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Anti-Cancer Agents in Medicinal Chemistry, 2019, 19, 1-19 1
REVIEW ARTICLE
1871-5206/19 $58.00+.00 © 2019 Bentham Science Publishers
Quercetin Loaded Nanoparticles in Targeting Cancer: Recent Development
Manjula Vinayak1,* and Akhilendra K. Maurya1,2
1Biochemistry & Molecular Biology Laboratory, Centre for Advanced Study in Zoology, Institute of Science, Banaras Hindu Univer-
sity, Va ranasi-221005, India; 2Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences,
University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Abstract: The spread of metastatic cancer cell is the main cause of death worldwide. Cellular and molecular
basis of the action of phytochemicals in the modulation of metastatic cancer highlights the importance of fruits
and vegetables. Quercetin is a natural bioflavonoid present in fruits, vegetables, seeds, berries, and tea. The
cancer-preventive activity of quercetin is well documented due to its anti-inflammatory, anti-proliferative and
anti-angiogenic activities. However, poor water solubility and delivery, chemical instability, short half-life, and
low-bioavailability of quercetin lim it its clinic al applicatio n in cancer chemoprevention. A better understanding
of the molecular mechanism of controlled and regulated drug delivery is essen tial for the development of novel
and effective therapies. To overcome the limitations of accessibility by quercetin, it can be delivered as nano-
conjugated quercetin. Nanoconjugated quercetin has attracted much attention due to its controlled drug release,
long retention in tumor, enhanced anticancer potential, and promising clinical application. The pharmacological
effect of quercetin conjugated nanoparticles typically depends on drug carriers used such as liposomes, silver
nanoparticles, silica nanoparticles, PLGA (Poly lactic-co-glycolic acid), PLA (poly(D,L-lactic acid)) nanoparti-
cles, polymeric micelles, chitosan nanoparticles, etc.
In this review, we described various delivery systems of nanoconjugated quercetin like liposomes, silver
nanoparticles, PLGA (Poly lactic-co-glycolic acid), and polymeric micelles including DOX conjugated micelles,
metal conjugated micelles, nucleic acid conjugated micelles, and antibody-conju gated mic elles on in vitro and in
vivo tumor models; as well as validated their potential as promising onco-therapeutic agents in lig ht of recent
updates.
Keywords: Drug delivery, bioavailability, cancer th erapy, nanoparticles, quercetin, PLGA.
1. INTRODUCTION
Although there is tremendous development in chemotherapeutic
drugs along with other therapies of cancer, the side effects caused
by drugs and drug resistance, poor bioavailability, nonspecific tar-
geting, and low therapeutic indices remain a challenge [1, 2]. Natu-
ral phytochemicals offer an emerging strategy for chemoprevention
of various diseases with lesser side effects. Several herbal ingredi-
ents and antioxidants have been reported to have anticancer effects
[3-5]. Scientific evidence suggests that phytochemicals may inhibit
the process of carcinogenesis and reduce the burden of a few can-
cers with certain limitations [6 -9].
A recent study suggests that phytochemicals serve as dynamic
surface ligands to control nanoparticle and protein interactions; of
which nanoparticles as carriers of phytochemicals [10]. Pharmacol-
ogical significance of quercetin has a long history due to its poten-
tial health-promoting effects against numerous diseases such as
cardiovascular, diabetes, thrombosis, neurological disorder, and
cancer as well as for longevity [11-13]. The importance of quercetin
is realized because of its potential in an ti-carcinogenic [14-17],
anti-inflammatory [18], anti-obesity [19], antioxidan t [20-22], anti-
viral [23], and antibacterial activities [24, 25]. Owing to its poor
aqueous solubility, low bioavailability, difficulty in crossing th e
*Address correspondence to this author at the Biochemistry & Molecular
Biology Laboratory, Centre for Advanced Study in Zoology, Institute of
Science , Banaras Hind u Univ ersity, Varanasi-221005, India;
E-mail: manjulavinayak@rediffmail.com
blood-brain-barrier, and poor chemical stability, its clinical applica-
tion is limited [26]. In order to overcome these inadequacies of
quercetin, many new drug delivery systems have been studied and
developed to increase solubility and dissolution, elevating bioavail-
ability, raising drug stab ility, controlled drug release, indorsing
antioxidant activity, and improving therapeutic effect [27-32].
2. FOOD SAFETY AND SOURCES OF QUERCETIN
Quercetin is a ubiquitous bioactive flavonoid. It occurs in a
wide variety of fruits, vegetables, and beverages [14]. Onion, black
tea, red wine as well as various fruit juices are identified as rich
dietary sources of quercetin [12]. Quercetin is estimated to be con-
sumed approximately 25-50 mg in the daily diet [15]. Dietary in-
take at estimated levels of quercetin is reported to have no undesir-
able health effects [33]. Quercetin has been utilized as a component
in food and pharm aceutical industries because of its health promis-
ing benefits. It has been marketed primarily as a dietary supplement
in the USA. Quercetin is commercially used as a supplement for
dog foods [34]. Quercetin shows no mutagenicity/genotoxicity in
vivo [12]. LD50 for quercetin is 160 mg and 3000 mg per kg body
weight in oral and intraperitoneal dose of mice, respectively [12].
Quercetin and its prodrug have entered phase 1 clinical trial for
human cancers [35, 36]. Although oral or intravenous administra-
tion of prodrug QC12 to the patient does not show promising clini-
cal significan ce, quercetin explores the possibility to fight against
other cancers [36]. Cmax and Tmax for quercetin are reported as 2.3 ±
1.5 µg/mL and 0.7 ± 0.3h, respectively [37].!
A R T I C L E H I S T O R Y
Received: April 29, 2019
Revised: May 23, 2019
Accepted: May 23, 2019
DOI:
10.2174/1871520619666190705150214
2 Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19 , No. 0 Vinayak and Maurya
3. STRUCTURE AND SOLUBILITY OF QUERCETIN
Quercetin (3, 3’, 4’, 5, 7-pentahydroxyflavone) is composed of
3, 5, 7-trihydroxy-4H-1-benzopyran-4-one (A and C) and a 3, 4-
dihydroxy-phenyl ring (B). The biochemical activity of quercetin is
due to the presence of hydroxyl groups which exert antioxidant
activity by scavenging free radicals. Quercetin possesses almost all
structural elem ents with characteristics of an antioxidant lik e (i) an
orthodihydroxy or catechol group in ring B (ii) a 2, 3-double bond
and (iii) 3- and 5-OH groups with 4-oxo group. Several factors
including pH, heat, and metal ions affect the chem ical stability of
quercetin [22, 38]. Quercetin is a lipophilic compound (log P = 1.82
+/- 0.32), and it is moderately soluble in ethanol and highly soluble
in DMSO. However, its solubility in water is only approximately
0.01 mg/mL at room temperature [39]. The half-life of quercetin is
approximately 11-24 h. It is th erefore difficult to directly incorpo-
rate high levels of quercetin into water-based food matrix and needs
to improve its solubility, bioaccumulation, and delivery into the
cellular system to target certain diseases like cancer [40].
Chemical structure of quercetin (C15H10O7).
4. ANTICANCER ACTIVITY OF QUERCETIN
Anticancer activity of quercetin has been widely studied in
several in vivo and in vitro tumor models including lymphoma [11,
41-44], hepatocellular carcinoma [15], breast cancer [17, 45-47],
and colorectal can cer [48, 49]. Nanocarriers such as polymeric
nanoparticles, liposome, lipid nanoparticles, and micelles have been
deliberate to reduce the side effects of drugs. Co-encapsulation of
quercetin and vincristine with lipid-polymeric nanocarriers has
potential as a novel therapeutic approach to overcome chemo-
resistant lymphoma [42]. Quercetin and its natural glycosides are
known to decrease cell proliferation and induce genetic instability
[50, 51]. Quercetin is a Multi-Drug Resistance (MDR) modulator
and thus a potential chemosensitizer [52]. It is involved in reversion
of MDR via transporter-mediated active efflux by modulating P-gp
protein (glycoprotein encoded by the human MDR1 gene) and
MRP1 (Multidrug Resistance Protein). Quercetin has been shown to
improve its therapeutic efficacy in combination with drugs against
different types of cancer. Combinatorial effect of quercetin and
resveratrol has been found to be antiproliferative against HT-29
colon cancer via induction of zinc finger protein ZBTB10 and sup-
pression of oncogenic microRNA [53]. A recent study demon-
strated that quercetin improves the synergistic anticancer efficacy in
combination with PI-103, rottlerin, and G0 6983 in MCF-7 and
RAW 264.7 cells [17]. The lower and higher dose of quercetin
(0.1% or 1% quercetin, respectively) enhanced the anti-tumor ef-
fects of Trichostatin A (TSA) in mice [54]. The combination of
quercetin with gemcitabine has been shown a synergistic effect in
the inhibition of pancreatic cancer cells [55].
