancer stem cells and targeted therapeutics modalities. (Abbreviations: EpCAM: epithelial cell adhesion molecule; ALDH: Acute myeloid
leukemia MK752; CLL: chronic lymphocytic leukemia; GI: gastrointestinal; ABC: ATP binding cassette; DEABs: N,N-diethylamino-benzaldehyde; OSM: oncostatin M;
ATRA: all-trans retinoic acid; BMPs: bone morphogenic proteins).
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Journal of Drug Delivery Science and Technology 64 (2021) 102681
CSCs. Researchers have reported existence of cancer stem cells in breast,
liver, lungs, colon, prostrate, pancreatic, head and neck, skin, ovarian
and mesenchymal tumors [15]. Currently, the therapeutic modalities
applied for the treatment of cancerous cells are based on targeting
different signaling pathways associated with immune microenviron­
ment and CSCs. Development of especial signaling pathways are crucial
for the survival of cancer stem cells, and therefore, targeting these
pathways could stop their multiplication or at least can slow down their
replication speed, which can prove to be an efficient strategy. In-vitro
experiments explored the pivotal role of CSCs in the development of
resistance against various forms of therapies. For instance, mutations in
signaling pathways like WNT, Notch and Hedgehog pathways affect
plasticity, and differentiation of CSCs [18].
The introduction of modern applied biocompatible technologies is
required to design modern ways of targeting cancer stem cells, which
exhibit various biological properties including abnormal plasticity and
lack of maturation, leading to accumulation of abnormal cellular mass.
Genetics instability gives rise to new genotypes and phenotypes of
cellular population. These different genotypes of cells are associated
with mutations, which ultimately are responsible for drug resistances
[9]. These mutated cells express new phenotypic characteristics that
varies in different forms of tumors and play important role in molecular
Y. Mao et al.
classification of tumors to stratify them into responsive and resistant to
specific therapy. CSCs-based therapeutics are powerful tool to treat
cancers successfully. These therapies target various components of
cancer stem cells e.g., signaling pathways, cellular niches, etc. Some­
times these strategies are also applied to overcome the drug resistance
[19]. Several types of therapies such as monoclonal antibodies, vaccines,
neoadjuvant therapies are being evaluated clinically at different stages
[20]. Comprehensive overview of scope of CSCs and targeted thera­
peutic modalities have been represented in Fig. 1. This review aimed to
summarize therapeutic resistant challenges of CSCs with recent scien­
tific progress in biomedical sciences using nanostructured cues to design
novel therapeutic options. Different CSCs-targeting methodologies
including PTT, PDT, hyperthermia, and radiotherapy-based approaches
have been discussed which could serve as the novel combination of
therapeutic approaches to eliminate CSCs and metastasis.
2. Therapeutic resistance – an open challenge for sciences
Although there are number of drugs being tested for their efficacy
against cancer stem cells and a proportion of drug has reached the
clinical trial phase. Current therapeutics reduce the bulk of tumor tissue
and have a significant impact on life expectancy. But due to heteroge­
neity, clonal evolution, lack of accurate proofread gene replication,
transcriptional mutations, and certain other factors are still non-
understandable and are the main sources which generate bugs to
interfere with therapeutic course and develop resistance against various
therapeutic modalities. CSCs are considered to be an important source of
such invisible enemies of therapies and supporter of drug resistance and
multidrug resistance [4,21–24]. It worth mentioning that recent clinical
investigations explore that epigenetic dysregulation are not solely
responsible for cancer [25,26]. Several cancerous cells survive from the
cytotoxic effect of therapies. These surviving cells give rise the relapse of
disease and possibly resistant types of cells [21], and therefore, causing
resistance to certain drugs. It is of great interest to focus on CSCs to
develop effective therapeutic plaining and possible ways to eradicate
cancers completely.
ATP binding cassettes (ABC) comparatively present in abundance
than that of normal stem cells, which have been explored to induce the
export of various drug types from intracellular milieu. Kinds of different
ABC transporter proteins push one drug out of the cells and are the most
common mechanism behind multidrug resistance [27–29]. However,
the inhibitors of ABC transporters may not overcome resistance entirely.
Tepotinib overcame the ABCB1-mediated multidrug resistance but was
not effective against ABCG2 and ABCC1 mediated multidrug resistance
[29]. TME inflections such as overproduction of growth factors, tumor
revascularization, hypoxia induced factor 1α and 2α, etc. favor rapid
multiplication and micro-metastasis [22]. These inflections in TME are
accompanied by dysregulated expression of ABC transport machinery.
These dysbalanced organization of positive and negative regulatory
factors becomes a potential driving factor for stemness and chemo­
resistance [30].
Hippo pathway is an important regulator of cells stemness and is
reported to be responsible for self-renewal of CSCs. Dysregulated
phosphorylation of Hippo signaling effectors heighten plasticity, che­
moresistance and proliferation of cancer stem cells [31,32]. Exosomes
are cell bounded vesicles released by the cells. They have function in
juxtacrine and paracrine signaling by releasing kinds of different bio­
molecules including cytokines and chemokines into tissue environment
for cellular communication. Recent investigations explore their presence
in niches of CSCs, and their potential role in tumor angiogenesis and
metastasis [33,34]. Besides, resistant cells use exosomes to export
chemotherapeutic drugs [35] and are the important mediator of resis­
tance to therapeutics against CSCs. Compromised DNA damage response
(DDR) is the main mechanistic approach to target the cancer cells.
However, enormous DDR in cancer stem cells confer their DNA preser­
vation, protect them from death, and impart proliferative characteristics
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Journal of Drug Delivery Science and Technology 64 (2021) 102681
in a highly efficient way [36]. Following therapy, intra-tumoral het­
erogeneity promotes clonal evolution through Darwinian selection and
subsequently survival of resistant types of cancer stem cells and thus,
promoting remaining more resistant, invasive, and aggressive cancer
stem cells dissemination [37]. Similarly, other types of mechanism like
exaggerated response to unfolded proteins, susceptibility to endo­
plasmic reticular stress, derailed autophagy (facilitated survival),
apoptotic evasion, and distinctive and highly efficient metabolic path­
ways also contribute to the resistance to therapies [38–40]. Detailed
overview of resistance mechanisms prevalent in cancer stem cells have
been presented in Fig. 2.
3. Strategies for targeting cancer stem cells
The active and passive targeting are two modes of targeting CSCs.
The fastest growth of endothelial cells demonstrates the leakage of these
cells, providing value to the passive targeting. The nanostructures and
nanoparticles can easily penetrate and assemble in the interstitial space.
This process is considered as ancient because of its non-particularity and
restricted diffusion. If the nanoparticles specifically attack cancerous
cells and being activated after their approach at target site, then more
beneficial result can be attained [41]. On the other hand, active tar­
geting requires the nanoparticle coupling with the targeted moiety for
the assembly of nanoparticle at the tumoral location and to secure the
specific receptor targeting. The receptor-mediated endocytosis is acti­
vated due to the over expression of antigens and receptors present on the
tumor cells, required for the efficient delivery of targeted dose [42]. A
large number of nano vectors are used to design the
nanotechnology-based drug delivery systems such as metallic nano­
particles, protein nanoparticles, polymeric nanoparticles, micelles,
dendrimers, and liposomes [10,43]. The particular places of tumors are
acquired by the drugs after their delivery by nano vectors. There are
three portions of drug delivery systems including surface modifiers, core
drug, and therapeutic drug. The purpose of particular targeted drug
delivery is achieved by the surface modifiers that play important role to
determine the distribution of vectors inside the body and their interac­
tion [44,45].
A subgroup of tumor cells is also shown by the stem cells, and these
are capable to liberate tumor synthesis, regeneration of tumor sur­
roundings, self-renew properties, and stimulation of resistance to mul­
tiple cytotoxic drugs. Thus, the effectiveness of anticancer therapeutics
has shown by targeting the tumor cells. However, the research just
paved the way towards the novel nanotherapeutics after reporting of
different mechanisms and properties of targeting stem cells and not
much research is available on the use of nanoparticles for targeting stem
cells. The cell markers such as the Notch and Wnt/β-catenin, and Sur­
vivin (smallest member of apoptosis inhibitor family linked with cluster
of differentiation 34+ (CD34+) and differentiation 38- (CD38− ) show the
association with the Survivin specific cytotoxic T-lymphocytes (CTLs),
and the regulation of human telomerase reverse transcriptase signaling
and leukemic stem/progenitor cell mechanisms corelated with the un­
favorable clinical prognosis [46,47]. The development of pancreatic
cancer stem growth is observed by the Survivin-DEx3 (Survivin splice
variant) which is attached with phosphorylation of cycle check point
and cause the DNA damaging, modification of sonic hedgehog devel­
opmental signaling pathways to promoted epithelial mesenchymal
transition and introduction of resistance to genotoxic therapies. The
transition of TGF-β signaling (transforming growth factor) is account­
able in liver cells to promote the pancreatic cancer. The antibiotic
establishment and induction of chromatin remodeling is observed by the
histone deacetylases (HDACs) and histone acetylation transferases
(HATs) mechanisms affected by the transition of TGF-β signaling. The
p53 signaling mechanisms control the suppression of p53 tumoral sup­
pression gene and crucial importance of Survivin in transcriptional in­
hibition of p21 gene was also observed [48].
The mammalian target of rapamycin (mTOR) reliable arrangement
Y. Mao et al. Journal of Drug Delivery Science and Technology 64 (2021) 102681

Fig. 2. Therapeutic resistance mechanism explored by cancer stem cells which reunite the distinctive characteristics to attain resistance to environmental factors. 1)
ABC support the cancer stem cells to reduce the cytoplasmic drug concentrations. 2) Hypoxia, Hippo pathway blockage, etc., encourage survival, pluripotency and
metastasis of various cancer stem cells subpopulations in the inhospitable tumor environment; 3) Genomic instability, changes in epigenetics drivers, hypo­
methylation nurture various cancer stem cell phenotypes; 4) Exosomes prime premetastatic niche by reorganizing extracellular matrix, proliferation and trans­
formation; 5) Heightened DNA damage repair of cancer stem cells, high response to unfolded protein, ER stress and DNA damage, 7) deregulated autophagy and 8)
highly efficient metabolism are factors responsible for survival, active proliferation and resistance development.

and p53 were used to develop the novel orphan nuclear receptor TR3
(NR41A) overexpression in lung carcinoma by Survivin [49]. The
mechanisms of systemic modifications include the different factors
which control the overall mechanisms e.g., modification of mitochon­
drial apoptosis linked with the second mitochondrial-derived activator
of caspase (Smac) in receptor activating protein-1 (RIP1)/caspase-8 and
nuclear factor-kappa beta (NF-kB) signaling, modification of DNA
methylation processes, interruption with tumor necrosis factors
inducing ligand (TRAIL)-linked anticancer treatments,
sphingosine-1-phosphate receptor which act as signal transducer and
transcription-3 (S1PR1-STAT3) signaling, transition of microRNA’s ar­
rays and Yes-associated protein (YAP) cause the transition into the
epidermal growth factor receptor (EGFR) and hippopotamus just like
phenotype tumor growth and yes-protein (hippo-YAP) support the
organogenesis developmental pathway [50–56]. The extensive studies
are available to target the Survivin by the use of nanotherapeutic ap­
proaches [45]. Currently, the gastric cancer has been treated with
docetaxel (DOC) and gelatinases-stimuli nanoparticles encapsulated
with microRNA-200c in order to check its therapeutic efficacy. The
study demonstrated various results such as the stimulation of induced
cell cytotoxicity to DOC by 75% as compared to control treatments and
increased uptake of miRNA by nanoparticles from the stem cells and
constant expression of miRNA-200c in tumors for 9 days. Moreover, the
expression of stem cells markers such as TUBB3 and CD44 was
down-regulated along with the tumor suppression due to the efficient
accumulation of nanoparticles in mice with gastric cancer stem cell
xenografts [57].
In another study, cancer stem cells in lungs were also targeted by the
distribution of miRNA-34a using solid-lipid nanoparticles. The increased
targeting and expression of miRNA-34 with these nanoparticles were
observed by the in-vitro studies. Further in contrast with nanoparticles
alone or free miRNA-34a, the miRNA 34a nanoparticles caused the
obstruction in enhanced cell migration, locomotion, and proliferation
activity of CD44+ stem cells. The ability of these nanoparticles was
confirmed after the biodistribution studies in which mice revealed the
highest expression of miRNA-34a in lungs after the accumulation of
nanoparticles within 1–2 h of intravenous injection [58]. Even though,
there is more requirement to explain the stem cell targeting through
active targeting by the use of peptides, aptamers, or antibodies. Some of
the bright results have been attained by some researchers through the

