Seminars in Cancer Biology xxx (xxxx) xxx–xxx

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Seminars in Cancer Biology

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

Review

Dietary flavonoids: Nano delivery and nanoparticles for cancer therapy

Paola Aielloa,b,c, Sara Consalvid, Giovanna Poced, Anna Raguzzinia, Elisabetta Totia,
Maura Palmeryb, Mariangela Biavad, Marco Bernardib, Mohammad A. Kamale,f,g,
George Perryh, , Ilaria Pelusoa,
⁎⁎ ⁎

a
Research Centre for Food and Nutrition, Council for Agricultural Research and Economics (CREA-AN), Rome, Italy
b
Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Italy
c
Universidad Católica San Antonio de Murcia (UCAM), Murcia, Spain
d
Department of Chemistry and Drug Technologies, University “La Sapienza”, Rome, Italy
e
King Fahd Medical Research Center, King Abdulaziz University, Saudi Arabia
f
Enzymoics, 7 Peterlee Place, Hebersham, NSW, 2770, Australia
g
Novel Global Community Educational Foundation, Australia
h
Department of Biology, University of Texas at San Antonio, TX, USA

ARTICLE INFO ABSTRACT

Keywords: Application of nanotechnologies to cancer therapy might increase solubility and/or bioavailability of bioactive
Epigallocatechin gallate compounds of natural or synthetic origin and offers other potential benefits in cancer therapy, including se-
Quercetin lective targeting. In the present review we aim to evaluate in vivo studies on the anticancer activity of nano-
Flavonoids particles (NPs) obtained from food-derived flavonoids. From a systematic search a total of 60 studies were
Cancer
identified. Most of the studies involved the flavanol epigallocatechin-3-O-gallate and the flavonol quercetin, in
Nanoparticle
both delivery and co-delivery (with anti-cancer drugs) systems. Moreover, some studies investigated the effects
of other flavonoids, such as anthocyanins aglycones anthocyanidins, flavanones, flavones and isoflavonoids. NPs
inhibited tumor growth in both xenograft and chemical-induced animal models of cancerogenesis.
Encapsulation improved bioavailability and/or reduced toxicity of both flavonoids and/or co-delivered drugs,
such as doxorubicin, docetaxel, paclitaxel, honokiol and vincristine. Moreover, flavonoids have been successfully
applied in molecular targeted nanosystems. Selectivity for cancer cells involves pH- and/or reactive oxygen

Abbreviations: 2-AAF, 2-acetylaminofluorene; 67LR, laminin receptor 67 kDa; ALP, alkaline aminotransferate; ALT, alanine aminotransferate; API, apigenin; AST,
aspartate aminotransferate; ATC, anthocyanin; AUC, area under the curve; BaP, Benzo[a]pyrene; BCL, baicalein; BR, biotin receptor; BSA, bovine serum albumin;
BW, body weight; CAT, catalase; CD44R, CD44 receptor; CH, chitin; CHOL, cholesterol; CIS, cisplatin; Cmax, maximum plasma concentration; CMS, colloidal
mesoporous silica; COX-2, cyclooxygenase-2; CS, chitosan; CSU, chondroitin sulfate; CTX, cyclophosphamide; Cy, cyanidin; DEN, diethyl nitrosamine; DMBA, 12-
dimethyl(a)benz anthracene; DOX, doxorubicin; Dp, delphinidin; DSPE-MPEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol);
EAC, Ehrlich ascites carcinoma; EGCG, epigallocatechin-3-O-gallate; EGFR, epidermal growth factor receptor; EIF5A2, oncogene eukaryotic translation initiation
factor 5A2; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; Eudragit, aminoalkyl methacrylate copolymer E; FA, folic acid; FITC, fluorescein
isothiocyanate; FR, folate receptors; FU, fucose; GEN, genistein; GPNLC, GeluPearl stabilized by Gelucire; GPSLN, GeluPearl with Precirol ATO 5 stabilized by
Gelucire; GSH, glutatione; GST, glutatione-S-transferase; HA, hyaluronic acid; Hb, haemoglobin; HES, hesperetin; IC50, half inibitory concentration; IFN, interferon;
IL, interleukin; IR, integrin receptor; KpK, kaempferol; MDA, malondialdeide; MDR, multidrug resistance; MNU, N-methyl-Nitrosurea; MPEG–PCL, monomethoxy
poly (ethylene glycol)–poly(ε-caprolactone); MPEG-PLA, methoxy poly (ethylene glycol)-poly(lactide); M-PLGA–TPGS, copolymer mannitol-functionalized Poly
(lactic-co-glycolic acid); MPO, myeloperoxidase; MPP, matrix metalloproteinases; MSN, mesoporous silica nanoparticles; Mv, malvidin; NF-κB, nuclear factor-κB;
NPs, nanoparticles; Nrf2, nuclear transcription factor-erythroid 2-related factor 2; PAA, poly (acrylic acid); PBS, phosphate buffered saline; PC, phosphatidylcholine;
PCL, poly(ε-caprolactone); PCNA, proliferating cell nuclear antigen; Pe, peonidin; PE, phosphatidylethanolamine; PEG, polyethylene glycol; PEG-DSPE, poly(ethy-
lene glycol)–distearoylphosphatidylethanolamine; PEG-PCL, poly(ethylene glycol)-poly(-caprolactone); Pg, pelargonidin; PLA, polylactic acid; PLGA, poly(lactic co-
glycolic acid); PMSN, arginine-glycine-aspartic acid peptide-MNS; pPhe-pHis-PEG, poly(phenylalanine)-b-poly(L-histidine) -b- poly(ethylene glycol); PS, particle
size; PSA, prostate specific antigen; PSMA, prostate-specific membrane antigen; Pt, petunidin; PTX, paclitaxel; PVA, poly-vinyl alcohol; QCT, quercetin; ROS, reactive
oxygen species; SA, stearic acid; SCID, severe combined immunodeficient; SNEDDS, self-nano-emulsifying drug delivery system; SOD, superoxide dismutase; SPC,
soybean phosphatidylcholine; Tf, transferrin; TfR, transferrin receptor; Tmax, time to reach peak concentration; TMX, tamoxifen; TNF, tumor necrosis factor; TPGS,
d-α-tocopheryl polyethylene glycol 1000 succinate; TPP, triphenylphosphine; TPs, tea polyphenols; TPT, topotecan; UVB, ultraviolet-B; VEGF, vascular endothelial
growth factor
⁎
Corresponding author at: Research Centre for Food and Nutrition, Council for Agricultural Research and Economics (CREA-AN), via Ardeatina 546, Rome, Italy.
⁎⁎
Corresponding author.
E-mail addresses: george.perry@utsa.edu (G. Perry), ilaria.peluso@crea.gov.it (I. Peluso).