Targeting metastatic expansion by cell survival and prolifera-
tion in murine T-cell lymphoma (Dalton’s lymphoma), a fast-
growing and highly metastasized cancer, is a cru cial target of can-
cer therapy. We highlighted a multi-factorial approach of quercetin
towards lymphoma prevention in mice via modulation of cell cycle
proteins, oncogenes, and tumor suppressor genes. Quercetin is re-
ported to modulate various signaling molecules in the regulation of
cell proliferation, apoptosis as w ell as angiogenesis towards the
suppression of murine T-cell lymphoma [3, 11, 41, 43]. We re-
ported the first morphological evidence to show regression in
Dalton’s lymphoma growth in mice by quercetin treatment along
with improvement in longevity [41]. Being nontoxic to Dalton’s
lymphoma bearing mice, quercetin exhibits cytotoxic potential to
ascites cells [11, 41]. Cancerous cells avoid apoptosis or pro-
grammed cell death and promote uncontrolled cell proliferation via
a series of cellular events. Apoptosis is induced by extrinsic and
intrinsic pathways. Cellular toxicity induces the intrinsic pathway
of apoptosis via mitochondrial activation leading to caspase 9 cas-
cade, and extrin sic pathway via receptor-mediated caspase 8 signal-
ing cascade as well as via activation of NF-kB which regulates a
large number of inflammatory genes [56, 57]. Mitochondrial induc-
tion of apoptosis by quercetin has been reported in various cell
lines, including nasopharyngeal carcinoma, hepatocellular carci-
noma, breast cancer, leukemia, and oral squamous carcinoma [11,
15, 58-62]. Quercetin enhances the expression of BAX and Cyt C
release as well as modulates mitochondrial membrane potential in
HaCaT keratinocytes, MDA-MB-231 breast cancer and epidermoid
carcinoma KBv200 [63-66]. Quercetin-induced apoptosis via
upregulation of p21WAF1/CIP1 and Cdc2-cyclin B1 complex has
been reported in MCF-7 breast cancer and KYSE-510 squamous
cell carcinoma [67, 68]. W e reported that quercetin suppresses cell
survival and promotes apoptosis via differential localization of
TNFR1 as well as improved activity of caspase 9 in ascite cells of
Dalton’s lymphoma bearing mice [11]. It is associated with an in-
crease in active caspase 3, a critical executioner of apoptosis by
partial or total cleavage of PARP [11]. PARP is one of the main
cleavage targets of caspase 3 in vivo; however, it is cleaved by dif-
ferent caspases in vitro. Quercetin also induces apoptosis via activa-
tion of the reactive oxygen species-dependent ASK1⁄ p38 pathway
[69]. Quercetin inhibits TRPM7 channel and MAPK signalin g
pathway in gastric cancer [70]. It increases the levels of JNK and
p53-dependent Bax in BEAS-2B cells [71]. The p53-dependent
apoptosis by quercetin is reported in lung cancer A549 cells and
cervical cancer Hela cells [72, 73]. Quercetin increases ERK-
mediated cell death in HL-60 cells, suppresses Twist via p38MAPK
signaling, and causes mitochondrial depolarization through down-
regulation of IL-6/STAT3 signaling [74, 75]. Signaling mechanism
of anticarcinogenic activity of quercetin is mainly confined to its
antioxidant and proapoptotic role via regulation of p53, caspases,
cell cycle arrest, angiogenesis via COX-2, MMPs. Quercetin at-
tenuates P I3K-AKT signaling pathway in T-cell lymphoma exposed
to hydrogen peroxide [3]. Quercetin attenuates prostate cancer by
inhibiting anti-apoptotic and survival signaling [76]. Warburg’s
effect demonstrates the necessity of aerobic glycolysis or glycolytic
metabolism to provide enough energy for maintenance of cancer
growth. Quercetin decreases glycolytic metabolism by lowering
LDH-A activity in ascites cells of Dalton’s lymphoma bearing
mice, causing their increased susceptibility to death [41]. Glycolytic
metabolism maintains acidic pH in the tumor microenvironment,
which facilitates cancer growth. Acidic pH stimulates disruption of
adherence junctions, metastatic potential, proteinase activity, and
drug resistance.
Quercetin attenuates the major survival signals, like PI3K,
AKT, and ERK in carcinoma HepG2 cells [77]. PI3K is implicated
in cell surviv al, proliferation, and angiogenesis via activation of
AKT. Quercetin treatment leads to inactivation of PI3K suggesting
its role in the inhibition of ascite cell survival of lymphoma bearing
mice [41, 78]. Declined phosphorylation of BAD by quercetin in
lymphoma suggests modulation of PI3K-PDK1-AKT-BAD signal-
ing pathway by quercetin in regression of cell survival [44, 79].
Apart from this pathway, BAD is also modulated via ERK activated
p90 ribosomal S6 kinase. GSK-3β is another downstream effector
of AKT which modulates a variety of functions including cell sur-
Quercetin Loaded Nanoparticles in Targeting Cancer: Recent Development Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19, No. 0 3
vival and growth metabolism. Inactivation of GSK-3β after phos-
phorylation by AKT promotes cell proliferation, whereas dephos-
phorylation of GSK-3β promotes apoptosis and suppresses tumor
growth [80-82]. We reported a declined phosphorylation of GSK-
3β by quercetin suggesting inhibition of cell proliferation as well as
NF-κB mediated cell survival in Dalton’s lymphoma ascite cells
[44]. AKT also activates mTOR and promotes cell survival by in-
creasing mTOR-dependant nutrient uptake [82, 83]. Hyperactivated
PI3K-AKT-mTOR signaling has been well documented in a wide
range of cancer [3, 84-86]. AKT has been identified as master regu-
lators of IKK activity which activates NF-κB [87]. Oxidative stress
is one of th e major causes of NF-κB activation. Antioxidant quer-
cetin inhibits cell survival by downregulating the phosphorylation
of IκBα and by declining survival factor NF-κB in DL ascite cells.
Quercetin has been shown to inhibit aflatoxin B1-induced hepatic
damage in mice [88]. It protects against liver injury induced by
alcohol in rats. Dietary supplement of quercetin inhibits the devel-
opment of the carcinogen-induced rat mammary cancer, colonic
neoplasia, and oral carcinogenesis. PI3K-AKT-BAD pathway is
deactivated by PTEN, a phosphatase which regulates the level of
PIP3 by its de-phosphorylation. Enhanced level of tumor suppressor
PTEN by quercetin supports the decreased activity of PI3K and
subsequent signaling pathway. PTEN is frequently lost or mutated
in cancer. Induced level of PTEN by quercetin is correlated with
upregulation of tumor suppressor p53, a principal mediator of
growth arrest, senescence, and apoptosis in response to a broad
array of cellular damage. AKT mediated oncogenic activation acts
as an anti-apoptotic signal via rapid destabilization of p53 [89-91].
We reported the anticancer effect of quercetin via induced mRNA
expression and protein level of p53 [41]. Cancer preventive effect
of quercetin is also validated against fatty acid synthase in liver
cancer [92]. Quercetin downregulates the Notch / AKT/mTOR sig-
naling pathway in U937 leukemia cell [73]. Quercetin attenuates
PI3K-AKT signaling pathway exposed to hydrogen peroxide in T-
cell lymphoma [3]. Quercetin attenuates AKT-mTOR pathway
mediated autophagy induction by inhibiting cell mobility and gly-
colysis in breast cancer [93].
Angiogenesis is an essential characteristic adaptation of tumor
growth for a continuous supply of glucose and oxygen as well as to
get rid of its waste products [94]. The angiogenic factor VEGF-A is
required for neovascularization and for angiogenic remodeling [95].
PI3K-AKT signaling is reported to increase VEGF-A secretion by
HIF-1 dependent, or by HIF-1 independent mechanism [95]. Down-
regulated level of VEGF-A by quercetin suggests its ability to re-
gress angiogenesis in Dalton’s lymphoma bearing mice via PDK1
[44]. PDK1 is vital to endothelial cell migration in response to
VEGF stimulation in a PI3K dependent manner. Further, overex-
pression of PTEN inhibits angiogenesis and tumor growth [44, 96,
97]. Loss of AKT1 is reported to reduce NO production and impair
tumor angiogenesis. The inflammatory enzymes iNOS and COX-2
are implicated in inflammato ry diseases and tumor progression
[98]. We have further reported that quercetin reduces inflammatory
response by decreasing the activity of iNOS and COX-2 in ascite
cells of Dalton’s lymphoma bearing mice as well as in HepG2 cells
[15, 44]. However, both promoting and deterring actions of iNOS
during tumor development have been reported, probably depending
upon the local concentration of NO within the tumor microenvi-
ronment [16, 99]. COX-2 and tumor suppressor p53 have been
reciprocally regulated by quercetin in the prevention of cancer [15].