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Y. Mao et al.
active targeting. The highest expression was observed in epithelial cell
adhesion molecules (Ep-CAM) and for targeting markers such as CD133
by the first time use of RNA aptamers. The binding was not seen in cells
and not in Ep-CAM, but the highest binding affinity was observed in
gastric cancer stem cells, colon, or breast by the 19 bases of Ep-CAM
[59].
Similarly, the binding to the CD133-negative cells, glioblastoma, and
kidney cells were avoided by the 15 nucleotide CD133 RNA aptamer but
connected particularly to the positive colon and liver cancer stem cells.
As compared to the antibody (>4 h) or scramble RNA aptamer (>4 h),
greater binding affinity and the powerful tumors infiltrate activity
(within 30 min) was observed by these aptamers particular to both
AC133 epitope and CD133 protein [60]. The study demonstrated that
there is a need to explain the difference between normal cells, stem cells,
and cancer cells by more particular markers, but the cell surface markers
are beneficial for stem cells targeting. Kanwar and coworkers treated the
colon cancer by the delivery of natural therapeutic proteins by the active
novel nano synthesis approach. Different types of cancers including
colon, breast, and chronic inflammatory arthritis were analyzed by the
alginate enclosed 100% iron saturated bovine lactoferrin encapsulated
chitosan-calcium phosphate nanoparticles [61,62]. These nanoparticles
were specific to deliver the drugs to infectious sites and showed
non-toxic behavior for mice.
The formation and development of solid tumors is not dependent
upon the cancer cells. However, the development of tumors is mainly
reliable on the CSCs present in the heterogenous tumor microenviron­
ment and have great significance for the tumor development. The CSCs
have ability of division from all cell types present in the tumor. Various
types of cells, responsible for tumor development are produced from
CSCs after their insertion into any new system. The importance of stem
cell function is still vague in tumor microenvironment but well under­
stood in normal organs to stable the functionality of an organ. These
stem cells have ability to remain in latent state to develop the relapses
events, also have ability to show correlation with different cells present
in the microenvironment dependent upon the signals transfer and to
convert themselves into different cell types called as tumor heteroge­
neity [63]. Generally, the CSCs are not efficiently attacked by the
traditional chemotherapeutic agents. As compared to the paclitaxel, the
Salinomycin attained from the Streptomyces albus showed more
anti-tumor activity and cause the reduction rate of CSCs. Moreover, the
tumor microenvironment also played important role in the Salinomycin
belonging to the class of polyether antibiotic. This drug also showed the
effective results against CSCs of leukemia and breast [64–66].
This drug showed the limitation of poor water solubility which was
resolved by the synthesis of micelles and then results were evaluated by
the comparison of Salinomycin polymeric micelles with the octreotide-
modified polymeric micelles of the drug paclitaxel by the Zhang et al.
[67]. The evaluation of combination and monotherapy in MCF-7 cells
and isolated stem cells showed the excellent effectiveness combination
therapy as compared to monotherapy. The obliteration of breast cancer
was observed due to the action of combination therapy on cancer stem
cells that provide the appropriate sources to proceed the cancer tar­
geting [67]. The researchers have also applied the conjugating tradi­
tional moieties with some novel techniques to particularly target cancer
stem cells in addition to Salinomycin-based therapy and hyaluronic
acid-modified nanoparticles. The targeting of doxorubicin (DOX) to
cancer stem cells was achieved through the DOX-anchored gold nano­
particles (hydrazone bond). The DOX alone was found to arouse the
growth of CSCs while the DOX-conjugated nanoparticles showed the
amazing results to reduce the progress of different breast cancer cell
lines along with particular assembly to cancer stem cells [68]. The
alternation of tumor microenvironment and nanoparticle synthesis is
under process through different techniques by various studies. The
parallel impact on cancer stem cell and cancer cells is observed by the
Salinomycin and Adriamycin co-loaded nano-liposomes as a potency of
synthesized nanocarriers. The synthesized nanoliposomes are seemed to
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Journal of Drug Delivery Science and Technology 64 (2021) 102681
capture the diverse range of traditional chemotherapeutic drug along
with the coupled impact of an anti-stem-cell drug [69]. Liver cancer
stem cells and liver cancer cells are easily discriminated by micelles in
targeting fashion. The high infiltration targeting peptide internalized
RGD peptide (CRGDK) and the micelle carrier act as wonderful tech­
nique for the treatment of liver cancer (Fig. 3) [70].
4. Nanomedicines for vasculature normalization and prevention
of angiogenesis
The passive targeting of nanomedicines to the tumor sites is proved
as the infrastructure due to the enhanced permeability and retention
(EPR) impact. The EPR effect is mainly influenced by the special prop­
erties of vascular pathophysiology and incompetent lymphatic drainage
[71]. The degree of angiogenesis and tumor vascularization regulate the
efficiency and targeting strategy of nanoparticles. The interstitial fluid
pressure act as barrier for excellent transport of drug and exalted by the
irregular and leaky vasculature of tumors as all the aforementioned
events are the properties of tumor metastasis [72]. The management of
metastasizing tumors is considered as concern related to the majority of
tumors having high level of interstitial fluid pressure [73]. The
pro-angiogenic proteins such as vascular endothelial growth factor
(VEGF) induces the formulation of new blood vessels for the most ma­
lignant solid tumors to expand and development [74–76]. The
enhancement in endothelial cells and abnormal perivascular cells is
resulted by the up regulation of pro-angiogenic proteins determines the
endothelial cell migration and proliferation. The traditionally delivered
cytotoxic drugs act as considerable barrier to their anticancer efficiency
and restrict their ability to diffuse into tumor core due to the poor
vascularization. The greater dissemination of chemotherapeutics is
achieved by the nanoparticle delivery systems to overcome the thera­
peutic hurdles that provide the basis of new technique for cancer
treatment.
The normalization of vasculature is observed after the elimination of
excessive endothelial cells due to the anti-angiogenic therapies. The
blood perfusion and oxygen tension are increased due to the normalized
vasculature that reduces the permeability, vessel diameter and density
along with the lower IFP [73,76,77]. The intracellular concentration of
drugs in tumor cells is increased by the extensive active vasculatures
targeting techniques using nanoparticles. The tumor cells and the tumor
vasculature are targeted by another system a PLGA polymeric nanoscale
delivery [77]. The angiogenic agent combretastatin was injected within
the outside lipid envelope and doxorubicin was covalently linked to the
inner PLGA core in this context. As compared to the free drugs or simple
liposomal formulations, the temporal release of both the drugs was
efficiently permitted by the successful encapsulation of both doxoru­
bicin and combretastatin into the nano-delivery system. The damage of
cytoskeletal structures was caused by the induction of rapid vascular
shutdown happened by the combretastatin released from the outer en­
velope. After the disruption of tumor vasculature, the nanoparticles
captured within the tumor. The improvement in the overall therapeutic
index with decreased toxicity was resulted due to the excellent absor­
bance of doxorubicin by the tumor from the inner nanoparticle [77]. The
improvement in angiogenesis, proliferation, improved oral bioavail­
ability and restriction of tumor growth without any in-vivo adverse im­
pacts was observed due to the successful loading of nano-polymeric
micelles loaded with the angiogenesis inhibitor TNP-470, called loda­
min. As compared to the free inhibitor TNP-470, the lodamin combined
with inhibitor decreased the growth of tumors after the treatment [78].
The enhanced bioavailability, vascular uptake of poorly soluble
anti-angiogenic small molecule drugs increased the retention time of
chemotherapeutic agents and anti-angiogenic within the tumors due to
the usability of nanoparticles by EPR effect, demonstrated by these
studies.
Y. Mao et al. Journal of Drug Delivery Science and Technology 64 (2021) 102681

Fig. 3. General scheme for nanoparticle-mediated targeting of tumor microenvironment with particular ligands (e.g., Anisamide) which can be specifically used for
cancer-associated fibroblast. RGD enable particular targeting of endothelial cells, while hyaluronic acid more specifically targets cancer stem cells. Reprinted from
Ref. [70] with permission from Elsevier. License Number: 5090411295176.

5. Extracellular tumoral-targeting by nanotherapeutics
The inefficient diffusion of drugs is caused due to the unusual dense
extracellular matrix. The cancer stem cells migration, proliferation,
angiogenesis, and invasion are caused by the guiding framework which
is provided by the tumor microenvironment linked with the extracel­
lular matrix [79]. The high interstitial fluid pressure is associated with
the hyaluronic acid that inhibits the penetration and diffusion of drugs
while the collagen is the main constituent of extracellular matrix that
can assemble the migration tracks for tumoral cells [80–82]. The
modification of components presents in extracellular matrix with the
nanoparticles in considered as the one of the promising strategies to
upgrade the intra-tumoral drug delivery. The nanoparticle diffusion into
the solid tumors is improved by the extracellular matrix-decomposing
enzymes e.g., hyaluronidase or collagenase proved in recent studies
along with the clinical trials. But the tumor metastasis is also enhanced
by the potential danger of these agents. The other chemotherapeutics
are mixed with currently discovered PEGylated form of recombinant
human hyaluronidase (PEGPH20) [83]. Patients having high level of
hyaluronidase are treated with the PEGPH2, have shown the therapeutic
effects on patients with metastatic pancreatic cancer. Fascinatingly, the
side effects were easily manageable and there was no interruption into
the medication. The patients with hyaluronidase-overexpressing tumors
were treated with the PEGPH20 combined with other