https://doi.org/10.1016/j.semcancer.2019.08.029
Received 9 July 2019; Received in revised form 8 August 2019; Accepted 22 August 2019
1044-579X/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Paola Aiello, et al., Seminars in Cancer Biology, https://doi.org/10.1016/j.semcancer.2019.08.029
P. Aiello, et al.
species-mediated mechanisms. Furthermore, flavonoids are good candidates as drug delivery for anticancer
drugs in green synthesis systems. In conclusion, although human studies are needed, NPs obtained from food-
derived flavonoids have promising anticancer effects in vivo.
1. Introduction
The main dietary sources of flavonoids, bioactive polyphenols of
natural origin, are cocoa products (1589–3410 mg/100 g) and green tea
(7.93–27.16 mg/100 ml) for flavanols, blackberries (595–1316 mg/
100 g) for anthocyanins, soy products (148–466 mg/100 g) for iso-
flavonoids, spinach and onions (119–158 mg/100 g) for flavonols, black
olives and artichokes (27–58 mg/100 g) for flavones, orange and
grapefruit juices (38–51 mg/100 ml) for flavanone [1,2]. However,
several studies reported differences in foods consumed in different
countries. In general, while tea [3–9] and fruits [4,8–11] are the most
important food sources of flavonoids, beer [8,9], cocoa products [5],
and beans [12] are within the major food sources in the US, Poland and
Brazil, respectively. Moreover, onions and apples are the main dietary
sources of flavonoids in Finland [7] and in The Netherlands [3],
whereas in the Mediterranean countries the most important source of
polyphenols are olives and olive oil [11]. In Italy, within the main
dietary sources of flavonoids there are various vegetables, such as ar-
tichokes and olives (flavones), spinach and beans (flavonols), and
cherries (anthocyanins), as well as citrus fruits (flavanones) and red
wine (flavanols) [13].
Preclinical studies reported that flavonoids, such as the flavanol
epigallocatechin-3-gallate (EGCG), the flavonol quercetin (QCT), the
flavone apigenin (API), the flavanone hesperetin (HES) and the iso-
flavone genistein (GEN) exerted anticancer activity by inhibiting cell
cycle and/or by inducing apoptosis [14–21]. Moreover QCT and GEN
interact with androgen receptors and estrogen receptor β, respectively
[14,20], and others suggested mechanisms for flavonoid anticancer
activities involving epidermal growth factor receptor (EGFR), vascular
endothelial growth factor (VEGF), nuclear factor-κB (NF-κB) and matrix
metalloproteinases (MPP) [14–20,22,23]. Although an inverse asso-
ciation between dietary flavonoid intake and certain cancers (upper
aero-digestive tract, colorectal, breast, and lung cancers) has been re-
ported from case-control studies, further prospective cohorts assessing
dietary polyphenol metabolism are needed to confirm health benefits
[24–26]. Despite the potential activity, pharmacokinetic studies re-
vealed low bioavailability and consequent controversial efficacy, re-
sulting from these agents being phytochemicals substrates of both phase
I and phase II detoxification enzymes and phase III transporters, as well
as of the microbial flora in the colon [22,23,27–29]. Estimated max-
imum plasma concentration (Cmax) and estimated time to reach this
peak concentration (Tmax) for flavonoids and their metabolites are
very variable within different flavonoids classes. Cmax is about 10−3M
for flavanones (Tmax range: 4.0–5.0 h) and anthocyanins (Tmax
range: < 1–1.5 h), between 10-5–10−3M for flavanols (Tmax range:
1.6–2.6 h) and isoflavones (Tmax range: 1.6–17.1 h) and between 10-5-
10-4M for flavonols (Tmax range: < 1-5.4 h) [29]. In order to improve
bioavailability and reduce toxicity and multidrug resistance (MDR),
research is focusing, as previously reviewed, on nanodelivery systems
[14,18,19,22,23,27,30–39]. In the present review we aim to evaluate in
vivo studies on the anticancer activity of nanoparticles (NPs) obtained
from food-derived flavonoids.
2. Study selection
We performed a systematic search on the Medline database for lit-
erature examining the effects of flavonoid nanoparticles on cancer in
vivo until May 2019. The search terms were: flavonoid AND nano-