Such reciprocal relation is reported earlier [100]. Hepatocellular
carcinoma is one of the major health threats and the third leading
cause among cancer-related deaths globally. Quercetin attenuates
cell survival and cell proliferation of HepG2 cells and elicits apop-
tosis by enhancing the expression of BAX and p53 through down-
regulation of ROS, PI3K, PKC, and COX-2 [15]. The independent
regulation of p53 by quercetin has been reported against hepatocel-
lular carcinoma [101].
5. BIOAVAILABILITY OF QUERCETIN
Nanoparticles have been serving as a tool to enhance the effec-
tiveness of phytochemicals by increasing bioavailability [102].
Digestion of quercetin in the human body occurs in the mouth,
small intestine, liver, and kidneys where it undergoes glucuronida-
tion, sulfation or methylation [8, 103-108]. Distribution of quercetin
after the intravenous and oral administration has been shown in rat.
It entails that the intake of quercetin from daily diet can lead to the
accumulation of quercetin throughout the body [109]. Bioavailabil-
ity of quercetin is related to its bio-accessibility. However, the pres-
ence of sugar moieties increases bioavailability and differences in
quercetin conjugated glycosides influence its bioavailability [110,
111]. Quercetin bioavailability increases when it is consumed as an
integral food component. The size and polarities of these com-
pounds can cause difficulty crossing membranes in the gut. How-
ever, the efficacy of qu ercetin is limited due to its hydrophobici ty,
poor gastrointestinal absorption, and instability in physiological
medium, extensive xenobiotic metabolism in liver and intestine via
glucuronidation or sulfation; which collectively contribute to low
oral bioavailability of quercetin [40, 112-114]. Bioavailability of
quercetin obtained from onion is more due to its greater absorption
[110]. Quercetin ingestion with brief chain fructooligosaccharide
progresses quercetin bioavailability [115]. Solid dispersions have a
greater surface area that promotes dissolution in the intestinal lu-
men, thereby promoting bioavailability of quercetin with cereal
ingredients [116]. Variations in gut microbiota metabolism, dietary
history, genetic polymorphisms, and interindividual variation play a
significant role in the bioavailability of quercetin [117]. Available
literature highlights that despite the tremendous anticarcinogenic
potential, quercetin could not show clinical utility. Efficient deliv-
ery of quercetin to target cells and its retention at the site is neces-
sary for its utilization as a therapeutical agent.
6. APPROACHES FOR QUERCETIN DELIVERY
Nanomedicines have broad research and application prospects.
There are more than 51 FDA approved nanomedicines and 77
products are under consideration of clinical trials [118]. A better
understanding of the molecular mechanism of controlled and regu-
lated drug delivery is essential for the development of novel and
effective therapies. Nanotechnology provides a method to create
novel formulations for numerous hydrophobic drugs. Quercetin
delivery through nanoparticles has pulled in much consideration for
its improved anticancer potential and promising clin ical application
[40]. Utilization of delivery systems including nanoparticles, lipid-
based carriers, micelles, inclusion complexes, and conjugates-based
encapsulation has the potential to improve both stability and
bioavailability and thus imposes health benefits of quercetin. These
delivery carriers are widely used for enhancing drug solubility in
water, absorption, circulation, retention time, and ultimately target
specificity.
Quercetin-containing self-nanoemulsifying drug delivery sys-
tem has improved oral bio availability [112]. Curcio et al. showed
the suitability of molecularly imprinted nanospheres for con-
trolled/sustained release of quercetin using methacrylic acid and
ethylene glycoldymethacrylate as a functional monomer and cross-
linking agent, respectively. The antiproliferative activity of quer-
cetin has maintained without interfering with the cell viability
[119]. Semi-engineered water-soluble isoquercetin and maltooligo-
syl isoquercetin are produced by manufactured glycosylation to
defeat solvency challenges and restorative methodologies. Liposo-
mal quercetin has significantly improved the solubility and
bioavailability of quercetin in MCF-7 breast cancer cell [120].
Regulated metabolism for nanosponge conjugated quercetin has
been demonstrated in breast cancer cells [121]. These delivery sys-
tems are generally designed to efficiently encapsulate an apprecia-
ble number of functional components to protect them against the
4 Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19 , No. 0 Vinayak and Maurya
Table 1. Molecular and bioche mical target of anticancer effects of nanoconjugated quercetin.
Sr.
No.
Delivery
System
Advantages
Chemical/Polymer
Effects/ Target s
Refs.
Cross-linked chitosan (TPP-
chitosomes)
Chitosan -quinoline
Fucoidan/chitosan
Quercetin shows resistance to acidic conditions and promoted
the release in alkaline pH mimicking the intestinal environment
pH-sensitive r elease beh avio r and promising anticancer activ ity
against HeLa cells
Contro lled release, pr eventing q uercetin degradation, strong
antioxidant activity
[125]
[126]
[127]
Piperine or polyethylene glycol 400
(PEG) or alginate
Inhibition of anti-inflammatory activities in terms of COX-2
and NF-κB in MCF-10A cells
[128, 129]
Liposomal quercetin
Improved bioavailability and cellular uptake of quercetin in
MCF-7
[120]
1,2-distearoyl-sn-glycero-3-
phosphoethanolamine-N-
[methoxy(polyethylene glycol)-2000]
Enhanced cellular uptake and effective nanocarrier for drug
delivery to a brain tumor
[63]
Phospholipid s
Improved intestinal absorption of quercetin
[130]
1
Liposomes
Transporters for both
lipophilic and hydr o-
philic
particles, targetability
Polyethyleneglycol
Magnetoliposomes
Declination of cyclin D1, NF-κB, histone deacetylase 1 and
induction of caspase 3 in esophageal sq uamous cell carcinomas
Efficient antitumoral agent against glioma cells
[131]
[30]
Assembly of siRNA/silver
Inhibition of bacterial propagation
[24]
Polyoxyethylene glycerol trio leate and
polyoxyethylene
Reduction in cytotoxicity, oxidative stress as well as improved
metabolic activity of Caco-2 cells
[132]
2
Silver
nanoparticles
High reactivity,
powerful antimicro-
bial activity, and low
propensity to induce
bacterial resistance
Selenium
Reduced cell viability of DL cells
[133]
Dichloromethane
Sustained rele ase of quercetin as well as decreased cell viability
of breast cancer cells MDA-MB231
[134]
Poly (ecaprolactone)-
co-d-a-tocopheryl polyethylene glycol
1000 succinate
Improved cytotoxicity, cellular uptake and delivery o f quercetin
to SKBR3 breast cancer cells
[135, 136]
Mannose / folate
Poly lactide-co-glycolide
Improved cytotoxicity of quercetin on HaCaT cells and A431
cells
[137]
Biotin
Inhibits the activity and expression of P-glycoprotein in MCF-
7/ADR cells
[138]
D-α-tocopheryl
Induced apoptosis in HepG2 cells
[139]
Arginine- glycineaspartic acid
Growth inhibition of HepG2 cells
[140]
Gold nanoparticles
Improved cell cytotoxicity, apoptosis, and reduc ed hi stone
deacetylases, reduced cell proliferation of HepG2 cells and
modulation of p21, cdk1, and AKT
[141]
3
Poly lactic-co-
glycolic acid
(PLGA)
Good biocompatibil-
ity, biodegradable
polymer, better load-
ing, and encapsulat-
ing efficacy
Etoposide
Significant increase in cytoto xicity on human lung adenocarci-
noma epithelial cells A549
[142]
Monomethoxy poly(ethylene glycol)–
poly(ε-caprolactone)
Improved apoptosis and cell growth inhibition in CT26 cells
[139]
DSPE-PEG2000
Induced apoptosis as well as enhanced permeability and reten-
tion in PC-3 cells
[143]
Lecithin, Pluronic P123, and 1,2-
distearoyl-sn-glycero-3-
phosphoethanolamine-N-
methoxy[poly(ethylene glycol)-2000]
Increased cellular uptake of quercetin and longer half-life in
MCF-7
[52]
Hyaluronic acid
Increased cytotoxicity of MCF-7 and growth inhibition on H22
tumor-bearing mice
[144]
Monomethoxy poly(ethylene glycol)-
poly(ε-caprolactone)
Induced apoptosis, mitochondrial transmembrane potential
change, decreased phosphorylation of p44/42 and AKT in
A2780S cells
[39]
Phosphatidyle thanolamine
Improved drug accumulation in A549 cancer cell line and
murine xenograft model
[145]
Pluronic P123 and D-a-tocopheryl
polyethylene glycol succinate
Increased IC50 values in MCF-7 cells
[146]
4
Polymeric
micelles
Small size (com-
monly <10nm),
thermodynamic
dependability, colloi-
dal dependability
Naphthyl or benzyl
Enhanced delivery and inhibition of growth of human erythro-
myelogenous leukemia cells (K562) and small lung carcinoma
cells (GLC4))
[147]
Quercetin Loaded Nanoparticles in Targeting Cancer: Recent Development Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19, No. 0 5
chemical or thermal degradation. Qu ercetin can be released at a
controlled rate and at the site of action or within a region of the
gastrointestinal tract [122, 123]. Therefore, the development of
nano-conjugated quercetin via nano-based carriers has gained much
attention for the improvement of delivery and bioavailability of
quercetin.