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Y. Mao et al.
chemotherapeutic, confirmed by some additional research. The
remodeling of extracellular matrix was also observed by some published
research emphasized on the enzymes such as lipoxygenase (LOX) or
proteases e.g., matrix metalloproteinases (MMPs). As compared to the
soluble anti-LOX antibody, the mammary tumor growth was inhibited
with efficiency by polymeric nanoparticles coated with a LOX inhibitory
antibody [84]. These studies paved the way for the treatment of cancer
with high efficiency and less undesirable reactions. Moreover, a
fibronectin-targeting peptide was applied along with the
paclitaxel-loaded PLA nanoparticles. The fibronectin is found in exces­
sive amount in the glioma microenvironment and also considered as the
central constitute of extracellular matrix. As compared to the other
treatment groups, the approximate 70% of survival time was observed
after the treatment with these targeted nanoparticle-drug conjugates in
mice [85]. Recently, only few researchers have studied this amazing
therapy for further future research and their studies indicated the
nanoparticle-assisted targeting of the tumoral extracellular matrix as the
novel approach [86].
As compared to the larger delivery vehicles, the cellular internali­
zation is facilitated by the nanocarriers consisting of particular drug
molecules. The nanoparticles have shown their capability to circulate
around the extracellular matrix of tumor cells and aid to achieve major
challenge of drug delivery molecules at the particular sites of action.
Several modifications such as surface modifications and the compati­
bility of extracellular matrix have revealed by the scientists about
nanocarriers-based strategies for cellular uptake as represented in Fig. 4
[88]. The higher efficacy and fewer damaging effects were observed
after the use of the nanocarriers for tumor site delivery [87]. Therefore,
in this reference, the movement of therapeutic agents can be minimized
due to the composite structure of ECM includes nutrient-stripped tumor
microenvironments, hypoxic, and weakly acidic microenvironment.
Tumoral barrier block the transportation interactions because of their
lowering between anticancer agents and cancer stem cells remotely
Fig. 4. The passive and active drug targeting methodologies. In passive targeting, nanostructured cues transport by the leaky walls and accumulate at tumoral site by
enhanced permeability and retention (EPR) effect. In active targeting, specific ligands are required that bind to the receptors on tumoral cells. Reprinted from
Ref. [88] with permission under creative common (CC-BY 4.0) attribution license (http://creativecommons.org/licenses/by/4.0/).
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Journal of Drug Delivery Science and Technology 64 (2021) 102681
located from blood vessels [89]. Furthermore, the enhanced IFP can be
occurred due to the vascular abnormalities, fibrosis, and contractions in
the tumor matrix that can also reduce the cellular internalization of
drugs and the trans-capillary transport [90]. But these restrictions can be
conquered by the use of nanocarriers or nanomedicines [10,91].
6. Tumor targeting methodologies
There are two ways to target tumors e.g., passive targeting and active
targeting. The biological markers such as carbohydrate, antibody and
aptamer are furnished on the surface of nanocarriers. The ligand-
receptor association will be used for the identification and binding of
the nano-size drug-carriers (ligand-conjugated nanocarriers) and inte­
gration inside the cells will be carried out by the bound nanocarriers
[92]. However, the passive targeting involves the dysfunctional
lymphatic drainage in tumor’s area as well as EPR effect (a particular
physiological parameter). After the direct delivery of drug to the tissues,
the modulation in drug distribution is caused in passive mode of tar­
geting [93].
6.1. Targeting of tumor by passive method
There are several limitations of passive targeting even if it is
considered as the base for clinical treatment. For instance, the loss of
control to target cells inside the tumor can occur due to lack of diffusible
property of many chemotherapeutic drugs inside the cells. In this situ­
ation, the cancer cells become resistant to the anticancer therapy which
is collectively called as multiple-drug resistance. Furthermore, the drug
diffusion processes are restricted at the final stage due to the modifi­
cation of cellular transport proteins caused by the uncontrolled differ­
entiations of cancer cells. Cancer cells will quickly be resistant against
generally used anticancer drugs after the drug discharge diffusion that
will automatically decrease the medicated activity. Several types of
Y. Mao et al.
tumors do not exhibit EPR effect that can restrict the efficacy of passive
targeting strategy and the distribution of drugs through the blood vessel
is not unique in any single tumor [93,94].
6.2. Targeting of tumor by active method
The maximum cells surface-binding and higher targeting potential­
ities are possible to achieve by the active tumor targeting. But the effi­
cacy of active targeting is reduced due to the absence of targeted
antigens available for nanocarriers binding within a tumor and higher
binding affinity can reduce internalization of nanocarriers into the solid
tumors due to the barrier of binding-site. The current restriction of
active targeting could be solved by generating novel binding sites or
increasing the number of binding sites [93,95–97].
7. Nanotherapeutics applications against cancer stem cells
The multistep process in cancer cells is metastasis which is dived into
four steps. The first step includes the migration and invasion from the
primary tumor, second step involves the intravasation and endurance in
the circulatory system, third step involves the extravasation into the far
away tissues while the final step involves the development of metastatic
foci in pre-specified organs [98,99]. The effective suppression of cancer
metastasis can result, if any of the aforementioned step come across any
interruption [99–102]. The photothermal therapy (PTT) alone or with
another therapy combined perform the attacking on local metastasis or
on cancer cell of primary tumors. It causes the elimination of metastatic
cancerous cells in long way sites along with inhibition of cell migration
and invasion activities [103,104]. The PTT in combination with
photodynamic therapy (PDT) is highly beneficial to minimize the
metastasis of different cancer types through the techniques presented in
Fig. 5 [105].
7.1. The photothermal therapy (PTT)
7.1.1. PTT alone
The PTT alone encouraged the direct elimination of cancer cells, but
the NIR laser technology has ability to infuse into softer tissues to a
couple of centimeters. The superficial tissues undergone the excision of
lymph metastasis or primary tumor through PTT [105–107]. The further
inhibition of metastasis in distant organs is initiated upon the NIR
radiotherapy and PTT can also directly kill the cancer stem cells and
tumor initiating cells or primary tumor places and lymphatic metastasis
via hyperthermia [108–110]. The inhibitory effects of hyperthermia on
the expression of a variety of metastasis-related factors consisting
transforming growth factor-β1 (TGF-β1), twist, vascular endothelial
growth factor, and matrix metalloproteinase (MMP-2/9) etc., inhibit the
Fig. 5. Schematic illumination of PDT-based synergistic approaches in com­
bination with other therapeutic modalities to fight against cancer. Reprinted
from Ref. [105] with permission from Elsevier. License Number:
5090420715830.
8
Journal of Drug Delivery Science and Technology 64 (2021) 102681
migration and invasion of cancer cells activity at the milder hyper­
thermia rate without any actual stimulation of cell death [111–113].
Table 1 summarizes the studies showing PTT alone or their combina­
torial therapies for the treatment of cancer metastasis.
7.1.2. Imaging-guided PTT
The improved therapeutic strategy could be constructed before and
after the operation of PTT in imaging guided PTT. The metastatic disease
is treated with real-time guidance through PTT combined with multi­
modal imaging [114–116]. When the PTN reaches the peak accumula­
tion to upgrade the therapeutic efficiency, then the imaging guidance
can be employed to reduce the adverse effects by particular elimination
of tumor or metastatic sites and to optimize the appropriate the time for
elimination [114]. The complete elimination of tumor cells with alone
PTT is complicated due to the diverse dispersion of PTN in tumor [117,
118]. Furthermore, it is a great challenge with PTT alone to eliminate
the metastatic nodules in distant organs and metastatic cancer cells due
to the restriction of penetration depth of NIR light in deep tissues. The
desired efficiency on cancer metastasis is achieved by the efficient
combination of PTT with recent management conditions of chemo­
therapy, immunotherapy, and radiotherapy to handle the metastatic and
cancerous cells.
The image guidance provides the valuable information to enhance
the therapeutic schemes with PTT and to secure the safety and efficiency
of the photothermal abduction [119–121]. The guidance investigation
has been determined through various techniques till now such as
multimodal imaging constating photoacoustic imaging, X-ray computed
tomography, and magnetic resonance imaging [122–124]. The SLNs are
the nearest host of metastatic cancer cells during the initial stage of
metastasis and the lymphatic metastasis is an essential pathway of
cancer cells dispersion [125,126]. The optimization of therapeutic
schemes in full course of PTT treatment and location of lymphatic node
metastasis are determined by the multimodal imaging guidance. But
these recent approaches are rarely employed in the imaging of distant
metastases in deep tissues of lung, liver or brain and restricted in the
lymph node metastasis mapping. The lymph node mapping during PTT
treatment is revealed through the widely used MRI (imaging guidance).
The imaging guidance is attained by the employing on the innate lymph
targeting and imaging capability of PTN. The effective theranostic
agents for diagnosis and treatment of lymphatic metastasis are devel­
oped by the manganese oxides functionalized MWNTs (MWNTs-MnO-­
PEG) and iron oxides nanoparticles modified graphene oxides
(GO-IONP) [127]. The metastatic lymph nodes were efficiently excised
by NIR irradiation and the regional lymph nodes nearby the primary
tumor could be readily mapped under the guidance of MRI and dark
imaging.
7.1.3. Multimodal-imaging guided PTT
The multimodal-imaging guided PTT is attained by the combination
of MRI with fluorescence imaging. The anchored metals in SWCNT
(PEGylated single-walled carbon nanotubes) were used to conduct the
T2-weighted MRI and for NIR-II fluorescence imaging (1000–1400 nm)
under low-power 808 nm laser excitation by SWCNT-PEG [114]. After
local injection, the delivery of (SWCNT-PEG) from principal tumor to
the SLNs was confirmed through the imaging results. The prolonged
survival benefits and the excellent inhibition of lungs metastasis or
breast cancer was achieved by the imaging guided PTT that demolished
the primary tumor and metastasized cancer cells in SLNs. Similarly, to
achieve the excellent dual imaging-guided PTT of cancer metastasis,
researchers also constructed a NIR dye (IR825) and gadolinium (Gd)
complexed albumin-based theragnostic agent (HSA-Gd-IR825) with
high lymph targeting ability [128]. For the multimodal imaging-guided
PTT of cancer metastasis, a strong theragnostic platform with bismuth
sulfide (Bi2S3) nanorods has been investigated [119]. These Bi2S3
nanorods act as photoacoustic imaging agent for inspection of their
real-time distribution in tumor sites and also act as a powerful CT
Y. Mao et al. Journal of Drug Delivery Science and Technology 64 (2021) 102681

Table 1
Photothermal therapy (PTT) alone or their combinatorial therapies for the treatment of cancer metastasis.
Medicinal technique Type of cancer PTN and its design Activity performed References

PTT combined with anti-CTLA-4
therapy
Chemo-photothermal therapy (PTT
combined with chemotherapy)
PTT combined with immune
adjuvant NPs and anti-cytotoxic T-
lymphocyte antigen-4 (CTLA4)
Synergistic Immune Photothermal
Nano therapy
Photothermal therapy combined
radiotherapy adjusted by CuS NPs
a single compartment nano-system
copper-64-labeled CuS NPs
Photothermal therapy combined
with imaging
Lung metastasis in mice Single walled carbon nanotubes modified with
polyethylene glycol (PEG)-grafted amphiphilic
polymer to obtain PEGylated-SWCNTs and
then combined with Anti-CTLA-4 Therapy
CT26 colon carcinoma Polydopamine-coated spiky gold nanoparticles
in animals (PDA-coated SGNPs) combined with sub-
therapeutic dose of doxorubicin (DOX)
4T1 breast tumor cells PLGA-ICG-R837 nanoparticles synthesis by
in mice and CT26 PLGA, ICG, R837 (TLR7 ligand), polyvinyl
colorectal cancer cell alcohol (PVA) and Polyethylene glycol (PEG)
lines
C57BL/6 mice PEG-functionalized GNS (GNS called gold nano
implanted with MB49 stars coated with polyethylene glycol) and
bladder cancer cells combined with anti-PD-L1 immunotherapy
Mice bearing Synthesis of CuS NPs and then combined with
subcutaneous BT474 radioactive amount of CuCl2 and non-
breast cancer model radioactive solution CuCl2
A549 cells lung cancer Synthesis of MWNTs (MWNTs-MnO-PEG) and
Lymph nodes metastasis evaluated by MRI and
dark imaging guided PTT
For in-vitro studies, bone marrow derived DCs [104]
separated from BALB/c mice.
For in-vitro studies, SGNP@PDAs as a PTT [166]
agent applied on CT26 colon cancer cells.
For in vivo studies, inoculation of BALB/c mice
on the right flank with 5 × 105 CT26 cells
For in-vitro studies, increase in DC maturation [167]
by the application of photothermal ablation
with PLGA-ICG-R837 4T1 breast tumor cells
after NIR-induction.
For in-vivo studies, BALB/c mice-bearing
subcutaneous 4T1 tumors and treated with
injected with PLGA-ICG or PLGA-ICG-R837
combined with together with CTLA-4 blockade
therapy
Increase in %age and cell number of PD- [168]
1+CD4 and PD-1+CD8 T cells and up-
regulation of PD-1 expression on CD4 and CD8
T cells shown in results after the combination
treatment
Tumor growth delay after the application of [110]
[Cu]CuS NPs followed by NIR laser treatment.
Removal of regional metastatic lymph nodes [127]

PTN: Photonanotherpeutics; PLGA: Polyethylene glycol (PEG) grafted PLGA co-polymer (mPEG-PLGA); CTLA4: anti-cytotoxic T-lymphocyte antigen-4.

contrast agent for angiography and organic imaging. The further
inhiation of lung metastases and removal of primary tumors are possibly
carried out upon the NIR laser with the Bi2S3 nanorods. Furthermore, the
targeting ligand alternation has been employed in lymphatic metastasis
imaging to enhance the selectivity of PTN to the metastatic cancer cells.
The antibody was developed for CT image guided PTT of HER-2 positive
breast malignancy along with the theragnostic W18O49 nanoparticles
altered with human epidermal growth receptor-2 (HER-2) [123]. The
extra survival period is observed in the mice bearing HER-2 positive
metastasis due to its clear differentiation CT guidance, optional removal
by NIR laser and due to the high X-ray attenuating and PTT potency.
Likewise, PA imaging with the folate conjugated golden carbon nano­
tubes was used for the detection of metastases in SLNs and then PTT was
used for the further execution [122].
7.1.4. Platinum nanoparticles mediated PTT
The photothermal therapy is used to prevent the early metastatic in
lymph nodes to reduce the further metastasis in distant organs or for the
prevention of cancer metastatic initiation [108,129]. The high speci­
ficity and less disturbance in lymph metastasis or in tumoral sites are
attained by the utilization of NIR laser irradiation that is adjusted to
stimulate the attack only on the cancer cells. Until now, different NIR
dyes-based nano agents, multi-walled carbon nanotubes and PTNs of
gold nanoparticles are utilized to combat with the cancer metastasis [99,
105]. For example, the effective abduction of bone metastasis by PTT
treatment is observed after the application of a polyethylene glycol
(PEG) functionalized MWNTs and trifolium-like platinum nanoparticles
[130]. An ammonium-tungsten-bronze [(NH4)xWO3] nano-cube in
NIR-II for the PTT of metastatic breast cancer by reviewing the deeper
tissue penetrating ability of laser in the second NIR window (1000–1400
nm, NIR-II) have been reported [108]. The efficient treatment of pri­
mary tumor and lung metastases in a metastatic breast cancer model is
treated by the implementation upon 1064 nm laser, the nano cube that
can cause the apoptosis and cell necrosis in metastatic cancer cells and
indicated as promising PTN treatment. Similarly, a potential therapeutic
mode for metastasis treatment in lymph nodes was introduced in which
they predicted that the gold nanorods (GNRs) upon NIR-II laser irradi­
ation could efficiently repress the tumor growth in the proper axillary
lymph nodes [105].
The PTN as particular targeting is considered as an essential pre­
requisite for the efficient treatment of primary tumor sites or lymph
node metastasis. A deep tumor penetrating NIR probe (DiR) loaded PTN
(DPN) for PTT of tumor progression and breast cancer metastasis was
used to upgrade the particular distribution of PTN in primary tumor site
[99]. For the photothermal removal of cancer cells, the 20–30 nm sized
DPN could diffuse deeply into the tissues of the tumor and upon NIR
irradiation, can be alter into the nano-firebombs. The DPN with NIR
irradiation was reported to inhibit the migration activities of metastatic
4T1 breast cancer cells and cell proliferation. Specifically, the single PTT
treatment efficiently repressed the tumor growth and lung metastasis of
breast cancer. Furthermore, the enhanced magnetic strategy was also
reported to treat the lymph node metastasis and to increase the targeting
avidity of PTN in lymph metastasis by the fabrication of PEGylated gold
shelled iron oxide nanocluster (IONC@Au-PEG) [106]. The accumula­
tion of PTN at the sentinel lymph nodes (SLNs) could be obviously
enhanced upon an external magnetic field focused on the tumor
metastasis region. The animal survival rate was increased with PTT
treatment after the inhibition of lung metastasis.
7.2. Photodynamic therapy (PDT)
Another potential therapy for cancer stem cells could be photody­
namic therapy (PDT), another light driven cancer treatment procedure
[131]. The visible light of suitable wavelength was used to activate the
photosensitizers of PDT to generate an excited state to produce the
cytotoxic species by various reactions. The first reaction includes the
synthesis of free radicals by an electron and transfer of hydrogen from
the substrate molecule also known as type-1 mechanism. The type-2
mechanism includes the transfer of energy to oxygen molecules that
produces the singlet oxygen that act as main cytotoxic species in PDT
[132,133]. The oxygen concentration of the tumor environment and the
photosensitizers are the principles of type-2 mechanism. In the hypoxic