particle AND cancer. The aim of the present review focused on the food-
derived flavonoids, studies on herbal extracts, silymarin or other
2
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
polyphenols (i.e.curcumin, resveratrol) were excluded. Studies that met
the following criteria were included: studies appeared in an edited
journal (peer-review criterion), written in English (language criterion),
focused on the anticancer effect of flavonoid nanoparticles (topic cri-
terion) and measured tumor growth in vivo (method criterion). Studies
were included when they met the above criteria regardless of dose and
treatment duration and/or type of animal model of cancerogenesis
(xenograft or chemical-induced). Through these criteria, a total of 60
studies were identified (Tables 1–5). Most of the studies involved EGCG
(Table 1) [40–46] and QCT (Table 2) [47–66], but some surveys in-
vestigated the effects of other flavonoids, such as anthocyanins, agly-
cones, anthocyanidins, flavanones, flavones and isoflavonoids (Table 3)
[67–76]. Furthermore, some studies investigated the effects of flavo-
noids as drug delivery and in co-delivery formulation (Table 4)
[77–83], as well as in molecular targeted nanosystems (Table 5)
[84–99]. Studies on bioavailability and in vitro evidence were main-
tained for discussion.
3. Flavanols
Encapsulation improved both stability and cellular uptake and/or
cytotoxic effect of EGCG [42,46,100–102] and cocoa procyanidins [103].
The effect of EGCG on tumor growth was investigated in vivo in studies
that used chitosan (CS) [40,41], fucose (FU)-CS-polyethylene glycol
(PEG)-CS [42], gold [43–45] and polylactic acid (PLA)-PEG [46] NPs
(Table 1). EGCG NPs showed lower half maximal inhibitory concentra-
tion (IC50) on cell viability/proliferation in vitro [43,46,102,104–106]
and induced high tumor growth inhibition in xenograft cancer models
compared to pure EGCG (Table 1). There was a dose-dependent inhibi-
tion of tumor growth by EGCG NPs [46] and the growth-suppressive
effect of EGCG NPs was found to be more effective in the group viain-
tratumor (i.t.) or intraperitoneally (i.p.) than that orally (p.o.) [44]
(Table 1). It has been reported, by using excised mouse jejunum in
chambers, that encapsulation significantly enhanced intestinal absorp-
tion [107]. Mass balance studies conducted during the experiment,
measuring the disappearance of catechins in the donor chamber, in-
dicated that enhancement of intestinal absorption most likely occurs as a
result of the stabilization of catechins in the donor chamber, which
subsequently drives their flux across the tissue [107]. Administration of
the CS EGCG NPs increased the concentrations of EGCG in the jejunum
(2.3-fold increase) of mice and enhanced the plasma exposure of total
EGCG by a factor of 1.5 relative to an EGCG solution (plasma AUC 179.3
and 116.4 nM/h, respectively) [108]. Despite the reported hepatotoxicity
of EGCG in humans [109–113], no toxicity was observed in vivo in terms
of differences in body weight (BW) gain, liver, kidney, spleen, and
uterine weight between control animals and treated groups [41,44], as
well as in terms of renal and hepatic toxicities (serum levels of creatinine,
blood urea nitrogen, bilirubin, alkaline phosphatase: ALP, alanine ami-
notransferase: ALT, and aspartate aminotransferase: AST) [45]. In Ehr-
lich ascites carcinoma (EAC), biochemical parameters in blood, such as
level of haemoglobin (Hb), glucose, cholesterol, triglycerides, urea, ALP,
ALT, AST, bilirubin and total protein improved, compared to controls, in
mice treated with and without tea polyphenols (TPs) NPs (10 mg/kg).
These mice were injected before tumor induction and after 2 days re-
ceived intraperitoneally EAC cells [114]. Lipid peroxidation was reduced
in EAC bearing mice administered (pre- and post-treated) with TPs NPs,
whereas it was high in EAC bearing control mice and EAC bearing mice
treated with unloaded NPs. The activities of the antioxidant enzymes
catalase (CAT) and superoxide dismutase (SOD) in EAC bearing mice
were significantly reduced and ameliorated by the oral administration of
P. Aiello, et al. Seminars in Cancer Biology xxx (xxxx) xxx–xxx