7. NANO-CONJUGATED QUERCETIN
Nanoparticle drug delivery system has increased impressive
consideration throughout the decad es. Therapeutics can be captured
in the nanoparticles to enhan ce bioavailability, to improve watery
dissolvability, to build dependability, and to control delivery [1, 16,
124]. These delivery vehicles are broadly pondered in translational
application for the revolution of anticancer action of quercetin
(Table 1).
Nanomedicine delivery system is preferred in cerebrum tumor
treatment utilizing gliom a-particular nanoparticles [148] and fer-
rocenyl complex (ansa-FcdiOH) through stealth Lipid Nanocap-
sules (LNCs) [149] because of their tunable physicochemical prop-
erties. Quercetin stacked self-nanoemulsifying drug conveyance
framework (QT -SNEDDS) advances cell reinforcement movement
of quercetin against breast cancer [150]. Oral organization of quer-
cetin stacked polymeric nanocapsules (N1QC) has been accounted
for expanded cerebrum take up and mitochondrial restriction [151].
Additionally, the enhanced calming impact of Zein nanoparticles
implanted quercetin was shown in the mouse model of incited en-
dotoxemia [152]. Improved bioavailability of quercetin conjugated
from almond gum nanoparticles without any toxicity has been stud-
ied in Caco-2 cells [153]. Specifically, nanoparticles have been
broadly explored to deliver anticancer drugs by methods for passive
targeting. The higher amount of nano-sized particles passively per-
meates through the leaky tumor blood vessel than the tight capillary
in healthy tissues [154]. Together with the insufficiency of the lym-
phatic arrangement of tumors, the nanoparticles are accumulated
and held longer in the tumors. This phenomenon is the so-called
Enhanced Permeability and Retention (EPR) effect. In this manner,
the polymeric nanoparticles are utilized to specifically deliver anti-
cancer drugs to the tumors. Nanoconjugated quercetin prompts EPR
through the dual mood of delivery i.e., active or passive transport.
Subsequently, it enhances drug release, solubility & stability, pro-
tection against endosomal degradation, inhibition of MDR as well
as absorption of free quercetin in the blood vessel which leads to
DNA fragmentation and programmed cell death or apoptosis at
metastatic sites as depicted in Fig. (1). Encapsulation of anti-cancer
agent in the nanoparticle is recognized as a novel strategy to over-
come resistance through several mechanisms including increasing
drug penetration into cancer cells, modulation of drug release, and
high endocytosis phenomenon. Several approaches have been gen-
erated to increase th e effi cacy of quercetin for cancer treatment
with a unique advantage and drawback of each formulation. To
overcome the burden or limitations of accessibility, quercetin can
be delivered through polymeric micelles [114, 155], liposomes [63,
129, 156], chitosan nanoparticles [125], silver nanoparticles [24],
PLGA (Poly lactic-co-glycolic acid) [137], PLA (poly(D,L-lactic
acid)) nanoparticles, and silica nanoparticles. In addition, delivery
systems may likewise shield the bioactive compounds from being
enzymatically met abolized or therm al/ light degradation and expan d
their stability [157]. Quercetin stacked solid lipid nanoparticles
enhance osteoprotective activity in po stmenopausal osteoporosis
[158]. Quercetin based solid lipid nanoparticle treatment recovers
bone loss over quercetin treatment group in ovariectomized rats.
Co-delivery with nanoconjugated quercetin enhances doxorubicin
mediated cytotoxicity against MCF-7 breast cancer cells. Phyto-
some technology can improve the efficacy of chemotherapeutics
potential of anticancerous drugs by increasing the permeability of
tumor cells. Poly (β-amino esters) polymers have emerged as highly
promising candidates for biomedical and drug delivery applications
Fig. (1). Schematic diagram showing targeting of metastatic cancer by polymeric quercetin. Nanoconjugated quercetin leads to Enhanced Permeability and
Retention (EPR) via dual mood of delivery i.e., active or passive transport. Subsequently, it enhances drug release, solubility & stability, protection against
endosomal degradation, inhibition of MDR as well as absorption of free quercetin in the blood vessel which leads to DNA fragmentation and programmed cell
death or apoptosis at metastatic sites.
6 Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19 , No. 0 Vinayak and Maurya
due to their pH sensitive, tuneable, and degradable properties.
These polymeric systems can serve as pro-drug carriers for the
delivery of bioactive compounds which are biologically unstable
and suffer from poor aqueous solubility, low bioavailability such as
the antioxidant quercetin [155].
7.1. Liposomes
Among different approaches to achieve intestinal drug delivery,
the use of natural polymers holds clinical promises. Oral admini-
stration of polymer-coated liposomes has been proposed for the
targeted delivery of drugs to the inflamed intestinal mucosa [159].
Liposomes have attractive biological properties including general
biocompatibility, biodegradability, and ability to encapsulate both
hydrophilic and hydrophobic therapeutic agents. Encapsulation of
hydrophobic drug into liposome can create aqueous intravenously
injectable formulations. In the meantime, liposomes can regulate
drug release and protect the encapsulated drugs from undesired
effects of extern al conditions. Doxil is the first lipo somal drug for-
mulation approved by the Food and Drug Authority for the treat-
ment of AIDS associated with Kaposi’s sarcoma. Encapsulation of
quercetin by liposome enhances quercetin solubility and improves
anticancer activity through longer exposure to cancer cells with a
high drug concentration. Cancer therapy with a combination of
drugs is an important strategy in clinical use. Liposomal quercetin
enhances the sensitivity of cancer to thermotherapy and thermo-
chemoth erapy [64]. Liposome conjugated quercetin inhibits th e
upregulation of hsp70 and enhances apoptosis induced by hyper-
thermia and thermochemotherapy. However, systemic administra-
tion of liposomal quercetin could sensitize CT26 cells to ther-
motherapy and chemothermotherapy. Liposomal quercetin demon-
strates the most effective tumor growth inhibition in the JIMT-1
human breast tumor xenograft as compared to monotherapy and
free vincristine/quercetin combinations [160]. The most widely
used strategy is to develop controlled drug released liposomes by
coating the surface with inert and biocompatible polymers such as
Polyethylene Glycol (PEG). PEG is an exceptionally hydrated
adaptable polymer chain that can enhance retention time by stabiliz-
ing and shielding liposome from opsonisation. Moreover, PEG is
non-toxic and non-immunogenic, making it su itable for clinical
applications. Liposomal quercetin is highly accumulated and has
long retention in liver, tumor, and spleen rather than kidney and
lung. In addition, liposomal quercetin demonstrated significant
tumor growth inhibition activity in vivo [64]. Many cancer active
targeting liposomes are developed to deliver quercetin and to fur-
ther improve the accumulation of quercetin in cancer cells. Liver-
specific liposomal quercetin is prepared by galacto sylation. Target-
ing the galactosyl receptors on th e surface of hepatic cells allowed
liver-specific delivery of quercetin, wh ereas intravenous admini-
stration of galactosylated liposomal quercetin demonstrated higher
inhibitory activ ity on the development of hepatocarcinoma and on
oxidative damage in rat liver as compared to free quercetin [156].
Customary liposomes can be barely utilized, due to their resis-
tance to gastric pH, enzymatic debasement, biocompatibility, bio-
degradability, biorenewability, and bioadhesion but they can be
effortlessly ensured by a polymeric coating [161]. Chitosan is util-
ized to coat polyethylene glycol containing vesicles for controlled
delivery of quercetin in colon cancer [159, 161]. Cross-linked chi-
tosan-lipo some combination sy stem speaks to a promising combi-
nation of nanovesicles and for delivery of quercetin into the diges-
tive system [125]. Quercetin loaded chitosan-quinoline nanoparti-
cles display pH-sensitive release behavior and promising anticancer
activity against HeLa cells [126]. The quercetin loaded fu-
coidan/chitosan nanoparticles has shown to exhibit controlled re-
lease, preventing quercetin degradation, strong antioxidant activity,
and increasing its oral bioavailability [127]. Quercetin conjugated
liposomes have been utilized to provide quercetin in rodent brain
[63, 129]. Piperine is among different ingredients joined with quer-
cetin liposomes to instigate the delivery of quercetin and increase
its retention in the small intestinal su rface. A lginate, an anionic
biopolymer can expand encapsulation proficiency of liposome.