9
Y. Mao et al. Journal of Drug Delivery Science and Technology 64 (2021) 102681

situation tumor microenvironment is responsible for the great restric­
tion of PDT efficacy. But the type-1 mechanism can address the limita­
tion of PDT due to its less sensitivity towards oxygen concentration. The
level of ROSs enhanced under hypoxic condition via type-1 mechanism
by the discovery of incorporated methylene blue into alginate-Aerosol
OTNPs discovered. This alginate polymer also mediates the interaction
enhancement of methylene blue with the solvent molecules. As
compared to the free methylene blue, the decrease in mammosphere
formation and excellent suppression of breast cancer stem cells were
observed in the results of PDT with methylene blue-NPs either under
hypoxia or normoxia condition [134]. Table 2 summarizes few recent
studies using PDT or combined PDT to reduce the cancer metastasis.
7.3. Radiotherapy along with the promising techniques
There are two ways of cancer stem cells targeting including the in­
hibition of pathway which are highly significant in cancer stem cells as
compared to the noncancer stem cells and targeting the overexpressed
structures in cancer stem cells. In context of radiotherapy, very limited
data is available to target the tumors. The currently utilized approaches
are given in Fig. 6. Different mammosphere-initiating cells of different
inflammatory and triple negative breast cancer cell lines are radio
sensitized in the translational study carried out by the HMG CoA
reductase (3-hydroxy-3-methylglutaryl-coenzyme-A-reductase) inhibi­
tor of simvastatin. As compared to these the other two non-
inflammatory breast cancer lines showed the radio protective effects
of simvastatin. The statins showed an independent link with the local
recurrence free survival in the retrospective clinical evaluation of 519
patients with inflammatory breast cancer [135]. This literature provides
the support for the highly risky breast cancer group due to the early
prospective clinical trial. The human HNSCC tumor model was treated
with fractionated irradiation along with an immuno-conjugate of an
anti-CD44v6 monoclonal antibody and the maytansinoid DM1 in the
pre-clinical experiments. A compared to the other combined majority
approaches, the alternating doe factor of 1.9 remain persistent in the
instant treatment that showed the improvement of permanent local
tumor control [136]. This data supports the analyzing the identical
techniques using targets that have tumor specificity, but the above uti­
lized compound was not further applied for the radiotherapy. The pa­
tients with lower expression were compared with the patients having the
high tumor expression of the standard isoform of CD44 linked with
considerably shorter overall survival in the aforementioned data. The
anti-CD44 antibodies were utilized alone or with the radiations in the
translational-preclinical experiments. The drug alone showed the
different effects on tumors such as the down regulation of stem cell
self-renewal genes, decrease in cell viability in-vitro and significant
cytotoxic effects on clonogenic tumor cells [137]. The use of therapeutic
techniques as the promising strategy can be the implementation of
radionuclide and radiolabeled antibodies combined with the with
positron emission tomography for the diagnosis. For example, the
improvement of local tumor was observed by the external beam radio­
therapy combined with the radio labeled anti-EGFR antibody cetuximab
[138]. As compared to the normal tissues, receptors or proteins
expressed in the tumors including putative CSC specific proteins are
responsible to conduct the targeting approaches [139].
7.4. Thermal therapy (hyperthermia)
The additional therapy used in various cancer treatments is called as
hyperthermia, in which the temperature of tumor loaded is increased
from 40 to 43 ◦ C. As compared to the alone chemotherapy, the
chemotherapy combined with hyperthermia demonstrated the signifi­
cant increase in cancer-survival rate of patients reported in several
studies. However, this procedure demands further clarity of molecular
processes as well as development of this technology. The tumor cells
with disarranged vascular structure show complication to absorb heat.
The hyperthermia attack or degenerate the tumor cells by selection and
stimulate the mechanism of apoptosis in cancer cells (Fig. 7) [140–142].
The multimodal anticancer strategies are combined with the clinical
application of hyperthermia. The combined hyperthermia with systemic
chemotherapy or ionizing radiation is dependent upon the scientific
evidence. Furthermore, the advanced tumor bodies, improvement to

Table 2
Recent studies on photodynamic therapy (PDT) or combined photodynamic to reduce the cancer metastasis.
Medicinal technique Type of cancer Nano mediators or used materials design Evaluation of results References

Synergistic chemiexcited
photodynamic therapy and
starvation therapy
Bioluminescence resonant
energy transfer (BRET)
combined with
photodynamic therapy
Photodynamic therapy
combined with enhanced
immunotherapy
Photodynamic therapy with
photosensitizer’s
Polymeric PDT with
conjugated fatty acid (oleic
acid)
BalB/C mice with lung
metastatic tumors
Insertion of CT26 cells into
mice at both flanks CT26
colorectal cancer cells and
LLC lung cancer cells
Pulmonary tumorous
metastasis mice model
BALB/c and nude mice
bearing CT26 mouse colon
carcinoma
L929 normal cell line of
mouse, human pancreas
cancer cells
PANC-1 and A549 human
lung cancer cell line
Preparation of SiO2–NH2, dSiO2, HMSNs and
HMSNs-NH2 synthesis of biomimetic
nanoreactor and modification of (HMSNs) with
the photosensitizer chlorin e6 (Ce6) and on the
surface of GOx. Preparation of HMSNs-GOx-
Ce6@CPPO-PFC/O2 and bio-NRs
Synthesis of self-illuminating conjugates Rluc8
(Luc) and QD (hereinafter Luc-QD).
Administration of Luc-QD conjugates into the
media and incubation. Analysis of cytotoxicity
in-vitro studies treatment of LN metastasis
through Peritumoral BL-PDT
Treatment of lymph node metastasis (B16F10)
Chimeric peptide C16–K(PpIX)-PEG8-KDEVD-
1MT designed as the PpIX-1MT nanoparticles
Formulation of photostable bacteriochlorin
(redaporfin) with intense infrared absorption to
increase the phototoxicity and ROS production
Synthesis of OPuC for the polymer
photosensitizer. Indication of OPuC efficacy by
the singlet oxygen production
Observation about unique role after the [169]
incubation of viability of cells with bio-NRs
lacking O2 reached 57.1% while the B16–F10
cells reduce to 20.7%. Complete removal of
lung metastasis in mice after the bio-NRs
Suppression of tumor growth in mice in-vivo [170]
indication of damage lymphatic structure and
cell death in LN cells by in-situ TUNEL. 0-fold
decrease in positive metastatic tumor cells
after the BL-PDT. Decrease in secondary LNs
and melanoma cells. Improvement in animal
survival and decrease in distant metastasis
Induction of apoptosis by light irradiation [171]
after the increase in ROS. Activation of
activate CD8+ T by inhibiting the IDO pathway
by the release of 1 MT from PpIX-1MT
nanoparticles discharged by caspase-3.
Inhibition and reduction of lung metastasis
High local inflammation and control of [172]
primary tumor observed by the Vascular-PDT
with redaporfin and control of metastasis
Generation of ROS species due to the enhanced [173]
solubility of OPuC in water. Survival rate was
3.61% in PANC-1, 7.07% in A549 and 33.48%
in HCT116 cancer positive cells

HMS-NPs: Hollow mesoporous silica nanoparticles; BL-PDT: BL-induced PDT (BL stands for bio luminance); ROS: reactive oxygen species; OPuC: oleic acid-pullulan-
Ce6.

10
Y. Mao et al.
Fig. 7. Various hyperthermic mechanisms involved in the destruction of tumors e.g., vessel destruction and necrotic cell death, activation of immune cells, heat-
shock proteins upregulation, membrane integrity loss. Reprinted from Ref. [165] with permission under a Creative Commons Attribution-Non Commercial 3.0
Unported Licence.
control local tumor and relapse free survival in patients with high risk
are attempted to improve through the combined hyperthermia with
systemic chemotherapy or ionizing radiation within the clinical pro­
tocols. The optimal toxic effects on tumor are necessary to attain after
the application of hyperthermia in patients with peritoneal carcinoma­
tosis of ovarian or gastrointestinal cancer and this condition is known as
hyperthermic intraperitoneal chemotherapy [143]. The radiation ther­
apy shows effectiveness after the increase in oxygenation caused by
selective temperature that induce the dilation of blood vessels. The
formation of DNA damaging free radicals is observed that facilitates the
oxygen to acts as radiosensitizer and increase the effective dose of ra­
diation. Hypoxic cells are resistant to the damage of radiation because
the oxygenated surroundings support the radiation damage. The sensi­
tivity of the radiation therapy is increased as the result of biochemical
11
Journal of Drug Delivery Science and Technology 64 (2021) 102681
Fig. 6. The strategies for targeting cancer
stem cells for combined treatment. The po­
tential high-dose radiotherapeutics for the
treatment of solid tumors by inactivation of
cancer stem cells. Reappearance commonly
existent by one or few remaining CSCs.
Strategy for specifically targeting pathways
or cancer stem cells with high importance as
compared to tumor cell mas, would be
promising to enhance tumoral control by
combined radiotherapeutic treatment.
Reprinted from Ref. [164] with permission
from Elsevier. License Number:
5090420981597.
effects such as heat shock that reduced the cell division. The exposure of
minor heat to the cells induces apoptosis while the intense heat causes
the coagulation and denaturation of proteins [144–146].
The easy synthesis and cost effectiveness of iron oxide nanoparticle
make them efficient candidate for the utilization in biomedical appli­
cations [147]. The technique of magnetic hyperthermia utilizes the iron
oxide nanoparticles due to their superparamagnetic properties and the
alternating magnetic field generate the heat by the magnetic nano­
particles [148]. Over the traditional hyperthermia techniques, the
magnetic hyperthermia has various benefits. The simultaneous diag­
nosis and therapy can be permitted due to the heat production impact of
magnetic nanoparticles under AFM excitation along with their contrast
enhancement capability in magnetic resonance imaging. The instant
delivery of hyperthermia in combination with other cancer techniques
Y. Mao et al. Journal of Drug Delivery Science and Technology 64 (2021) 102681

such as radiotherapy and chemotherapy enable MNPs to realize the
importance of combinatorial cancer treatment strategy [149]. The MNPs
have ability to distribute energy into the smaller portions of tissues so,
the MHT is able to choose and deliver heat uniformly to the tumors.
Without any penetration restriction, the magnetic hyperthermia can
especially attack on deep-seated areas of the body [147]. The efficient
targeting of cancer stem cells is seen due to the particular attack of MHT
on the tumor vasculature or hypoxic tumor cells [150].
Magnetic hyperthermia use two type of nanoparticles such as
magnetite (Fe3O4) and maghemite (γ-Fe2O3) due to their excellent
biodegradability and biocompatible properties [151,152]. The synthesis
of ROS is enhanced due to the magnetic nanoparticles observed by
several reports [153–155]. The leaching of iron molecules generates the
ROS and modify the other organelle and mitochondrial functions along
with the stimulation of cell signaling pathways. The direct synthesis of
ROS from the nanoparticles surface is happened through the basic ori­
gins of oxidative stress in response to IONPs [156]. The DNA damage
and cytotoxicity can be caused due to the synthesis of ROS and high level
of Fe ions [157]. The nanoparticle mediated magnetic hyperthermia can
efficiently kill the cancer stem cells and suppress the tumor growth re­
ported by many current investigations. The MDA-MB-231 cancer cell
lines and cancer stem cells in A549 are reported to eradicate through the
induction of MHT induced by the SPIONs. The lower killing potency was
observed after the exposure traditional hyperthermia for 30 min while
the MHT resulted 90% cell death in both cell lines indicated by the re­
sults. The MHT decrease the population of cancer stem cells efficiently
through two pathways indicated by further experiments. After the MHT,
the acute necrotic cell death happens instantly called as the first
pathway and it is short term. The enhanced level of ROS synthesis ul­
timately results to apoptosis after some reaction, and it is the second
pathway with long term effects [158]. The highest value of specific
absorption rate was determined by the magnetic nanocluster of size 60
nm while the impact of particle size was determined among the mag­
netic nanocluster (MNC) of various sizes within 20–140 nm range,
investigated by the Kwon and coworkers in another report. The MNC
with 60 nm showed the reduction in cell viability and increase in
temperature under AMF as compared to other particle size. The MHT
was utilized further for the down regulation of HSP 70 and 90 along with
their expression levels that provide protection against heat stress to
achieve to process of apoptosis at the end. The MHT also tend to
decrease the expression of breast cancer stem cell markers (ALDH1 and
CD44+/CD24− ) [159]. Further studies on hyperthermia or combined
hyperthermia to reduce the cancer metastasis are summarized in
Table 3.
8. Conclusions and outlook
Nanocarriers have shown promising characteristics to accelerate the
development of efficient methodologies to efficiently treat recurrent
cancers and drug resistance. Despite significant advancements in
nanotherapeutics, the development of nanoplatform-based methodolo­
gies and targeted drug delivery approaches face serious limitations and
challenges in effective treatments in-vivo. Herein, we have made an
effort to summarized various challenges and limitations of nano­
structures e.g., poor distribution and ineffective uptake of drug mole­
cules in tumoral area, limited oral availability, and retention in
macrophages of reticuloendothelial system and in bypassing organs
after systemic administration. Moreover, various drug delivery systems
by overplaying several factors i.e., type of vector, surface modification,
size, charge, and architecture, may influence the characteristics and
efficiency of nano-formulated drug. As a solution, science needs sub­
stantial and systemic research studies regarding drug administration
routes. Currently, major directions in drug resistant therapeutics and the
targeting of cancer stem cells are associated with designing novel
methodologies for gene-targeting against proteins responsible for the
survival of cancer stem cells and intrinsic drug resistance, e.g., nano­
carriers and polymer-drug conjugates, development of novel inhibitors
and drug molecules having improved efficiency, underlying signaling
pathways, antiapoptotic proteins, and drug efflux transporters which are
able to reach cancer stem cells and their microenvironment (niche).
The designing of bioimaging modalities with high sensitivity
including theranostics for precise site of cancer stem cells, and