Table 1
Anticancer effect of EGCG nanoparticles in animal models.
Formulation Animal model Treatment and Tumor growth Ref.
(Mean PS) administration route

CS Xenograft: Control (Chit-nano) 25-60 days [40]

(EGCG NPs) Athymic nude mice, human prostate carcinoma 22Rv1 EGCG (40 mg/) EGCG ↓
(200-207 nm) cells EGCG NPs (3 mg/kg), EGCG NPs (3) ↓↓
EGCG NPs (6 mg/kg) EGCG NPs (6) ↓↓↓
Orally (treatment started one day post inoculation, 5/ week)
CS Xenograft: Control 27-32 days [41]
(EGCG NPs) Athymic nude mice, human melanoma Mel 98 cells EGCG (1 mg/mice), EGCG 1 mg ↓↓
(PS n.r.) EGCG (100 μg/mice) EGCG 100 μg ↓
EGCG NPs (100 μg/mice) EGCG NPs ↓↓↓
Orally (treatment started one day post inoculation, 5/ week)
FU-CS-PEG-CS Xenograft: Control (blank NPs) 16 days [42]
(EGCG NPs) Athymic nude mice, gastric adenocarcinoma Luc MKN45 EGCG (40 mg/kg) EGCG ↓
(250-540 nm) cells EGCG NPs (40 mg/kg) EGCG NPs ↓↓
Orally (treatment started 14 days post inoculation, once daily).
Gold Xenograft: Control (PBS), 28 days [43]
(EGCG NPs) C57/BL6 mice, murine melanoma B16F10 cells EGCG (2 mg /mouse) EGCG ↓
(64.7 nm) EGCG NPs (2 mg/mouse) EGCG NPs ↓
Intratumorally (treatment started on day 14 post inoculation, 2/
week)
Gold Xenograft: Control (water) 29 days [44]
(EGCG NPs) C3H/HeN mice, murine bladder tumor MBT-2 cells EGCG (2 mg /mouse) EGCG (TR p.o.) ↔
(20-1200 nm) EGCG NPs (2 mg /mouse) EGCG (PR p.o.) ↓
Prevention (PR): orally EGCG NPs (PR p.o.) ↓↓
Treatment (TR): orally (p.o.), ↓
intraperitoneally (i.p.) EGCG NPs (TR p.o.) ↓
or intratumor (i.t.). EGCG NPs (TR i.p.) ↓↓
PR: once daily every other day for 7 days before inoculation. EGCG NPs (TR i.t.) ↓↓
TR: every other day on day 14 post inoculation.
Gold Xenograft: Control 29 days [45]
(EGCG NPs) C3H/He mice, MBT-2 murine bladder tumor cells EGCG (2 mg /mouse) EGCG (p.o.) ↓
(50 nm) EGCG NPs (2 mg /mouse) EGCG NPs (p.o.) ↓↓
Orally (o.p.) or intraperitoneally (i.p) EGCG NPs (p.o.) ↓↓↓
(treatment started 14 days post inoculation).
LA-PEG Xenograft: Control (no treatment) Weeks 5-7 [46]
(EGCG NPs) Athymic nude mice, 22Rv1 cells (human prostate EGCG (1 mg/mice) EGCG ↓
(285 nm) carcinoma) EGCG NPs (100 mg/mice) EGCG NPs ↓
(treatment started after inoculation, 3/week)

CS: Chitosan; EGCG: Epigallocatechin-3-O-gallate; FU: Fucose; NPs: nanoparticles; PEG: Polyethylene glycol: PLA: Polylactic acid; PS: particle size (mean).