Formulations of nano-sized quercetin liposomes inhibit the
expression of COX-2 and NF-kB in MCF-10A Cells [128]. The
nano-sized quercetin encap sulated by liposomes enhanced the cellu-
lar uptake in MCF-7 breast cancer cells [120]. These polymers
penetrate the polar medium inside the cells and to protect them
against the highly toxic effect induced by cum ene hydroperoxide.
Liposomes build up especially at tumor sites due to their ability to
extravasate through pores in the capillary endothel ium. These pores
seem to be important for rapid angiogenesis in tumors. Quercetin
liposomes and spherical nanoparticles consisting of a phospholipid
bilayer with an aqueous compartment, own the unique capability to
effectu ally deliv er both water-soluble chemical antioxidants in the
aqueous phase and lipid-soluble chemical antioxidants in the lipid
bilayer. Their surface can be conjugated with specific ligands that
target liposomes to their location of action. The size, composition,
surface charge, and other formulation possessions of liposomes is
well documented to encounter the necessities of specific conditions.
Additionally, it is believable that gene therapy medications might
be delivered by liposomes. Nanoparticles with entrapped siRNA
inhibit bacterial propagation [24, 162]. Quercetin loaded magnetol-
iposomes are designed to study as a stable and efficient antitumoral
agent against glioma cells [30].
7.2. Silver Nanoparticles
Silver nanoparticles (AgNPs) have numerous applications in
healthcare, food packaging and conservation, and household mate-
rials. With their increasing use, human exposures to silver nanopar-
ticles become the current concern with potential unexpected health
complications mainly due to their high reactiv ity. The toxic effects
of silver nanoparticles on human cells and the environment have
been extensively studied [163]. Combined treatment with gemcit-
abine and AgNPs caused increased cytotoxicity and apoptosis in
A2780 cells [163]. However, normally silver toxicity has been well
detoxified by small periplasmic silver-binding proteins, which bind
silver at the cell surface and by efflux pumps propels the incoming
metals and protects the cytoplasm from toxicity. The organic matrix
contains silver binding proteins that provide amino acid moieties,
which serve as nucleation sites for the formation of silver nanopar-
ticles. Silver nanoparticles are the mo st widely explored nano-
agents because of their broad antimicrobial spectrum with powerful
antimicrobial activity and low propensity to induce bacterial resis-
tance [25]. AgNPs provid e extremely attractive scaffolds for the
creation of transfection agents as they exhibit several advantages
including bioinertia, ready synthesis, and easy functionalization
[138, 164-166]. Quercetin conjugated with silver nanoparticles
shows a synergistic effect on antibacterial activity [24]. However,
silver nanoparticles conjugated quercetin applies negligible impact
on numerous sorts of drug-resistant bacteria including Pseudo-
monas aeruginosa and Bacillus subtilis. Quercetin being a charac-
teristic natural antioxidant compound can possibly conjugate with
silver nanopart icles pertinent in the treatment of cancer. Numerous
parameters like reducing agents, temperature, concentration of salt
and microenvironment affect the conjugation of quercetin and silver
nanoparticles. Quercetin loaded AgNPs reduces cytotoxicity, oxida-
tive stress as well as increases the metabolic act ivity of quercetin in
Caco-2 cells [132]. Silver nanoparticles in conjugation with sele-
nium improve drug delivery of quercetin and reduce cell viability of
Dalton’s lymphoma cells [133].
AgNPs not only induce apoptosis but also sensitize cancer cells.
The anticancer property of starch-coated silver nanoparticles was
studied in normal human lung fibroblast cells (IMR-90) and human
glioblastoma cells (U251). AgNPs induced alterations in metabolic
activity, and increased oxidative stress leading to mitochondrial
Quercetin Loaded Nanoparticles in Targeting Cancer: Recent Development Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19, No. 0 7
damage and increased production of ROS, ending with DNA dam-
age. Among these two cell types, U251 cells show more sensitivity
than IMR-90 [167]. The cellular uptake of AgNPs occurred mainly
through endocytosis. AgNPs treated cells exhibited various abnor-
malities, including upregulation of metallothionein, downregulation
of major actin-binding protein, filamin, and mitotic arrest [167].
The analysis of cancer cell morphology suggests that biologically
synthesized AgNPs could significantly induce cell death. Silver
nanoparticles were used to target breast-cancer cells (SKBR3) and
leukemia cells (SP2/O). Chitosan-based nanocarrier (NC) delivery
of AgNPs induces apoptosis at very low concentrations [168].
Lower concentrations of nanocarriers with AgNPs showed better
inhibitory results than AgNPs alone. Chitosan-coated silver
nanotriangles (Chit-AgNTs) show an increased cell mortality rate.
The anticancer property of bacterial -AgNPs and fungal extract-
conjugated AgNPs (F-AgNPs) has been demonstrated in human
breast cancer MDA-MB-231 cells. Both biologically produced
AgNPs exhibited significant cytotoxicity. Recent studies indicate
cell-specific toxicity by AgNPs. Plant extract-mediated synthesis of
AgNPs showed more pronounced toxic effect in human lung carci-
noma cells (A549) than non-cancer cells like human lung cells,
indicating that AgNPs could target cell-specific toxicity, probably
based on the lower pH in the cancer cells [169]. AgNPs showed
significant toxicity in MCF7 and T47D cancer cells by higher en-
docytic activity than MCF10-A normal breast cell line [170]. The
nanoconjugated quercetin through silver nanoparticles can be em-
ployed in the treatment of tumor models via influen cing its cytotox-
icity, delivery, and targeting site. However, further preclinical and
clinical study is needed to establish a chemoth erapeu tic agent
against a certain form of can cer.
Food-related applications of silver nanoparticles need to gain a
better understanding of the cellular and molecular mechanisms
involved in their interaction with the cells of the gastrointestinal
tract as well as with gastrointestinal fluid s, food matrix, microflora,
etc. Therefore, the safety of nanoparticles in the food matrix and
cancer cells remains to be explored and further understood.
7.3. PLGA (Poly Lactic-Co-Glycolic Acid)
Combination of arginine-glycineaspartic acid - sorafenib- quer-
cetin (RGD-SRF-QT) nanoparticles could provide a promising
platform for co-delivery of multiple anticancer drugs for the
achievement of combinational therapy and could offer the potential
for enhancing the therapeutic efficacy on hepatocellular carcinoma
[140]. Anticancer efficacy of poly (lactic acid)-quercetin nanoparti-
cles has been reported for sustained release kinetics revealing novel
vehicle for the treatment of breast cancer [134, 171]. Quercetin-
loaded poly (lactic-co-glycolic acid)-d-α-tocopheryl polyethylene
glycol succinate nanoparticles could be used as a potential intrave-
nous dosage for treatment of liver cancer owing to the enhanced
pharmacological effects of quercetin with increased liver targeting
[139]. Tamoxifen (Tmx) embedded PLGA nanoparticles (PLGA-
Tmx) is prepared to evaluate its better DNA cleavage potential,
cytotoxicity using Dalton’s lymphoma ascite cells and MDA-
MB231 breast cancer cells. PLGA-Tmx shows excellent DNA
cleavage potential as compared to pure Tamoxifen raising better
bioavailability. Sustained-release kinetics of PLGA-Tmx nanoparti-
cles shows mu ch better anticancer efficacy through enhanced DN A
cleavage potential and nuclear fragmentation and, thereby, reveals a
novel vehicle for the treatment of cancer [134]. Poly (e-
caprolactone) (P(CL)) is one of the biodegradab le and biocompati-
ble polyester polymers. The cellular uptake of P (CL)-TPGS
nanoparticles by SKBR3 cells is reported through cholesterol-
dependent endocytosis. The P (CL)-TPGS nanoparticles show im-
proved toxicity and uptake efficiency and could be potentially used
for the delivery of quercetin to breast cancer cells [136]. The retar-
dation of drug release from the nanoparticles depends on tempera-
ture and crystallin ity of the polymer. However, other factors must
be considered such as the compatibility and interaction of polymer
and drug [135]. A few studies hav e established the investigation of
P (CL)-TPGS copolymers with and without other co-monomers for
the delivery of genistein, paclitaxel, and TRAIL/endostatin [172-
176]. Quercetin-PLGA nanoparticles can be used as effective drug
delivery systems for skin cancer treatment encompassing natural
drugs [137].