Table 3
Recent studies on hyperthermia or combined hyperthermia to reduce the cancer metastasis.
Medicinal technique Type of cancer Nano mediators or materials used Evaluation of results References
design

Mild magnetic hyperthermia
combined with immune check point
therapy
Short-time focused ultrasound (FUS)
hyperthermia
Hyperthermia combined with the
ionizing radiation
Modulated Electric Hyperthermia
Magnetic nanoparticle hyperthermia
(2× 43 ◦ C/45 min) or immunogenic
virus-like nanoparticle (VLP, 2 ×
200 μg) or Hypo fractionated
radiation (6 × 6Gy)
Orthotopic 4T1 tumor model
and lung metastasis
Brain metastasis of breast
cancer
Mouse melanoma cell line
B16–F10
Human liver cancer cell (HCC)
lines Huh7 and HepG2
Six canine tumor models (two
oral melanoma, three oral
amelioblastomas and one non-
oral carcinomas)
Synthesis of biocompatible PEGylated
FVIOs as source of heat generation
under AMF
Pegylated liposomal doxorubicin
(PLD) used in the experiment
PRIMART linear accelerator of 6 mV
to irradiate the tumors locally with
the 2Gy dose
LAB-EHY100 device to induce the
electric hypothermia
Bionised nanoferrite (BNF) iron oxide
nanoparticles to generate alternating
magnetic field. Viral like nanoparticle
(modified version of cowpea mosaic
virus)
Prevention of lung metastasis through the mild [174]
magnetic hyperthermia combined with anti-
PD-L1
Activation of anti-tumor immunity of tumor
specific T-cells in vivo. Inhibition of the
immunosuppressive response of tumors in vivo
Increase in the PLD delivery to the brain and to [175]
the tumor affected tissues through the FUS.
Increase in cytotoxic ability of PLD due to the
FUS. Inhibition of tumors proliferation
Attained the mixture of apoptotic and necrotic [176]
cells after the application of hyperthermia
combined with ionized radiation. Increase in
release of danger signals HMGB1 and Hsp70.
Inhibition of tumor growth through
hyperthermia combined with ionized radiation
Inhibition of tumor proliferation and induction [177]
of apoptosis in HCC lines after the (mEHT)
treatment revealed by in vitro studies
In vivo studies revealed the suppression of
cancer cells growth by mEHT.
Indication of tumor free site, 30 months post- [178]
treatment after the application iron oxide
nanoparticle with AMF. Indication of post-
treatment fibrosis and chronic inflammation,
but no tumor cells six months post treatment
after the viral like nanoparticle treatment

FVIOs: ferrimagnetic vortex-domain iron oxide nano rings; mEHT: modulated electric hyperthermia; AMF: alternating magnetic field.