TPs NPs [114]. In this context, oral administration of TPs NPs for 3 days
prior to irradiation exposure has been shown to protect mice from he-
matological injuries that result in the reduction of radiation-induced
lethality and of radiation-induced oxidative damage and apoptosis, by
restoring the redox status through the nuclear transcription factor-ery-
throid 2-related factor 2 (Nrf2)-extracellular signal-regulated kinase
(ERK) pathway and reducing Bax expression, respectively [115].
On the other hand, there was a significant inhibition in serum
prostate-specific antigen (PSA, marker of disease progression) in EGCG
treated mice. The EGCG-NPs treatment led to an additional decrease in
the levels of serum PSA [40,46]. High efficacy and lower toxicity in
cancerogenesis in vivo models can be due to NPs biodistribution com-
pared to non-conjugates.
In vivo tumor accumulation and clearance of green tea [116] and
EGCG [117] NPs have been reported. Studies presented in Table 1 re-
port inhibition of proliferation in tumor tissues, by measuring Ki-67,
proliferating cell nuclear antigen (PCNA) and CDK 4 and 6 [40–42].
Fucose-carboxymethyl chitosan graft EGCG with gold NPs
(30–70 nm) displayed cancer weakening as suggested by the lowly
nuclear thickness of cancers in mice undergoing pre-cancerous vacci-
nation with gastric tumor cells (MKN45) [117].
Moreover, in tumor tissues isolated from EGCG NPs treated mice a
shift in the Bax/Bcl-2 ratio in favor of apoptosis [41,45] and an increase
in the activation of caspases-3, -8 and -9 were observed [40,45]. Ac-
cordingly, enhanced apoptosis and/or inhibition of proliferation, by
modulations of Bcl-2/Bax, cyclin dependent kinase inhibitors WAF1/
p21 and CIP1/p27, cyclins and caspases, were observed in cancer cells
treated with EGCG NPs compared with free EGCG [41,45,46,102].
Furthermore, EGCG NPs showed to inhibit angiogenesis [45,46].
Khan et al. [40] observed a 5.7- to 8.2-fold expression of CD31 and 4.1-
to 5.9-fold VEGF-positive cells in control group than in EGCG NPS
treated groups. Similar decreased VEGF levels after treatment with
EGCG NPs were found by Hsieh et al. [44,45] and inhibition of neo-
angiogenesis have been observed also in zebrafish xenotransplants for
catechin NPs (50 μg/ml) [101].
Gold EGCG NPs also showed immunomodulating activity in tumor-
bearing mice, decreasing the expression levels of interleukin-4 (IL-4)
and IL-6 significantly and increasing the expression levels of IL-2 and
interferon-γ (IFN-γ) [44]. These results suggested that the anti-tumor
effect of EGCG plus pNG viaoral administration could be correlated to
the cell-mediated immunity. To verify this hypothesis, authors ex-
amined the cytotoxic activity of natural killer (NK)-cells in tumor-
bearing mice and found an increased NK cell-activity in the group
subjected to early intervention of EGCG plus pNG [44]. Moreover, a
possible involvement of Th1 (by virtue of IFN-γ production) and Th17
cells (viaproduction of IL-17A) in cancer immunosurveillance has been
suggested [44].
4. Flavonols
Although studies reported both the anti-cancer effect in vitro of
morin NPs [118] and kaempferol (KPF) NPs [119,120] and the brain
delivery of intranasal administration of KPF NPs [119], among flavo-
nols only QCT NPs have been assessed for tumor growth inhibition

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P. Aiello, et al. Seminars in Cancer Biology xxx (xxxx) xxx–xxx

Table 2
Anticancer effect of quercetin (QCT) nanoparticles in animal models.
Formulation Animal model Treatment and Tumor growth Ref.
administration route

Gold DMBA-induced mammary carcinoma in Sprague-Dawley Control (NPs) 8 days [47]