Metastatic breast cancer is the fundamental driver of death from
breast cancer. We have reported the efficacy of trans-copper (II) β-
dithioester complexes and homoleptic zinc (II) complexes ag ainst
breast cancer [177, 178]. However, medicines are not focused on or
successful at this stage probab ly because of the presence of Breast
Cancer Stem Cells (BCSCs). The propinquity of BCSC is the criti-
cal explanation behind resistance and failure of therapy. As BCSC
originates from normal breast stem cells and having self-renewal,
high proliferation rate, ability to generate heterogeneity, etc. fur-
ther, Mesenchymal to Epith elial Transition (MET) is important for
invasion, intravasation, circulation and extravasation; and ulti-
mately leads to colonization of metastatic cells. Afterward, Lungs,
bone, liver, and brain are the main site of metastasis for breast can-
cer. Nanoconjugated quercetin in this regard has attracted much of
interest du e to effective therapeutic approaches against various
molecular targets during breast cancer metastasis in vitro as well as
in vivo system [120, 134, 157, 179-185] as depicted in Fig. (2). The
combination of a chemotherapeutic drug with a chemosensitizer has
emerged as a promising strategy for cancers showing multidrug
resistance. The improved synergistic efficacy of doxorubicin with
Boron Nitride Quantum Dots (BNQDs) has been reported in terms
of anticancer activity via DNA cleavage, ROS accumulation, and
interaction of doxorubicin-BNQDs with DNA in MCF-7 cells [186].
Biotin conjugated poly (ethylene glycol)-b-poly(ε-caprolactone)
nanoparticles encapsulating the chemotherapeutic drug doxorubicin
and the chemosensitizer quercetin (BNDQ) has a potential role in
the treatm ent of drug-resistant breast cancer [138]. BNDQ is more
effectively taken up with less efflux by doxorubicin-resistant MCF-
7 breast cancer cells (MCF-7/ADR cells) than by the cells treated
with the free drugs or non-biotin conjugated nanoparticles. BNDQ
exhibit ed clear inhibition of the activity and expression of p-
glycoprotein, an MDR marker in MCF-7/ADR cells [138]. Quer-
cetin-chitosan conjugate has been studied for oral delivery of
doxorubicin to improve its oral bioavailability by increasing its
water solubility, opening tight junction and bypassing the P-
glycoprotein in Caco-2 cells [118]. Quercetin loaded within
poly(lactic‐co‐glycolic acid) biodegradable nanoparticles, plays
a major role in drug t argeting to tumors due to its ability to interact
with CD44 receptor [55]. Chitosan is used to coat polyethylene
glycol containing vesicles for controlled delivery of quercetin in
colon cancer [159]. Cross-linked chitosan-liposom e fusion system
represents a promising combination of nanovesicles and for delivery
of quercetin into intestine [125]. Quercetin conjugated liposomes
have been used to deliver quercetin in rat brain [129].
7.4. Polymeric Micelles
Polymeric micelles have attracted enormous attention with suc-
cess in clinical studies of cancer targeting. Polymeric micelles are
constructed through self-assembly of block copolymers as nano-
scaled drug carriers. These micelles have a core-shell structure
where the drug-loaded core is encompassed by a bio compatible
PEG shell of 10-100nm [187]. Engineering the micelle-forming
block copolymers endowed polymeric micelles with smart on-
demand functionalities such as environment-sensitivity and target-
ability. Polymeric m icelles have been considered as the most prom-
ising nano-carriers because their critical size, drug incorporation
efficiency, stability, and release rate can be squeezed by setting up
the basic block copolymers. Utilization of polymeric micelles has
been reported in some tumor models and in some clinical studies
[188]. Colorectal cancer developing in the large intestine has been
8 Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19 , No. 0 Vinayak and Maurya
the third leading cause of cancer-related death globally. The en-
hanced delivery by quercetin conjugated monomethoxy poly (ethyl-
ene glycol)–poly(ε-caprolactone) MPEG-PCL nanomicellar system
in the CT26 tumor model, indicates a promising potential applica-
tion against colorectal tumor chemotherapy [114]. Further, quer-
cetin loaded nanomicelles significantly increase drug accumulation
at the tumor site and exhibit superior anticancer activity in prostate
cancer [143].
Biodegradable polyesters such as poly (D, L-lactide-co-
glycolide), poly (D, L-lactide), poly (ecaprolactone), and long-chain
alkyl derivatives appear to be widely used as a core-forming poly-
mer [189, 190]. The utilities of polymeric micelles have been ac-
counted for in experimental tumor models in mice as well as in
clinical examinations. In this manner, polymeric micelles can un-
derstand protected and successful treatment, and offer personalized
meds for individual patients. Various molecular interactions such as
hydrophobic interactions, hydrogen bonding, electrostatic interac-
tion and metal complex formation in the core-forming segments can
be a driving force of the formation of polymeric micelles [191-193].
A wide range of therapeutic molecules including hydrophobic sub-
stances, charged compounds, and metal complexes can be stably
and efficiently incorporated into the micellar core, and their release
can be controlled in a sustained or environment-sensitive manner.
Several micelles formulations of anticancer drugs are currently
under evaluation in preclinical and clinical studies [187]. Novel
nanoparticles containing polymeric microspheres loaded with pacli-
taxel and quercetin utilize as a promising pneumonic delivery sys-
tem for combined chemotherapy [194].
Because of characteristic core-shell structures and limited size
dispersions in the scope of 10-100nm, the drug-loaded center of
polymeric micelles can hinder interaction with plasma proteins and
cells, avoiding the recognition of the micelle by the reticulo-
endothelial system in the bloodstream [195]. Th erefore, polymeric
micelles can display prolonged circulation with a half-life longer
than 10h. The polymeric micelles separate into the constitu ent
square copolymers, the extent of which is beneath the edge of
glomerular discharge, in this way keeping away from long haul
amassing in the body. Long-circulating polymeric micelles success-
fully aggregate in large tumor because of the expanded brokenness
of tumor neo vasculature and impeded lymphatic seepage. Subse-
quently, polymeric micelles release incorporated drugs in a sus-
tained or microenvironment responsive manner [187, 191]. In this
manner, polymeric micelles can accomplish tumor-specific drug
activity while limiting side effects in normal tissues [187]. Contin-
gent upon the definitions, polymeric micelles are masked by malig-
nancy cells, and after that apply the impact of drug in an organelle-
specific way [191]. In such a w ay, polymeric micelles potentially
circumvent drug efflux or intracellular detoxification mechanisms,
overcoming drug resistance in cancer cells [196]. Encapsulated
polymeric micelle in conjugation with curcumin attenuates the pro-
gression of colon cancer. Polymeric micelles are formed from vari-
ous block copolymers. Poly (ethylene glycol) is generally utilized
as a shell-shaping polymer because of its hydration property and
large excluded volume impact averting cooperation with seru m
proteins. The micellar core is composed of a variety of synthetic
polymers, which critically affect the critical prop erties of polymeric
micelles as drug vehicles, including size, association number, criti-
cal micelle concentration, drug loading and release, and stability in
the bloodstream [187]. Dev elopment of α-helix of poly (L-
glutamate) may incredibly add to delayed blood distribution and
accumulation of cisplatin-stacked micelles in tumors under stage III
clinical assessm ent [197]. The technique for drug incorporation can
be characterized into 'non-covalent' and 'covalent' convention. In
Fig. (2). Targeting metastasis breast cancer through nanoconjugated quercetin. Metastasis breast cancer is the fundamental driver of death from breast cancer.
Medications are not fo cused on or successful at this stage might be because of the presence of Breast Cancer Stem Cells (BCSCs). The propinquity of BCSC is
the critical explanation behind resistance and failure of therapy. BCSC originates from normal breast stem cells and having self-renewal, high proliferation
rate, ability to generate heterogeneity, etc. EMT is impo rtant for invasion, intravasation, circu lation, and extravasation; and ultimately leads to colonization of
metastatic cells by Mesenchymal to Epithelial Transition (MET). Lungs, bone, liver, and brain are the main site of metastasis for breast cancer. Nanoconju-
gated quercetin in this regard has attracted much of interest due to effective therapeutic approaches against various molecular targets in metastasis breast can-
cer in vitro as well as in vivo sy stem.
Quercetin Loaded Nanoparticles in Targeting Cancer: Recent Development Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19, No. 0 9
the non-covalent drug stacking technique, water-insoluble com-
pounds are physically ensnared into the micelle center by dialysis,
ultrasound-helped scattering or as oil in water emulsion. A rela-
tively high drug loading capacity of approximately 20% can be
achieved without a chemical modification of drug molecules. For
successful drug incorporation, the similarity between a drug mole-
cule and th e core shaping fragments should be comp ared. Addition-
ally, the properties of the center shaping sections, for example,
hydrophobicity, the glass transition temperature, level of crystallin-
ity, and optional structure (α-helix development) are vital as they
fundamentally influence the productivity and limit of drug stacking
and its discharge conduct.