12
Y. Mao et al.
applications of physical destruction methods e.g., photothermal therapy
(PTT), photodynamic therapy (PDT), hyperthermia, and radio­
therapeutic methodologies and so on. Advanced nano-formulations of
drug-nanocarrier conjugate for effective cancer stem cells targeting and
drug resistant must be synthesized by targeting ligands that specifically
bind with cancer stem cells-specific receptors, nanocarriers having
supporting drug molecules, high drug-loading capability, e.g., inhibitors
of proapoptotic proteins or P–gp, and pathways capable of sensing
therapeutic drugs, cancer stem cells, drug molecules efficient against
mitotic-inactivation of cancer stem cells, and conventional therapies to
eliminate dominant tumoral mass. The multi-modal drug transport
methodologies to overcome tumoral drug resistance of cancer stem cells
have also been summarized in this review. Following such ideas, sci­
entists recently developed nanogel hydrophilic carriers which can
transport cancer drugs, activated nucleoside analogs, gene targeting
molecules e.g., siRNA against resistant types of cancer stem cells
[160–162]. Drug encapsulated in nanogels occasionally show more than
100-folds of improved efficiency against cancer stem cells, lymphomas,
prostate, and breast cancers as compared with free drugs. Specific
combination of nano-formulations and drug molecules could impart
effectiveness against cancer stem cells and drug-resistant cells. The
principal idea of striking more promising and competitive cells with low
resistance to chemo-/radiotherapeutics and proliferation rate to prevent
tumoral relapse remain challenged. Although potential of nano­
medicines is not fully understood, and its effectiveness against immu­
nological or chemotherapeutic methodologies continue to be
established.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgement
Consejo Nacional de Ciencia y Tecnología (MX) is thankfully
acknowledged for partially supporting this work under Sistema Nacional
de Investigadores (SNI) program awarded to Hafiz M.N. Iqbal (CVU:
735340). Authors are thankful to their representative universities for
providing literature facilities.
References
[1] F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global
cancer statistics 2018: GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries, CA A Cancer J. Clin. 68 (6) (2018)
394–424.
[2] American Cancer Society, Global Cancer Facts & Figures, fourth ed., American
Cancer Society, Atlanta, 2018. Available at: https://www.cancer.org/research/ca
ncer-facts-statistics/global.html. (Accessed 2 April 2021).
[3] K.M. Coyle, J.E. Boudreau, P. Marcato, Genetic mutations and epigenetic
modifications: driving cancer and informing precision medicine, BioMed Res. Int.
2017 (2017), 9620870.
[4] Y. Zhao, M. Bilal, A. Raza, M.I. Khan, S. Mehmood, U. Hayat, H.M. Iqbal, Tyrosine
kinase inhibitors and their unique therapeutic potentialities to combat cancer,
Int. J. Biol. Macromol. 168 (2020) 22–37.
[5] M.I. Khan, F. Batool, F. Kalsoom, R. Ali, F. Li, J. Wang, B. Qiu, New insights on
unique therapeutic potentialities of prostacyclin and prostacyclin synthase,
Materials Today Chemistry 16 (2020) 100258.
[6] M. Sasako, Role of surgery in multidisciplinary treatment for solid cancers, Int. J.
Clin. Oncol. 9 (5) (2004) 346–351.
[7] B. Mansoori, A. Mohammadi, S. Davudian, S. Shirjang, B. Baradaran, The
different mechanisms of cancer drug resistance: a brief review, Adv. Pharmaceut.
Bull. 7 (3) (2017) 339.
[8] V. Schirrmacher, From chemotherapy to biological therapy: a review of novel
concepts to reduce the side effects of systemic cancer treatment, Int. J. Oncol. 54
(2) (2019) 407–419.
[9] Y. Pan, S. Ma, K. Cao, S. Zhou, A. Zhao, M. Li, C. Zhu, Therapeutic approaches
targeting cancer stem cells, J. Canc. Res. Therapeut. 14 (7) (2018) 1469.
13
Journal of Drug Delivery Science and Technology 64 (2021) 102681
[10] S.A. Qamar, M. Asgher, N. Khalid, M. Sadaf, Nanobiotechnology in health
sciences: current applications and future perspectives, Biocatalysis and
Agricultural Biotechnology 22 (2019) 101388.
[11] M. Asgher, S.A. Qamar, H.M. Iqbal, Microbial exopolysaccharide-based nano-
carriers with unique multi-functionalities for biomedical sectors, Biologia (2020)
1–13.
[12] M. Asgher, S.A. Qamar, M. Sadaf, H.M. Iqbal, Multifunctional materials
conjugated with near-infrared fluorescent organic molecules and their targeted
cancer bioimaging potentialities, Biomedical Physics & Engineering Express 6 (1)
(2020), 012003.
[13] S. Liu, S.A. Qamar, M. Qamar, K. Basharat, M. Bilal, Engineered nanocellulose-
based hydrogels for smart drug delivery applications, Int. J. Biol. Macromol. 181
(2021) 275–290.
[14] D. Nassar, C. Blanpain, Cancer stem cells: basic concepts and therapeutic
implications, Annu. Rev. Pathol. 11 (2016) 47–76.
[15] S. Dawood, L. Austin, M. Cristofanilli, Cancer stem cells: implications for cancer
therapy, Oncology (Williston Park) 28 (12) (2014) 1101–1107.
[16] M.A.S. Moore, N. Williams, D. Metcalf, In vitro colony formation by normal and
leukemic human hematopoietic cells: characterization of the colony-forming
cells, J. Natl. Cancer Inst. 50 (3) (1973) 603–623.
[17] T. Lapidot, C. Sirard, J. Vormoor, B. Murdoch, T. Hoang, J. Caceres-Cortes, J.
E. Dick, A cell initiating human acute myeloid leukaemia after transplantation
into SCID mice, Nature 367 (6464) (1994) 645–648.
[18] A. Kuşoğlu, Ç.B. Avcı, Cancer stem cells: a brief review of the current status, Gene
681 (2019) 80–85.
[19] A.G. Smith, K.F. Macleod, Autophagy, cancer stem cells and drug resistance,
J. Pathol. 247 (5) (2019) 708–718.
[20] L.T.H. Phi, I.N. Sari, Y.G. Yang, S.H. Lee, N. Jun, K.S. Kim, H.Y. Kwon, Cancer
stem cells (CSCs) in drug resistance and their therapeutic implications in cancer
treatment, Stem Cell. Int. 2018 (2018), 5416923.
[21] L. Ding, T.J. Ley, D.E. Larson, C.A. Miller, D.C. Koboldt, J.S. Welch, J.F. DiPersio,
Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome
sequencing, Nature 481 (7382) (2012) 506–510.
[22] Y. Garcia-Mayea, C. Mir, F. Masson, R. Paciucci, M.E. LLeonart, February).
Insights into new mechanisms and models of cancer stem cell multidrug
resistance, in: Seminars in Cancer Biology, vol. 60, Academic Press, 2020,
pp. 166–180.
[23] V. Smidova, P. Michalek, Z. Goliasova, T. Eckschlager, P. Hodek, V. Adam,
Z. Heger, Nanomedicine of tyrosine kinase inhibitors, Theranostics 11 (4) (2021)
1546.
[24] W. Wang, F. Li, S. Li, Y. Hu, M. Xu, Y. Zhang, B. Qiu, M2 macrophage-targeted
iron oxide nanoparticles for magnetic resonance image-guided magnetic
hyperthermia therapy, J. Mater. Sci. Technol. 81 (2021) 77–87.
[25] H. Easwaran, H.C. Tsai, S.B. Baylin, Cancer epigenetics: tumor heterogeneity,
plasticity of stem-like states, and drug resistance, Mol. Cell 54 (5) (2014)
716–727.
[26] A.C. Obenauf, Y. Zou, A.L. Ji, S. Vanharanta, W. Shu, H. Shi, J. Massagué,
Therapy-induced tumour secretomes promote resistance and tumour progression,
Nature 520 (7547) (2015) 368–372.
[27] Y. Hou, Q. Zhu, Z. Li, Y. Peng, X. Yu, B. Yuan, X. Li, The FOXM1–ABCC5 axis
contributes to paclitaxel resistance in nasopharyngeal carcinoma cells, Cell Death
Dis. 8 (3) (2017) e2659-e2659.
[28] R. Ohashi, K. Kawahara, S. Namimatsu, R. Okamura, T. Igarashi, I. Sugitani,
Z. Naito, Expression of MRP1 and ABCG2 is associated with adverse clinical
outcomes of papillary thyroid carcinoma with a solid component, Hum. Pathol.
67 (2017) 11–17.
[29] Z.X. Wu, Q.X. Teng, C.Y. Cai, J.Q. Wang, Z.N. Lei, Y. Yang, Z.S. Chen, Tepotinib
reverses ABCB1-mediated multidrug resistance in cancer cells, Biochem.
Pharmacol. 166 (2019) 120–127.
[30] T. Boulding, R.D. McCuaig, A. Tan, K. Hardy, F. Wu, J. Dunn, S. Rao, LSD1
activation promotes inducible EMT programs and modulates the tumour
microenvironment in breast cancer, Sci. Rep. 8 (1) (2018) 1–18.
[31] M. Bartucci, R. Dattilo, C. Moriconi, A. Pagliuca, M. Mottolese, G. Federici, R. De
Maria, TAZ is required for metastatic activity and chemoresistance of breast
cancer stem cells, Oncogene 34 (6) (2015) 681–690.
[32] T. Lu, Z. Li, Y. Yang, W. Ji, Y. Yu, X. Niu, S. Lu, The Hippo/YAP1 pathway
interacts with FGFR1 signaling to maintain stemness in lung cancer, Canc. Lett.
423 (2018) 36–46.
[33] H. Cha, S. Hong, J.H. Park, H.H. Park, Stem cell-derived exosomes and
nanovesicles: promotion of cell proliferation, migration, and anti-senescence for
treatment of wound damage and skin ageing, Pharmaceutics 12 (12) (2020)
1135.
[34] J. Wang, X. Zhuang, K.S. Greene, H. Si, M.A. Antonyak, J.E. Druso, H. Wang,
Cdc42 functions as a regulatory node for tumour-derived microvesicle biogenesis,
J. Extracell. Vesicles 10 (3) (2021), e12051.
[35] R. Safaei, B.J. Larson, T.C. Cheng, M.A. Gibson, S. Otani, W. Naerdemann, S.
B. Howell, Abnormal lysosomal trafficking and enhanced exosomal export of
cisplatin in drug-resistant human ovarian carcinoma cells, Mol. Canc. Therapeut.
4 (10) (2005) 1595–1604.
[36] C. Peitzsch, I. Kurth, L. Kunz-Schughart, M. Baumann, A. Dubrovska, Discovery of
the cancer stem cell related determinants of radioresistance, Radiother. Oncol.
108 (3) (2013) 378–387.
[37] A. Kreso, C.A. O’Brien, P. Van Galen, O.I. Gan, F. Notta, A.M. Brown, J.E. Dick,
Variable clonal repopulation dynamics influence chemotherapy response in
colorectal cancer, Science 339 (6119) (2013) 543–548.
Y. Mao et al.
[38] T.B. Toh, J.J. Lim, E.K.H. Chow, Epigenetics in cancer stem cells, Mol. Canc. 16
(1) (2017) 1–20.
[39] K. Nio, T. Yamashita, S. Kaneko, The evolving concept of liver cancer stem cells,
Mol. Canc. 16 (1) (2017) 1–12.
[40] C.R. Arnold, J. Mangesius, I.I. Skvortsova, U. Ganswindt, The role of cancer stem
cells in radiation resistance, Frontiers in oncology 10 (2020) 164.
[41] H. Chen, W. Zhang, G. Zhu, J. Xie, X. Chen, Rethinking cancer nanotheranostics,
Nature Reviews Materials 2 (7) (2017) 1–18.
[42] T.G.G.M. Lammers, W.E. Hennink, G. Storm, Tumour-targeted nanomedicines:
principles and practice, Br. J. Canc. 99 (3) (2008) 392–397.
[43] P. Chen, L. Wang, X. Fan, X. Ning, B. Yu, C. Ou, M. Chen, Targeted delivery of
extracellular vesicles in heart injury, Theranostics 11 (5) (2021) 2263.
[44] F.M. Kievit, M. Zhang, Cancer nanotheranostics: improving imaging and therapy
by targeted delivery across biological barriers, Adv. Mater. 23 (36) (2011)
H217–H247.
[45] R.M. Samarasinghe, J. Gibbons, R.K. Kanwar, J.R. Kanwar, Nanotechnology
based platforms for survivin targeted drug discovery, Expet Opin. Drug Discov. 7
(11) (2012) 1083–1092.
[46] B.Z. Carter, Y. Qiu, X. Huang, L. Diao, N. Zhang, K.R. Coombes, S.M. Kornblau,
Survivin is highly expressed in CD34+ 38− leukemic stem/progenitor cells and
predicts poor clinical outcomes in AML. Blood, The Journal of the American
Society of Hematology 120 (1) (2012) 173–180.
[47] S. Anguille, V.F. Van Tendeloo, Z.N. Berneman, Leukemia-associated antigens
and their relevance to the immunotherapy of acute myeloid leukemia, Leukemia
26 (10) (2012) 2186–2196.
[48] L. Tang, X. Ling, W. Liu, G.M. Das, F. Li, Transcriptional inhibition of p21WAF1/
CIP1 gene (CDKN1) expression by survivin is at least partially p53-dependent:
evidence for survivin acting as a transcription factor or co-factor, Biochem.
Biophys. Res. Commun. 421 (2) (2012) 249–254.
[49] S.O. Lee, T. Andey, U.H. Jin, K. Kim, M. Sachdeva, S. Safe, The nuclear receptor
TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53,
Oncogene 31 (27) (2012) 3265–3276.
[50] J. Deng, Y. Liu, H. Lee, A. Herrmann, W. Zhang, C. Zhang, H. Yu, S1PR1-STAT3
signaling is crucial for myeloid cell colonization at future metastatic sites, Canc.
Cell 21 (5) (2012) 642–654.
[51] D.D. De Carvalho, S. Sharma, J.S. You, S.F. Su, P.C. Taberlay, T.K. Kelly, P.
A. Jones, DNA methylation screening identifies driver epigenetic events of cancer
cell survival, Canc. Cell 21 (5) (2012) 655–667.
[52] J.M. Huang, I. Nagatomo, E. Suzuki, T. Mizuno, T. Kumagai, A. Berezov, Q. Wang,
YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is
negatively regulated by the non-receptor type protein tyrosine phosphatase 14,
Oncogene 32 (17) (2013) 2220–2229.
[53] Y. Xie, L.A. Tobin, J. Camps, D. Wangsa, J. Yang, M. Rao, K.F. Kwong, MicroRNA-
24 regulates XIAP to reduce the apoptosis threshold in cancer cells, Oncogene 32
(19) (2013) 2442–2451.
[54] L.Y. Dimberg, C.K. Anderson, R. Camidge, K. Behbakht, A. Thorburn, H.L. Ford,
On the TRAIL to successful cancer therapy? Predicting and counteracting
resistance against TRAIL-based therapeutics, Oncogene 32 (11) (2013)
1341–1350.
[55] F. Nazio, M. Bordi, V. Cianfanelli, F. Locatelli, F. Cecconi, Autophagy and cancer
stem cells: molecular mechanisms and therapeutic applications, Cell Death Differ.
26 (4) (2019) 690–702.
[56] M. Shirmohamadi, E. Eghbali, S. Najjary, A. Mokhtarzadeh, A.B. Kojabad,