(QCT NPs) rats DMBA QCT ↓
(5.2 nm) QCT (25 mg/kg); QCT NPs ↓↓
QCT NPs (25 mg/kg)
Intratumoural (treatment started after 60 days, 8
days)
n.r. DEN-induced hepatocarcinogenesis in rats Control (medium/NPs) 18 weeks [48]
(QCT NPs) QCT Preneoplastic lesions
(40-100 nm) QCT NPs (8.98 μmol/kg) QCT ↔
Intravenously (once a week for 16 weeks) QCT NPs ↓
PLGA- rutin (RT quercetin-3- DEN-induced hepatocarcinogenesis in rats Control (olive oil) 22 weeks [49]
O-rutinoside) RT (5 mg/kg) RT (5) ↓
(RT NPs) RT (100 mg/kg) RT (100) ↓↓
(211 nm) RT NPs (5 mg/kg) RT NPs ↓↓↓
Orally (daily for 22 weeks)
PLGA DEN-induced hepatocarcinoma in rats Control (olive oil/NPs) 18 weeks [50]
(QCT NPs) DEN (200 mg/kg) QCT ↔
(270 nm) QCT (8.98 mmol/l) QCT NPs ↓
QCT NPs (8.98 mmol/l)
Orally (weekly for 16 weeks)
PLGA DEN-induced hepatocarcinoma in rats Control (untreated/NPs) 18 weeks [51]
(QCT NPs) DEN Preneoplastic
(270 nm) QCT (8.98 mmol/l) lesions:
QCT NPs (8.98 mmol/l) QCT ↔
Orally (weekly for 16 weeks) QCT NPs ↓
DSPE-MPEG Xenograft: Control (saline) 40 days [52]
(QCT NPs) Balb/c nude mice, human prostate cancer cells PC-3. QCT (30 mg/kg) QCT ↓
(13.21 nm) QCT NPs (30 mg/kg). QCT NPs ↓↓
Intravenously (treatment started when the tumor
volume reached 150 mm3, at days 23, 26, 29, 32, 35
and 38)
CS Xenograft: Control (PBS) Weeks 4 [53]
(QCT NPs) Immunocompromised C57BL6 mice, A549 and MDA MB QCT (25 mg/kg) QCT ↓
(100-200 nm) 468 cells QCT NPs (25 mg/kg) QCT NPs ↓↓
Intravenously (treatment started when the tumor
volume reached 80-100mm3, twice in a week)
Freeze-dried Xenograft: Control (saline) 28 days [54]
(FD QCT NPs) Mice, C6 glioma cells QCT (25 mg/kg) QCT ↓
(56.5 nm, QCT NPs QCT NPs (25 mg/kg) QCT NPs ↓↓
104.6 nm) FD QCT NPs (25 mg/kg) FD QCT NPs ↓↓
Orally (treatment started when tumors reached
40–100 mm3, every 7 days)
QCT GPSLN Xenograft: Control (No treatment) 14-22 days [55]
QCTGPNLC C57BL/6 mice, 105 B16F10 melanoma cells QCT (50 mg/Kg) QCT ↓
(400 nm) QCT GPSLN (50 mg/Kg) QCT GPSLN ↓↓↓
QCT GPNLC (50 mg/Kg) QCT GPNLC ↓↓
Orally (treatment started after tumor induction, days
1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21)
Gold –PLA Xenograft: Inoculated cells treated with/without 5 weeks [56]
(QCT NPs) BALB/c nu/nu nude mice, Caski cells QCT NPs Low (10 mg/ml) QCT NPs Low ↓
(PS n.r.) QCT NPs High (20 mg/ml) QCT NPs High ↓↓
Gold –PLA Xenograft: Control (PBS) 5 weeks [57]
(QCT NPs) BALB/c nu/nu nude mice, MHCC97H cells QCT NPs (30 mg/kg) QCT NPs (30) ↓
(106.7 nm) QCT NPs (40 mg/kg) QCT NPs (40) ↓↓
QCT NPs (50 mg/kg) QCT NPs (50) ↓↓↓
Intra-peritoneally (treatment started when the tumor
reached 3 mm, every day)
Gold –PLA Xenograft: Control (PBS) 5 weeks [58]
(QCT NPs) BALB/c-nude mice, U87 cells QCT NPs Low (40 mg/kg) QCT NPs Low ↓
(106.7 nm) QCT NPs High (80 mg/kg) QCT NPs High ↓↓
Intraperitoneally (treatment started after two weeks,
when the tumor reached to 3 mm, every day)
MPEG-PLA Xenograft: Control (saline/NPs) 22 days [59]
(QCT NPs) BALB/c mice, T1 cancer cells QCT (4 mg/kg) QCT ↓
(155.3 nm) QCT NPs (0.5 mg/kg) QCT NPs (0.5) ↓
QCT NPs (4 mg/kg) QCT NPs (4) ↓↓
Peritumoral (treatment started on day 10 when
tumors reached 100–200 mm3, every 3rd day till day
19)
MPEG–PCL Xenograft: Control (saline/NPs) 22 days [60]
(QCT NPs) BALB/c mice, CT26 colon carcinoma cells. QCT (50 mg/kg) QCT ↓
(34.8 nm) QCT NPs (50 mg/kg) QCT NPs ↓↓
(continued on next page)