Drug molecules are chemically conjugated to the core-forming
segments in the covalent drug loading system. For drug conjuga-
tion, the environment-responsive cleavable linkage is mistreated to
guarantee the drug release at the target site [191]. Because the tu-
mor microenvironment is known to develop an acidic condition due
to the production of lactate by predominant anaerobic glycolysis in
cancer cells (Warburg effect), the corrosive cleavable linkage, for
example, hydrazone bond is valuable for tumor-particular drug
discharge [191]. The PEG-β-PAA copolymers are helpful for on-
request drug incorporation because of the opportunity of the choice
of amino acids and flexible side chain adjustment.
7.4.1. DOX Conjugated Micelles
The ‘non-covalent’ drug incorporation through chemical conju-
gation of doxorubicin (DOX) to the side chain of PAA by a stable
amide linkage resulted in loss of cytotoxic movement of conjugated
DOX yet stabilized the physical capture of free DOX through the p-
p bond between the anthracycline structures of conjugated and un-
conjugated drugs [188, 198]. In this way, improv ement of micellar
core-forming portions relying upon drug molecule is possible. DOX
was conjugated through the hydrazone bond between the carbonyl
gathering at C13 of DOX and the hydrazide bunch acquainted with
poly (D, L-aspartate). The DOX conjugated square copolymers
shaped polymeric micelles, which indicated acidic pH-responsive
DOX discharge. Currently, the micellar formulation of a less car-
diotoxic epimer, epirubicin (code name NC-6300/ K-912) is under
phase I clinical study [199]. Co-delivery with nanoconjugated quer-
cetin upgrades DOX mediated cytotoxicity against MCF-7 cells.
Monoclonal antibody (MAb604.107) builds the affectability of
doxorubicin and shows higher affection for Notch1 in T acute lym-
phoblastic leukemia (T-ALL) [157].
7.4.2. Metal Conjugated Micelles
Notwithstanding hydrophilic particles, metal complexes incor-
porated PEG-β-PAA micelles are complexed with PEG-β-poly(L-
glutamate) through Pt(II)-carboxylate complex formation, leading
to the formation of narrowly distributed micelles with the size of 30
nm [187, 200]. In these frameworks, the reversible ligand exchange
reaction of Pt (II) allows the ideal influx of dynamic platinum com-
plexes from the micelles, warranting their intense cytotoxic activity.
After systemic administration, cisplatin-loaded micelles were re-
vealed to show prolonged circulation and effective tumor accumu-
lation, achieving remarkable in vivo antitumor efficacies with re-
duced side-effects. Currently, CDDP and DACHPt-loaded micelles
(code names NC-6004 and NC-4016) are under phase III and phase
I clinical studies, respectively [197]. Intracellular drug release using
the vehicles may enhance the drug poten cy. For example, N-(2-
hydroxypropyl) methacrylamide copolymer-DOX conjugate an d
pH-responsiv e DOX stacked polymeric micelles were accounted to
conquest the DOX-hindrance in cancer cells because of intracellular
drug release. Micelles accelerate drug release in low pH conditions
emulating the late endosomal condition. Confocal microscopic
observation uncovered that DACHPt loaded micelles accomplished
intracellular drug release under both in vitro and in vivo conditions
[196]. Thusly, DACHPt-stacked micelles d emonstrated excellen t in
vitro and in vivo antitumor activities against oxaliplatin-safe tumor
cells [196].
7.4.3. Nucleic Acid Conjugated Micelles
Nucleic acids-based drugs such as plasmid, antisense DNA, and
siRNA can be incorporated into polymeric micelles through polyion
complex formation between negatively charged nucleic acids and
positively charged PEG-β-PAA copolymers. Polymeric micelles
immensely enhan ce the stability of nucleic acids-based drugs under
in vivo conditions, prompting delayed blood circulation. The clini-
cally approved polyethylene glycol-coated (PEGylated) liposomes
such as Doxil and albumin nanoparticles named Abraxane have the
measure of roughly 100nm. These polymeric micelles are accumu-
lated in the tumor due to the EPR impact. Transport of nanoparti-
cles depends on th e origin of tumor cells and the microenvironment.
Solid tumors have a pore cut-off size bigger than 200nm apart from
some malignancies, for ex ample, glioblastoma (GBM). In such
manner, pancreatic tumors and diffuse-type gastric cancers (scir-
rhous gastric diseases) have trademark histological highlights by
less porous vasculature with pericyte scope and thick fibrosis,
which may be a hindrance to extravasation and intrusion of
nanoparticles [200]. Co-administration of 30 and 70nm micelles in
mice bearing tumors uncovered that 30-nm micelles demonstrate a
uniform intratumoral microdistribution while 70nm micelles indi-
cate heterogeneous limitation at perivascular dist ricts [200]. The
gathering and entrance of polymeric micelles in pancreatic malig-
nancy models rely upon their size, as the 30nm micelles can avoid
the difficulties in transvascular transport and in filtrate tumor
stroma. The 30nm DACHPt-stacked micelles demonstrated strik-
ingly drawn out survival in malignancy bearing mice and the com-
parable impact was seen in gastric tumor. The extent of polymeric
micelles is additionally vital for focusing on tumor metastasis.
Lymph nodes are regular courses for metastasis in a few tumors. It
is realized that nearby organization of nanoparticles to primary
tumors prompts collection in the neighboring lymph node; however,
the lymphatic vessels are clinically associated in the sentinel lymph
node biopsy [201]. The sentinel lymph node is defined as the first
lymph node or group of nodes draining metastasizing cancer cells
from the tumor. Lymph node metastasis is one of the most impor-
tant prognostic signs as it determines if cancer has spread beyond a
primary tumor into the very first draining lymph node or not. Senti-
nel lymph node biopsy has been considered as a standard of care in
early breast cancers [201]. Polymeric micelles can accumulate se-
lectively in lymph node metastases through th e blood vascular
route, which is believed to be specific to the active recruitment of
lymphocytes to lymph nodes. Organization of COX-2 inhibitor
(celecoxib) brought about a huge reduction in collection of polym-
eric micelles in pre angiogenic metastases; therefore, the inflamma-
tory microenvironment seems to be a mechanism for the retention
of micelles in the metastatic niche.
7.4.4. Antibody Conjugated Micelles
Antibody and its fragments are likewise valuable as targetable
ligands to design effectively targetable micelles. Antibody conju-
gated micelles (immunomicelles) have been accounted against os-
teopontin, an epidermal development factor receptor for delivery of
antitumor drugs. Immunomicelles are conjugated with antagonistic
to Tissue Factor (TF) antibody parts, a known essential initiator of
blood coagulation, and assumes an imperative part in tumor multi-
plication, intrusion, and metastasis. Articulation level of TF on
cancer is related to the patient's prognosis. Anti-TF antibody frag-
ment conjugated micelles incorporating epirubicin and DACHPt
were efficiently internalized by TF-over expressing cancer cells and
showed superior in vitro and in vivo antitumor activity to non-
targeted micelles [202]. Immunomicelles can deliver several drug
particles per antibody which increase the choice of anticancer drugs
and practical outline. In this way, immunomicelles are more flexi-
10 Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19, No. 0 Vinayak and Maurya
ble stages for drug delivery. Antibody-mediated treatments includ-
ing Antibody Drug Conjugates (ADCs) have indicated much poten-
tial in growth treatment by tumor-focused on delivery of cytotoxic
drugs. Targeted delivery of DOX through immune polymeric mi-
celles where antibody C225 against EGFR is coupled with poly (L-
glutamic acid)-co-PEG, shows improved activity in inhibiting the
growth of A431 cells than free DOX [203]. Coordination of anti-
bodies to drug stacked nanocarriers expands the appropriateness of
antibodies to an extensive variety of therapeutics. Antibody frag-
ment-installed polymeric micelle in conjugation with maleimide-
thiol has been studied for the treatment of pancreatic cancer [202].
However, there is a limitation of loads that can be delivered through
antibody drug conjugates. The measure of drugs that can be deliv-
ered by a solitary antibody is the real test being developed of anti-
body drug conjugates, since over-burdening may lessen the binding
affinity of the antibody or affect pharmacokin etics, solubility, and
stability of the drug. Generally, 2 to 4 drugs for each antibody can
be presented in a neutralizer drug conjugate for achieving a suc-
cessful therapeutic response. Certain cytotoxic drugs such as aur-
istatins, maytansines, and calicheamicins have been conjugated to
the antibody, which are thousand-fold high er cytotoxic than typical
anticancer drugs; however, there are some concerns of side effects
[196, 200, 204]. This antibody conjugated nanoparticles o ffer better
delivery system achieving superior therapeutic efficacy while re-
ducing side effects.