K. Hajiasgharzadeh, B. Baradaran, Regulatory mechanisms of microRNAs in
colorectal cancer and colorectal cancer stem cells, J. Cell. Physiol. 235 (2) (2020)
776–789.
[57] Q. Liu, R.T. Li, H.Q. Qian, J. Wei, L. Xie, J. Shen, B.R. Liu, Targeted delivery of
miR-200c/DOC to inhibit cancer stem cells and cancer cells by the gelatinases-
stimuli nanoparticles, Biomaterials 34 (29) (2013) 7191–7203.
[58] S. Shi, L. Han, T. Gong, Z. Zhang, X. Sun, Systemic delivery of microRNA-34a for
cancer stem cell therapy, Angew. Chem. 125 (14) (2013) 3993–3997.
[59] S. Shigdar, J. Lin, Y. Yu, M. Pastuovic, M. Wei, W. Duan, RNA aptamer against a
cancer stem cell marker epithelial cell adhesion molecule, Canc. Sci. 102 (5)
(2011) 991–998.
[60] S. Shigdar, L. Qiao, S.F. Zhou, D. Xiang, T. Wang, Y. Li, W. Duan, RNA aptamers
targeting cancer stem cell marker CD133, Canc. Lett. 330 (1) (2013) 84–95.
[61] J.R. Kanwar, G. Mahidhara, R.K. Kanwar, Novel alginate-enclosed
chitosan–calcium phosphate-loaded iron-saturated bovine lactoferrin
nanocarriers for oral delivery in colon cancer therapy, Nanomedicine 7 (10)
(2012) 1521–1550.
[62] J.R. Kanwar, G. Mahidhara, K. Roy, S. Sasidharan, S. Krishnakumar, N. Prasad, R.
K. Kanwar, Fe-bLf nanoformulation targets survivin to kill colon cancer stem cells
and maintains absorption of iron, calcium and zinc, Nanomedicine 10 (1) (2015)
35–55.
[63] K. Kise, Y. Kinugasa-Katayama, N. Takakura, Tumor microenvironment for cancer
stem cells, Adv. Drug Deliv. Rev. 99 (2016) 197–205.
[64] A. Urbaniak, M. Delgado, M. Antoszczak, A. Huczyński, T.C. Chambers,
Salinomycin derivatives exhibit activity against primary acute lymphoblastic
leukemia (ALL) cells in vitro, Biomed. Pharmacother. 99 (2018) 384–390.
[65] J. Dewangan, S. Srivastava, S. Mishra, A. Divakar, S. Kumar, S.K. Rath,
Salinomycin inhibits breast cancer progression via targeting HIF-1α/VEGF
mediated tumor angiogenesis in vitro and in vivo, Biochem. Pharmacol. 164
(2019) 326–335.
[66] H. Shen, C.C. Sun, L. Kang, X. Tan, P. Shi, L. Wang, J. Gong, Low-dose
salinomycin inhibits breast cancer metastasis by repolarizing tumor hijacked
14
Journal of Drug Delivery Science and Technology 64 (2021) 102681
macrophages toward the M1 phenotype, Eur. J. Pharmaceut. Sci. 157 (2021)
105629.
[67] Y. Zhang, H. Zhang, X. Wang, J. Wang, X. Zhang, Q. Zhang, The eradication of
breast cancer and cancer stem cells using octreotide modified paclitaxel active
targeting micelles and salinomycin passive targeting micelles, Biomaterials 33 (2)
(2012) 679–691.
[68] T.M. Sun, Y.C. Wang, F. Wang, J.Z. Du, C.Q. Mao, C.Y. Sun, J. Wang, Cancer stem
cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone
bonds, Biomaterials 35 (2) (2014) 836–845.
[69] S. Thakkar, D. Sharma, K. Kalia, R.K. Tekade, A cross-talk on tumor
microenvironment targeted nanotherapeutics for cancer therapy and diagnosis,
2019. Available at: SSRN 3396277.
[70] S. Thakkar, D. Sharma, K. Kalia, R.K. Tekade, Tumor microenvironment targeted
nanotherapeutics for cancer therapy and diagnosis: a review, Acta Biomater. 101
(2020) 43–68.
[71] S.S. Linton, S.G. Sherwood, K.C. Drews, M. Kester, Targeting cancer cells in the
tumor microenvironment: opportunities and challenges in combinatorial
nanomedicine, Wiley Interdisciplinary Reviews: Nanomedicine and
Nanobiotechnology 8 (2) (2016) 208–222.
[72] M.Z. Ahmad, M. Rizwanullah, J. Ahmad, M.Y. Alasmary, M.H. Akhter, B.
A. Abdel-Wahab, A. Haque, Progress in nanomedicine-based drug delivery in
designing of chitosan nanoparticles for cancer therapy, International Journal of
Polymeric Materials and Polymeric Biomaterials (2021) 1–22.
[73] R.K. Jain, Normalization of tumor vasculature: an emerging concept in
antiangiogenic therapy, Science 307 (5706) (2005) 58–62.
[74] D. Banerjee, R. Harfouche, S. Sengupta, Nanotechnology-mediated targeting of
tumor angiogenesis, Vasc. Cell 3 (1) (2011) 1–13.
[75] M. Cesca, F. Bizzaro, M. Zucchetti, R. Giavazzi, Tumor delivery of chemotherapy
combined with inhibitors of angiogenesis and vascular targeting agents, Frontiers
in oncology 3 (2013) 259.
[76] V. Riabov, A. Gudima, N. Wang, A. Mickley, A. Orekhov, J. Kzhyshkowska, Role
of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis,
Front Physiol. 2014 5 (2014) 75.
[77] S. Sengupta, D. Eavarone, I. Capila, G. Zhao, N. Watson, T. Kiziltepe,
R. Sasisekharan, Temporal targeting of tumour cells and neovasculature with a
nanoscale delivery system, Nature 436 (7050) (2005) 568–572.
[78] O. Benny, O. Fainaru, A. Adini, F. Cassiola, L. Bazinet, I. Adini, J. Folkman, An
orally delivered small-molecule formulation with antiangiogenic and anticancer
activity, Nat. Biotechnol. 26 (7) (2008) 799–807.
[79] O. Trédan, C.M. Galmarini, K. Patel, I.F. Tannock, Drug resistance and the solid
tumor microenvironment, J. Natl. Cancer Inst. 99 (19) (2007) 1441–1454.
[80] F. Klemm, J.A. Joyce, Microenvironmental regulation of therapeutic response in
cancer, Trends Cell Biol. 25 (4) (2015) 198–213.
[81] V. Gkretsi, A. Stylianou, P. Papageorgis, C. Polydorou, T. Stylianopoulos,
Remodeling components of the tumor microenvironment to enhance cancer
therapy, Frontiers in oncology 5 (2015) 214.
[82] I.M. Adjei, S. Blanka, Modulation of the tumor microenvironment for cancer
treatment: a biomaterials approach, J. Funct. Biomater. 6 (1) (2015) 81–103.
[83] S.R. Hingorani, W.P. Harris, J.T. Beck, B.A. Berdov, S.A. Wagner, E.
M. Pshevlotsky, C.E. Devoe, Phase Ib study of PEGylated recombinant human
hyaluronidase and gemcitabine in patients with advanced pancreatic cancer, Clin.
Canc. Res. 22 (12) (2016) 2848–2854.
[84] M. Kanapathipillai, A. Mammoto, T. Mammoto, J.H. Kang, E. Jiang, K. Ghosh, D.
E. Ingber, Inhibition of mammary tumor growth using lysyl oxidase-targeting
nanoparticles to modify extracellular matrix, Nano Lett. 12 (6) (2012)
3213–3217.
[85] B. Zhang, S. Shen, Z. Liao, W. Shi, Y. Wang, J. Zhao, X. Jiang, Targeting
fibronectins of glioma extracellular matrix by CLT1 peptide-conjugated
nanoparticles, Biomaterials 35 (13) (2014) 4088–4098.
[86] E.L. Siegler, Y.J. Kim, P. Wang, Nanomedicine targeting the tumor
microenvironment: therapeutic strategies to inhibit angiogenesis, remodel
matrix, and modulate immune responses, Journal of Cellular Immunotherapy 2
(2) (2016) 69–78.
[87] D.S. Kohane, Microparticles and nanoparticles for drug delivery, Biotechnol.
Bioeng. 96 (2) (2007) 203–209.
[88] P.N. Navya, A. Kaphle, S.P. Srinivas, S.K. Bhargava, V.M. Rotello, H.K. Daima,
Current trends and challenges in cancer management and therapy using designer
nanomaterials, Nano Convergence 6 (1) (2019) 1–30.
[89] A.I. Minchinton, I.F. Tannock, Drug penetration in solid tumours, Nat. Rev. Canc.
6 (8) (2006) 583–592.
[90] C.H. Heldin, K. Rubin, K. Pietras, A. Östman, High interstitial fluid pressure—an
obstacle in cancer therapy, Nat. Rev. Canc. 4 (10) (2004) 806–813.
[91] H. Kobayashi, R. Watanabe, P.L. Choyke, Improving conventional enhanced
permeability and retention (EPR) effects; what is the appropriate target?
Theranostics 4 (1) (2014) 81.
[92] B. Rajitha, R.R. Malla, R. Vadde, P. Kasa, G.L.V. Prasad, B. Farran, G.P. Nagaraju,
Horizons of nanotechnology applications in female specific cancers, in: Seminars
in Cancer Biology, Academic Press, 2019, July.
[93] S.M. Sharker, J.E. Lee, S.H. Kim, J.H. Jeong, I. In, H. Lee, S.Y. Park, pH triggered
in vivo photothermal therapy and fluorescence nanoplatform of cancer based on
responsive polymer-indocyanine green integrated reduced graphene oxide,
Biomaterials 61 (2015) 229–238.
[94] D. Peer, J.M. Karp, S. Hong, O.C. Farokhzad, R. Margalit, R. Langer, Nanocarriers
as an emerging platform for cancer therapy, Nat. Nanotechnol. 2 (12) (2007)
751–760.
Y. Mao et al.
[95] R. Bazak, M. Houri, S. El Achy, S. Kamel, T. Refaat, Cancer active targeting by
nanoparticles: a comprehensive review of literature, J. Canc. Res. Clin. Oncol.
141 (5) (2015) 769–784.
[96] N. Muhamad, T. Plengsuriyakarn, K. Na-Bangchang, Application of active
targeting nanoparticle delivery system for chemotherapeutic drugs and
traditional/herbal medicines in cancer therapy: a systematic review, Int. J.
Nanomed. 13 (2018) 3921.
[97] X. Wang, W. Zheng, Q. Shen, Y. Wang, Y. Tseng, Z. Luo, J. Liu, Identification and
construction of a novel biomimetic delivery system of paclitaxel and its targeting
therapy for cancer, Signal transduction and targeted therapy 6 (1) (2021) 1–3.
[98] L. Wan, K. Pantel, Y. Kang, Tumor metastasis: moving new biological insights into
the clinic, Nat. Med. 19 (11) (2013) 1450–1464.
[99] X. He, X. Bao, H. Cao, Z. Zhang, Q. Yin, W. Gu, Y. Li, Tumor-penetrating
nanotherapeutics loading a near-infrared probe inhibit growth and metastasis of
breast cancer, Adv. Funct. Mater. 25 (19) (2015) 2831–2839.
[100] A. Schroeder, D.A. Heller, M.M. Winslow, J.E. Dahlman, G.W. Pratt, R. Langer, D.
G. Anderson, Treating metastatic cancer with nanotechnology, Nat. Rev. Canc. 12
(1) (2012) 39–50.
[101] X. He, H. Yu, X. Bao, H. Cao, Q. Yin, Z. Zhang, Y. Li, pH-responsive wormlike
micelles with sequential metastasis targeting inhibit lung metastasis of breast
cancer, Advanced healthcare materials 5 (4) (2016) 439–448.
[102] H. Cao, Z. Zhang, S. Zhao, X. He, H. Yu, Q. Yin, Y. Li, Hydrophobic interaction
mediating self-assembled nanoparticles of succinobucol suppress lung metastasis
of breast cancer by inhibition of VCAM-1 expression, J. Contr. Release 205 (2015)
162–171.
[103] Q. Chen, C. Liang, C. Wang, Z. Liu, An imagable and photothermal “Abraxane-
like” nanodrug for combination cancer therapy to treat subcutaneous and
metastatic breast tumors, Adv. Mater. 27 (5) (2015) 903–910.
[104] C. Wang, L. Xu, C. Liang, J. Xiang, R. Peng, Z. Liu, Immunological responses
triggered by photothermal therapy with carbon nanotubes in combination with
anti-CTLA-4 therapy to inhibit cancer metastasis, Adv. Mater. 26 (48) (2014)
8154–8162.
[105] M. Rizwan, T. Rasheed, A. Raza, M. Bilal, R. Yahya, M. Yar, H.M. Iqbal,
Photodynamic-based therapeutic modalities to fight against cancer–A review
from synergistic viewpoint, J. Drug Deliv. Sci. Technol. 51 (2019) 70–82.
[106] S. Liang, C. Li, C. Zhang, Y. Chen, L. Xu, C. Bao, X. Wang, CD44v6 monoclonal
antibody-conjugated gold nanostars for targeted photoacoustic imaging and
plasmonic photothermal therapy of gastric cancer stem-like cells, Theranostics 5
(9) (2015) 970.
[107] T.A. Henderson, L.D. Morries, Near-infrared photonic energy penetration: can
infrared phototherapy effectively reach the human brain? Neuropsychiatric Dis.
Treat. 11 (2015) 2191.
[108] C. Guo, H. Yu, B. Feng, W. Gao, M. Yan, Z. Zhang, S. Liu, Highly efficient ablation
of metastatic breast cancer using ammonium-tungsten-bronze nanocube as a
novel 1064 nm-laser-driven photothermal agent, Biomaterials 52 (2015)
407–416.
[109] J. Wang, K. Sefah, M.B. Altman, T. Chen, M. You, Z. Zhao, W. Tan, Aptamer-
conjugated nanorods for targeted photothermal therapy of prostate cancer stem
cells, Chemistry–An Asian Journal 8 (10) (2013) 2417–2422.
[110] M. Zhou, J. Zhao, M. Tian, S. Song, R. Zhang, S. Gupta, C. Li, Radio-photothermal
therapy mediated by a single compartment nanoplatform depletes tumor
initiating cells and reduces lung metastasis in the orthotopic 4T1 breast tumor
model, Nanoscale 7 (46) (2015) 19438–19447.
[111] X. Xie, X. Shao, F. Gao, H. Jin, J. Zhou, L. Du, J. Tang, Effect of hyperthermia on
invasion ability and TGF-β1 expression of breast carcinoma MCF-7 cells, Oncol.
Rep. 25 (6) (2011) 1573–1579.
[112] J. Zhao, Y. Cai, C. Yin, Y. Lv, W. Wei, X. Wang, J. Chen, Study on the inhibition of
hyperthermic CO2 pneumoperitoneum on the proliferation and migration of
colon cancer cells and its mechanism, Oncol. Rep. 35 (2) (2016) 985–991.
[113] Y.L. Tang, J. Jiang, J. Liu, M. Zheng, Y.W. He, W. Chen, X.H. Liang, Hyperthermia
inhibited the migration of tongue squamous cell carcinoma through TWIST 2,
J. Oral Pathol. Med. 44 (5) (2015) 337–344.
[114] C. Liang, S. Diao, C. Wang, H. Gong, T. Liu, G. Hong, Z. Liu, Tumor metastasis
inhibition by imaging-guided photothermal therapy with single-walled carbon
nanotubes, Adv. Mater. 26 (32) (2014) 5646–5652.
[115] Y. Liu, J.R. Ashton, E.J. Moding, H. Yuan, J.K. Register, A.M. Fales, T. Vo-Dinh,
A plasmonic gold nanostar theranostic probe for in vivo tumor imaging and
photothermal therapy, Theranostics 5 (9) (2015) 946.
[116] S. Wang, Q. Zhang, X.F. Luo, J. Li, H. He, F. Yang, D.L. Fu, Magnetic graphene-
based nanotheranostic agent for dual-modality mapping guided photothermal
therapy in regional lymph nodal metastasis of pancreatic cancer, Biomaterials 35
(35) (2014) 9473–9483.
[117] X. Cai, X. Jia, W. Gao, K. Zhang, M. Ma, S. Wang, H. Chen, A versatile
nanotheranostic agent for efficient dual-mode imaging guided synergistic chemo-