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Table 2 (continued)

Formulation Animal model Treatment and Tumor growth Ref.

administration route

Intravenously (treatment started when the tumor

reached 6 mm, once daily for nine consecutive days).
PLGA and Xenograft: Control (medium/NPs) 10 days [61]
TPGS Kunming mice, HCa-F cells QCT (10 mg/kg) QCT ↔
(QCT NPs: QNPs (10 mg/kg) QPNs ↓
QPNs and QPTNs) QPTNs (10 mg/kg) Intravenously (treatment for 10 QPTNs ↓↓
(100-200 nm) consecutive days, once a day)
PEG-TPP Xenograft: Control 14 days [62]
(QCT NPs) Mice, H22 cells QCT QCT ↔
(80-100 nm) QCT NPs QCT NPs ↓
SPC-CHOL Xenograft: Control (PBS/NPs) 16 days [63]
(QCT NPs) Mice, U14 cervical cancer ascites QCT (2 mg/kg) QCT ↓
(143.1 nm) QCT NPs (2 mg/kg) QCT NPs ↓↓
Intravenously (treatment started 24 h after
inoculation, 15 days)
PEG Xenograft: Control (PBS/NPs) 17 days [64]
(QCT NPs) C57BL/6 mice, B16-F10 melanoma cells QCT (5 mg/ kg) QCT ↓
(20 nm) QCT NPs (5 mg/ kg) QCT NPs ↓↓
Orally (treatment started 7 days after tumor
induction, twice/week)
PEG-PE Xenograft: Control (untreated) 10 weeks [65]
(QCT NPs) Rag-2 M mice, human lung A549 cells. QCT (30 mg/kg) QCT ↔
(15.4-18.5 nm) QCT NPs QCT NPs↓
Orally (treatment started when tumor volume
reached 80 mm3, 3 times/week, 3 weeks)
PEG-liposomal Xenograft: Control (saline/NPs) 31 days [66]
(QCT NPs) BALB/c athymic nude mice, cisplatin-sensitive (A2780s) or QCT (50 mg/kg) Both tumor models
(163 nm) cisplatin-resistant (A2780cp) human ovarian cancer cells QCT NPs (50 mg/kg) QCT ↓
Intravenously (treatment started when tumor volume QCT NPs ↓↓
reached 100 mm3, every three-day for 27 days)

CHOL cholesterol; CS: Chitosan; DEN: diethyl nitrosamine; DMBA: 12-dimethyl(a)benz anthracene; DSPE-MPEG: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-
N-methoxy (polyethylene glycol); GPNLC: GeluPearl stabilized by Gelucire; GPSLN: GeluPearl with Precirol ATO 5 stabilized by Gelucire; MPEG–PCL Monomethoxy
poly (ethylene glycol)–poly(ε-caprolactone); MPEG-PLA: Methoxy poly (ethylene glycol)-poly(lactide); NPs: nanoparticles; PE: phosphatidylethanolamine; PEG:
Polyethylene glycol; PLA Polylactic acid; PLGA: Poly(lactic co-glycolic acid); PS: particle size (mean); SPC: soybean phosphatidylcholine; TPGS: d-α-tocopheryl
polyethylene glycol 1000 succinate; TPP: triphenylphosphine.