During the last two decades, polymeric micelles as drug vehi-
cles have made rapid p rogress and several formulations are already
being evaluated in late-stage clinical trials. The approval of these
micellar anticancer drugs and generation of innovative m icellar
nanomedicines with smart functionalities for a clinical trial is ex-
pected soon. Polymeric micelle such as Paclitaxel (PTX)-loaded
polymeric micelles, SP1049C, Genexol-PM, NK012, NK105,
NC6300, K-912, NK 6004 are now under clinical trial against cer-
tain form s of cancer like breast cancer, non-small-cell lung cancer
and ovarian can cer, adenocarcinoma of oesophagus, gastroesophag-
eal junction and stomach, NSCLC, renal, stomach and pancreatic
cancer, advance stomach cancer, liver cancer and solid tumors,
respectively [197-199, 202, 205-212] (Table 2).
7.5. Other Delivery System for Nanoconjugated Quercetin
Apart from several nano-sized platform s including polymeric
micelle, liposomes, PLGA (Poly lactic-co-glycolic acid), silver
nanoparticles; other carriers are also evolv ed for delivery of quer-
cetin. In this series, nanosponges, poly (β-amino esters) nanogels,
solid lipid, carbon nanotubes, and silicon quantum dots are under
evaluation nowadays for safe and efficient delivery of quercetin to
target various cancerous cells [121, 137, 158, 213-215] (Table 3).
In recent research, a certain new combination of quantum dots
is being explored for clinical imaging and drug targeting. Use of
quantum dots plays a central theme in nanotechnology for medical
imaging due to small size w ith special electrical and electronic
properties. Quantum dots have been connected in the biomedical
field because of subordinate optical properties, high fluorescence
quantum yields, amazing reliability against photobleaching, and
lower toxicity. Certain types of quantum dots such as boron nitride
quantum dots [165, 166, 186] and graphene oxide quantum dots
[213, 216, 217] are being studied for their fluorescence properties,
lower cytotoxicity, and increased accumulation in cancer cells;
which can provide sufficient information for drug delivery. Gra-
phene oxide has been implicated for controlled loading and targeted
delivery of doxorubicin in MCF-7 breast cancer cells [218]. Re-
cently, silicon quantum dots possess strong luminescence character-
istics as well as low inherent cytotoxicity compared to conventional
heavy metal quantum dots, thus making them a potential for bio-
logical applications. Quercetin encapsu lated silicon quantum dots
results in red fluorescent, inhibits hydrogen peroxide-induced DNA
damage, allows monitoring of delivery, improvement of aqueous
solubility and enhanced biocompatibility in HepG2 hepatocarci-
noma cells [213]. Quercetin encapsulated silicon quantum dots emit
red fluorescen ce allowing monitoring of delivery, inhibits hydrogen
peroxide-induced DNA damage, improves aqueous solubility,
and enhanced biocompatibility in HepG2 hepatocarcinoma cells
[213, 216].
Utilization of silica nanoparticles as controlled drug delivery
system has been studied because of their high stability, high surface
area and better ability to function alize by various ligands, high drug
loading efficiency and low in vivo toxicity. The increased oral
bioavailability of drug after loading with mesoporous silica
nanoparticles has been studied [219]. The US Food and Drug Ad-
ministration (FDA) permitted silica nanoparticles for the first hu-
man clinical trial against cancer. Quercetin incorporated with
aminopropyl functionalized mesoporous silica nanoparticles p ro-
vides better nanocarrier for quercetin delivery. It is reported as an
improved chemo-preventive agent for in vitro system [220]. Al-
though silica nanoparticles conjugated quercetin delivery sy stem
requires the evaluation of toxicity so that it may be utilized against
cancer in the near futu re. Further, there is a need for monitored
bioimaging to understand the function of the delivery system more
precisely. Phytosome innovation can enhance the adequacy of che-
motherapeutics capability of anticancerous tranquilizes by expand-
ing the permeability of tumor cells. Poly (β-amino esters) polymers
have emerged as highly promising candidates for drug delivery and
biomedical applications due to their pH sensitivity, tuneable and
degradable properties. These polymeric frameworks can fill in
as pro fessional drug transporters for the delivery of bioactive
compounds such as quercetin which experience the poor watery
solvency and low bioavailability. Treatment of quercetin based
solid lipid nanoparticles recovers bone loss in ovariectomized rats
[158].
Additionally, the discovery, characterization, and implication of
carbon nanotubes having unexpected el ectrical, mechanical, an d
Table 2. Polymeric micelles under clinical evaluation.
Sr. No.
Polymeric Micelle
Cancer
Clinical Evaluation
Refs.
1
Paclitaxel (PTX)-loaded polymeric micelles
Breast can cer, non-small-cell lung cancer, and ovarian cancer
Approved
[206, 207]
2
SP1049C
Adenocarcinoma of oesophagus, gastroesophageal junction and stomach
Clinical p hase III
[208]
3
Genexol-PM
NSCLC
Clinical p hase II
[202]
4
NK012
Renal, sto mach and Panc reatic c ancer
Clinical p hase I/II
[209]
5
NK105
Advance stomach cancer
Clinical p hase II
[210]
6
NC6300
Liver cancer
Clinical p hase I
[199, 211]
7
K-912
Solid tumors
Clinical p hase I
[198]
8
NK 6004
Solid tumors
Clinical p hase I/II
[197, 205, 212]
Quercetin Loaded Nanoparticles in Targeting Cancer: Recent Development Anti-Cancer Agents in Medicinal Chemistry, 2019, Vol. 19, No. 0 11
thermal properties further explore the possibility of drug delivery
and targeting of anticancerous drugs. The release of quercetin from
carbon nanotubes attributes the increased hydrophilicity and solu-
bility of quercetin at acid microenvironment of cancer [214]. Im-
proved efficiency and reduced toxicity of quercetin carbon nano-
tube composite implicated in HeLa cells, suggests the consid erable
potential advantages of quercetin-carbon nanotube composite in
cancer therapy [215]. Furth er, the suitability of the nanosponges has
been implicated not only as a dual release drug delivery system but
also with regulated metabolism through nano network [137]. The
variety in crosslinking allows a dual release with regulated release
kinetics and recommends enhanced bioavailability supported by a
reduced metabolism. Dual drug delivery of tamoxifen and quercetin
with nanosponges in regulated metabolism has been suggested for
anticancer treatment [121]. An embodiment of polyester nano-
sponge co-stacked with quercetin is examined for successful load-
ing, release, and in vitro digestion. Lockhart et al. reported that
improved bioavailability of the nanoparticles formulations of nano-
sponge is supported by drug release, cytotoxicity, and enhanced
anti-cancer effects in the recovery condition [121].
CONCLUSION AND FUTURE PERSPECTIVE
Nanoparticles have been extensively investigated to deliver
anticancer drugs due to their enhanced anticancer potential and
promising clinical application. Recent research in nanoconjugated
quercetin is proposed to overcome its limitations of low bioavail-
ability, chemical instability, and short biological half-life. The
pharmacological effect of quercetin conjugated nanoparticles
mostly depends on drug carriers used. Quercetin conjugated polym-
eric micelles, liposomes, silver nanoparticles, PLGA (Poly lactic-
co-glycolic acid) have shown better inhibition of tumor growth in
vivo. Controlled drug release, long retention in tumor, improved
efficiency in invagin ation and extravagation through pores in the
capillary endothelium of tumor by nanoconjugated drugs have built
the future hope of their clinical application in metastatic cancer.
Delivery of quercetin nanoparticles and their anticancer efficacy are
mostly confined to laboratory animals and in vitro system. How-
ever, certain other nanoconjugated anticancer drugs are under clini-
cal trials. Despite numerous in vitro and in vivo anti-cancer studies
of quercetin formulations, there exist certain limitations for clinical
translation such as cost, safety, and side effects. Locating key target
molecules, safe and stable delivery systems with superior strategy
to overcome resistance and reduce the side effects of chemothera-
peutic agents are the main goals of ideal cancer treatment. Addition
of cancer cell-specific targeting moieties on the nanoparticles has
been evolved to not only enhance target-specific delivery of nano-
formulations but also to reduce their interaction with the normal
cells, p reventing side effects of drugs.
AUTHOR CONTRIBUTIONS
All authors have participated in planning or drafting of the
manuscript and approved the final version.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
This work was supported by Department of Science and Tech-
nology, India (Grant No. SR/S0/AS-97/2007); and University
Grants Commission, India (Grant Nos. F.31-217/2005; F.40-
209/2011 SR).
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or other-
wise.
ACKNOWLEDGEMENTS
Declared none.
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