thermal tumor therapy, Adv. Funct. Mater. 25 (17) (2015) 2520–2529.
[118] S. Su, Y. Ding, Y. Li, Y. Wu, G. Nie, Integration of photothermal therapy and
synergistic chemotherapy by a porphyrin self-assembled micelle confers
chemosensitivity in triple-negative breast cancer, Biomaterials 80 (2016)
169–178.
[119] R. Liu, L. Jing, D. Peng, Y. Li, J. Tian, Z. Dai, Manganese (II) chelate
functionalized copper sulfide nanoparticles for efficient magnetic resonance/
photoacoustic dual-modal imaging guided photothermal therapy, Theranostics 5
(10) (2015) 1144.
[120] J. Yu, W. Yin, X. Zheng, G. Tian, X. Zhang, T. Bao, Y. Zhao, Smart MoS2/Fe3O4
nanotheranostic for magnetically targeted photothermal therapy guided by
magnetic resonance/photoacoustic imaging, Theranostics 5 (9) (2015) 931.
15
Journal of Drug Delivery Science and Technology 64 (2021) 102681
[121] H. Deng, Y. Zhong, M. Du, Q. Liu, Z. Fan, F. Dai, X. Zhang, Theranostic self-
assembly structure of gold nanoparticles for NIR photothermal therapy and X-Ray
computed tomography imaging, Theranostics 4 (9) (2014) 904.
[122] E.I. Galanzha, M.S. Kokoska, E.V. Shashkov, J.W. Kim, V.V. Tuchin, V.P. Zharov,
Vivo Fiber-based Multicolor Photoacoustic Detection and Photothermal Purging
of Metastasis in Sentinel Lymph Nodes Targeted by Nanoparticles, 2009.
[123] D. Huo, J. He, H. Li, A.J. Huang, H.Y. Zhao, Y. Ding, Y. Hu, X-ray CT guided fault-
free photothermal ablation of metastatic lymph nodes with ultrafine HER-2
targeting W18O49 nanoparticles, Biomaterials 35 (33) (2014) 9155–9166.
[124] H. Liu, C. Li, Y. Qian, L. Hu, J. Fang, W. Tong, H. Wang, Magnetic-induced
graphene quantum dots for imaging-guided photothermal therapy in the second
near-infrared window, Biomaterials 232 (2020) 119700.
[125] S. Valastyan, R.A. Weinberg, Tumor metastasis: molecular insights and evolving
paradigms, Cell 147 (2) (2011) 275–292.
[126] M.E. Bonnet, J.B. Gossart, E. Benoit, M. Messmer, O. Zounib, V. Moreau, A.
L. Bolcato-Bellemin, Systemic delivery of sticky siRNAs targeting the cell cycle for
lung tumor metastasis inhibition, J. Contr. Release 170 (2) (2013) 183–190.
[127] S. Wang, Q. Zhang, P. Yang, X. Yu, L.Y. Huang, S. Shen, S. Cai, Manganese oxide-
coated carbon nanotubes as dual-modality lymph mapping agents for
photothermal therapy of tumor metastasis, ACS Appl. Mater. Interfaces 8 (6)
(2016) 3736–3743.
[128] Q. Chen, C. Liang, X. Wang, J. He, Y. Li, Z. Liu, An albumin-based theranostic
nano-agent for dual-modal imaging guided photothermal therapy to inhibit
lymphatic metastasis of cancer post-surgery, Biomaterials 35 (34) (2014)
9355–9362.
[129] C. Liang, X. Song, Q. Chen, T. Liu, G. Song, R. Peng, Z. Liu, Magnetic field-
enhanced photothermal ablation of tumor sentinel lymph nodes to inhibit cancer
metastasis, Small 11 (37) (2015) 4856–4863.
[130] C. Wang, X. Cai, J. Zhang, X. Wang, Y. Wang, H. Ge, Y. Cheng, Trifolium-like
platinum nanoparticle-mediated photothermal therapy inhibits tumor growth and
osteolysis in a bone metastasis model, Small 11 (17) (2015) 2080–2086.
[131] W. Li, G. Tan, J. Cheng, L. Zhao, Z. Wang, Y. Jin, A novel photosensitizer 31,131-
phenylhydrazine-Mppa (BPHM) and it’s in vitro photodynamic therapy against
HeLa cells, Molecules 21 (5) (2016) 558.
[132] Y.N. Konan, R. Gurny, E. Allémann, State of the art in the delivery of
photosensitizers for photodynamic therapy, J. Photochem. Photobiol. B Biol. 66
(2) (2002) 89–106.
[133] S. Kwiatkowski, B. Knap, D. Przystupski, J. Saczko, E. Kędzierska, K. Knap-Czop,
J. Kulbacka, Photodynamic therapy–mechanisms, photosensitizers and
combinations, Biomed. Pharmacother. 106 (2018) 1098–1107.
[134] M. Usacheva, S.K. Swaminathan, A.R. Kirtane, J. Panyam, Enhanced
photodynamic therapy and effective elimination of cancer stem cells using
surfactant–polymer nanoparticles, Mol. Pharm. 11 (9) (2014) 3186–3195.
[135] L. Lacerda, J.P. Reddy, D. Liu, R. Larson, L. Li, H. Masuda, W.A. Woodward,
Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines
and is associated with improved local control in inflammatory breast cancer
patients treated with postmastectomy radiation, Stem cells translational medicine
3 (7) (2014) 849–856.
[136] K. Gurtner, F. Hessel, W. Eicheler, A. Dörfler, D. Zips, K.H. Heider, M. Baumann,
Combined treatment of the immunoconjugate bivatuzumab mertansine and
fractionated irradiation improves local tumour control in vivo, Radiother. Oncol.
102 (3) (2012) 444–449.
[137] L. Li, X. Hao, J. Qin, W. Tang, F. He, A. Smith, L. Xu, Antibody against CD44s
inhibits pancreatic tumor initiation and postradiation recurrence in mice,
Gastroenterology 146 (4) (2014) 1108–1118.
[138] L. Koi, R. Bergmann, K. Brüchner, J. Pietzsch, H.J. Pietzsch, M. Krause,
M. Baumann, Radiolabeled anti-EGFR-antibody improves local tumor control
after external beam radiotherapy and offers theragnostic potential, Radiother.
Oncol. 110 (2) (2014) 362–369.
[139] A. Dietrich, L. Koi, K. Zöphel, W. Sihver, J. Kotzerke, M. Baumann, M. Krause,
Improving external beam radiotherapy by combination with internal irradiation,
Br. J. Radiol. 88 (1051) (2015) 20150042.
[140] L.B. Harrison, M. Chadha, R.J. Hill, K. Hu, D. Shasha, Impact of tumor hypoxia
and anemia on radiation therapy outcomes, Oncol. 7 (6) (2002) 492–508.
[141] J. Varlotto, M.A. Stevenson, Anemia, tumor hypoxemia, and the cancer patient,
Int. J. Radiat. Oncol. Biol. Phys. 63 (1) (2005) 25–36.
[142] R. Colombo, A. Salonia, Z. Leib, M. Pavone-Macaluso, D. Engelstein, Long-term
outcomes of a randomized controlled trial comparing thermochemotherapy with
mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer
(NMIBC), BJU Int. 107 (6) (2011) 912–918.
[143] J.O. Pelz, M. Vetterlein, T. Grimmig, A.G. Kerscher, E. Moll, M. Lazariotou,
M. Gasser, Hyperthermic intraperitoneal chemotherapy in patients with
peritoneal carcinomatosis: role of heat shock proteins and dissecting effects of
hyperthermia, Ann. Surg Oncol. 20 (4) (2013) 1105–1113.
[144] P. Wust, B. Hildebrandt, G. Sreenivasa, B. Rau, J. Gellermann, H. Riess, P.
M. Schlag, Hyperthermia in combined treatment of cancer, Lancet Oncol. 3 (8)
(2002) 487–497.
[145] J. Van der Zee, Heating the patient: a promising approach? Ann. Oncol. 13 (8)
(2002) 1173–1184.
[146] B. Hildebrandt, P. Wust, The Biologic Rationale of Hyperthermia, Peritoneal
carcinomatosis, 2007, pp. 171–184.
[147] N.G. Shetake, M.M. Balla, A. Kumar, B.N. Pandey, Magnetic hyperthermia
therapy: an emerging modality of cancer treatment in combination with
radiotherapy, Journal of Radiation and Cancer Research 7 (1) (2016) 13.
[148] M.M.G. Saldívar-Ramírez, C.G. Sánchez-Torres, D.A. Cortés-Hernández, J.
C. Escobedo-Bocardo, J.M. Almanza-Robles, A. Larson, I.O. Acuña-Gutiérrez,
Y. Mao et al.
Study on the efficiency of nanosized magnetite and mixed ferrites in magnetic
hyperthermia, J. Mater. Sci. Mater. Med. 25 (10) (2014) 2229–2236.
[149] Q.A. Pankhurst, J. Connolly, S.K. Jones, J. Dobson, Applications of magnetic
nanoparticles in biomedicine, J. Phys. D Appl. Phys. 36 (13) (2003) R167.
[150] L.R. Kelland, Targeting established tumor vasculature: a novel approach to cancer
treatment, Curr. Canc. Ther. Rev. 1 (1) (2005) 1–9.
[151] W. Wu, Z. Wu, T. Yu, C. Jiang, W.S. Kim, Recent Progress on Magnetic Iron Oxide
Nanoparticles: Synthesis, Surface Functional Strategies and Biomedical
Applications. Science and Technology of Advanced Materials, 2015.
[152] A.B. Salunkhe, V.M. Khot, S.H. Pawar, Magnetic hyperthermia with magnetic
nanoparticles: a status review, Curr. Top. Med. Chem. 14 (5) (2014) 572–594.
[153] J.E. Kim, J.Y. Shin, M.H. Cho, Magnetic nanoparticles: an update of application
for drug delivery and possible toxic effects, Arch. Toxicol. 86 (5) (2012) 685–700.
[154] V.I. Shubayev, T.R. Pisanic II, S. Jin, Magnetic nanoparticles for theragnostics,
Adv. Drug Deliv. Rev. 61 (6) (2009) 467–477.
[155] S. Sharifi, S. Behzadi, S. Laurent, M.L. Forrest, P. Stroeve, M. Mahmoudi, Toxicity
of nanomaterials, Chem. Soc. Rev. 41 (6) (2012) 2323–2343.
[156] G. Liu, J. Gao, H. Ai, X. Chen, Applications and potential toxicity of magnetic iron
oxide nanoparticles, Small 9 (9-10) (2013) 1533–1545.
[157] L. Lei, J. Ling-Ling, Z. Yun, L. Gang, Toxicity of superparamagnetic iron oxide
nanoparticles: research strategies and implications for nanomedicine, Chin. Phys.
B 22 (12) (2013) 127503.
[158] T. Sadhukha, L. Niu, T.S. Wiedmann, J. Panyam, Effective elimination of cancer
stem cells by magnetic hyperthermia, Mol. Pharm. 10 (4) (2013) 1432–1441.
[159] Y.S. Kwon, K. Sim, T. Seo, J.K. Lee, Y. Kwon, T.J. Yoon, Optimization of magnetic
hyperthermia effect for breast cancer stem cell therapy, RSC Adv. 6 (109) (2016)
107298–107304.
[160] X. Wei, T.H. Senanayake, G. Warren, S.V. Vinogradov, Hyaluronic acid-based
nanogel–drug conjugates with enhanced anticancer activity designed for the
targeting of CD44-positive and drug-resistant tumors, Bioconjugate Chem. 24 (4)
(2013) 658–668.
[161] C. Gao, Z. Lin, B. Jurado-Sánchez, X. Lin, Z. Wu, Q. He, Stem cell membrane-
coated nanogels for highly efficient in vivo tumor targeted drug delivery, Small
12 (30) (2016) 4056–4062.
[162] D. Huang, H. Qian, H. Qiao, W. Chen, J. Feijen, Z. Zhong, Bioresponsive
functional nanogels as an emerging platform for cancer therapy, Expet Opin. Drug
Deliv. 15 (7) (2018) 703–716.
[164] M. Krause, A. Dubrovska, A. Linge, M. Baumann, Cancer stem cells:
radioresistance, prediction of radiotherapy outcome and specific targets for
combined treatments, Adv. Drug Deliv. Rev. 109 (2017) 63–73.
[165] C.M. Clavel, P. Nowak-Sliwinska, E. Păunescu, P.J. Dyson, Thermoresponsive
fluorinated small-molecule drugs: a new concept for efficient localized
chemotherapy, MedChemComm 6 (12) (2015) 2054–2062.
16
Journal of Drug Delivery Science and Technology 64 (2021) 102681
[166] J. Nam, S. Son, L.J. Ochyl, R. Kuai, A. Schwendeman, J.J. Moon, Chemo-
photothermal therapy combination elicits anti-tumor immunity against advanced
metastatic cancer, Nat. Commun. 9 (1) (2018) 1–13.
[167] Q. Chen, L. Xu, C. Liang, C. Wang, R. Peng, Z. Liu, Photothermal therapy with
immune-adjuvant nanoparticles together with checkpoint blockade for effective
cancer immunotherapy, Nat. Commun. 7 (1) (2016) 1–13.
[168] Y. Liu, P. Maccarini, G.M. Palmer, W. Etienne, Y. Zhao, C.T. Lee, T. Vo-Dinh,
Synergistic immuno photothermal nanotherapy (SYMPHONY) for the treatment
of unresectable and metastatic cancers, Sci. Rep. 7 (1) (2017) 1–6.
[169] Z. Yu, P. Zhou, W. Pan, N. Li, B. Tang, A biomimetic nanoreactor for synergistic
chemiexcited photodynamic therapy and starvation therapy against tumor
metastasis, Nat. Commun. 9 (1) (2018) 1–9.
[170] Y.R. Kim, S. Kim, J.W. Choi, S.Y. Choi, S.H. Lee, H. Kim, S.H. Yun,
Bioluminescence-activated deep-tissue photodynamic therapy of cancer,
Theranostics 5 (8) (2015) 805.
[171] W. Song, J. Kuang, C.X. Li, M. Zhang, D. Zheng, X. Zeng, X.Z. Zhang, Enhanced
immunotherapy based on photodynamic therapy for both primary and lung
metastasis tumor eradication, ACS Nano 12 (2) (2018) 1978–1989.
[172] L.B. Rocha, L.C. Gomes-da-Silva, J.M. Dąbrowski, L.G. Arnaut, Elimination of
primary tumours and control of metastasis with rationally designed
bacteriochlorin photodynamic therapy regimens, Eur. J. Canc. 51 (13) (2015)
1822–1830.
[173] S. Lee, K. Na, Oleic acid conjugated polymeric photosensitizer for metastatic
cancer targeting in photodynamic therapy, Biomater. Res. 24 (1) (2020) 1–8.
[174] X. Liu, J. Zheng, W. Sun, X. Zhao, Y. Li, N. Gong, X.J. Liang, Ferrimagnetic vortex
nanoring-mediated mild magnetic hyperthermia imparts potent immunological
effect for treating cancer metastasis, ACS Nano 13 (8) (2019) 8811–8825.
[175] S.K. Wu, C.F. Chiang, Y.H. Hsu, T.H. Lin, H.C. Liou, W.M. Fu, W.L. Lin, Short-time
focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and
antitumor efficacy for brain metastasis of breast cancer, Int. J. Nanomed. 9 (2014)
4485.
[176] N. Werthmöller, B. Frey, M. Rückert, M. Lotter, R. Fietkau, U.S. Gaipl,
Combination of ionising radiation with hyperthermia increases the immunogenic
potential of B16-F10 melanoma cells in vitro and in vivo, Int. J. Hyperther. 32 (1)
(2016) 23–30.
[177] T.W. Jeon, H. Yang, C.G. Lee, S.T. Oh, D. Seo, I.H. Baik, Y.H. Lee, Electro-
hyperthermia up-regulates tumour suppressor Septin 4 to induce apoptotic cell
death in hepatocellular carcinoma, Int. J. Hyperther. 32 (6) (2016) 648–656.
[178] P.J. Hoopes, K.L. Moodie, A.A. Petryk, J.D. Petryk, S. Sechrist, D.J. Gladstone, S.
N. Fiering, February). Hypo-fractionated radiation, magnetic nanoparticle
hyperthermia and a viral immunotherapy treatment of spontaneous canine
cancer, in: Energy-based Treatment of Tissue and Assessment IX, vol. 10066,
International Society for Optics and Photonics, 2017, p. 1006605.