(Table 2). The in vivo anticancer effect of QCT NPs has been in-
vestigated in 7,12-dimethyl(a)benz anthracene (DMBA)-induced
(n = 1) and diethyl nitrosamine (DEN)-induced (n = 4), of which one
with the glycosylated form of QCT: rutin (RT) quercetin-3-O-rutinoside)
carcinogenesis, as well as in xenograft models (Table 2).
RT NPs, through oral route, reduced tumor growth and exhibited
significant improvement in BW, hematologic (white blood cells (WBC);
red blood cells (RBC) and Hb) and hepatic/non-hepatic (AST, ALP, ALT,
total protein, albumin and bilirubin) parameters. Moreover, RT NPS in-
hibited the DEN-induced increases in serum α-fetoprotein and alterations
of Phase I enzymes, such as NADPH-cytochrome P450 reductase, NADH-
cytochrome-b5-reductase, cytochrome P450 and cytochrome-b5 in rats
[49]. Furthermore, higher activity was observed in regulating oxidative
stress (malondialdehyde (MDA); glutathione (GSH); GSH-S-transferase
(GST), CAT, SOD, myeloperoxidase (MPO) and protein carbonyls) and
inflammatory markers (IL-1β, tumor necrosis factor (TNF)-α, IL-6 and
NF-κB) [49]. Similarly, QCT NPs improved inflammatory (TNF-α, IL-6,
cyclooxygenase-2 (COX-2) and NF-κB) [48,57] and oxidative stress
markers (CAT, SOD, GST, GSH, protein carbonyls, conjugated diene, li-
pohydroperoxides and Reactive Oxygen Species (ROS) production)
[48,50,53] in vivo; and significantly inhibited hydrogen peroxide-in-
duced DNA damage in HepG2 cells [121]. Immunochemistry in tumor
bearing animals revealed decreases in proliferation (assessed by PCNA,
KI-67 and Cyclin-D1) [52,56,58,60,66] and increases in apoptosis
(evaluated by apoptotic index, Bcl-2, Bax, Bad, and caspases)
[52,54,56–58,66]. The suppression of cancer-induced JAK2 activation
has been suggested for QCT NPs, having the JAK2 inhibitor similar anti-
cancer effects in vitro and in vivo [56]. However, in vitro evidence sug-
gested that there are several components such as ROS, mitochondrial,
Bcl-2 family and JAK2/STAT3 shared by the necrotic and apoptotic
pathways and QUE NPs, at high concentrations, induced necrotic cell
death [122,123].
Among molecular mechanisms, reductions in the protein expression
of MMPs, p-EGFR and VEGFR-2 have been reported in tumor bearing
animals [47,48]. Moreover, QCT NPs inhibited angiogenesis in vivo
[60,66] and new blood vessel formation in chick embryos [47], more
efficiently compared with free QCT.
Regardless the formulation and the animal model, NPs improved
QCT efficacy in reducing tumor growth (Table 2). In agreement, in vitro
results showed significantly higher cytotoxicity and/or cellular uptake
of QCT NPs compared to free QCT [52,53,61,63,121,124–128]. Com-
pared to the control group the tumor growth was significantly inhibited
in vivo, after treatment, by around 15% with free QCT, by 66% with
QCT NPs and by 59% with the positive control drug cisplatin (CIS) at a
dose of 1 mg/kg [64]. Similarly, by using cyclophosphamide (CTX,
10 mg/kg) as the positive control, CTX, free QCT and QCT NPs sig-
nificantly inhibited tumor growth and the inhibition rates were
65.99%, 23.03% and 54.06%, respectively [63].QCT NPs showed the
highest tumor suppression of about 65.7% compared with control (0%),
free QCT (11.7%) and positive control doxorubicin (DOX) (54.2%)
[62]. The BW increase rate of the QCT NPs group was similar to the
control group, while a slower rate was visualized in the DOX group; and
blood biochemistry assessment confirmed the safety of QCT NPs [62].
Other studies reported that QCT NPs were well tolerated by the
animals, as reflected by changes in the BW of animals, altered behavior,
histological pathologic changes in the heart, liver, spleen, lung, kidney,
and/or intestine, as well as by biochemical markers of liver (AST, ALT)
and/or renal (urea and creatinine) impairment [52,53,57,60,63–66].
Pharmacokinetics profile of QCT NPs revealed higher AUC in
plasma and/or tumor tissue, compared to free QCT [59–61]. Besides, in

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Table 3
Anticancer effect of Anthocyanidins, Flavanones, Flavones and Isoflavonoids in animal models.
Flavonoid Formulation Animal model Treatment and administration route Tumor growth Ref.
(mean PS)

Anthocyanidins (Antho, Exosomal: Xenograft: Control (50 mg Exo protein/kg) 5 weeks [67]
extract of (ExoAnthos) Female athymic nude mice, Anthos (10 mg/kg) Anthos ↓
bilberry): (83 nm) human lung A549 cells. ExoAnthos (5 mg Anthos) ExoAnthos ↓
Dp, Cy, Mv, Pe and Pt ratio: Orally (treatment started when tumor volume Weeks 6-7
33:28:16:16:7 reached 80 mm3, 3 times/ week) ExoAnthos ↓
Flavanone Soluthin- Xenograft: Control (saline solution/ Physical mixture: PM) 30 days [68]
Naringenin maltodextrin BALB/c mice, colon-26 cells. NAR (40 mg/kg) NAR ↓
(NAR) (NAR NPs) NAR NPs (40 mg/kg) PM ↓↓
(< 250 nm) Orally (treatment started when the tumor was˜8 NAR NPs ↓↓↓
mm3, every day)
Flavanone Eudragit E100 Xenograft: Control (saline solution) 30 days [69]
Naringenin (NAR NPs) BALB/c mice, colon-26 cells. NAR (40 mg/kg) NAR ↓
(NAR) (430 nm) physical mixture (PM) PM ↓↓
NAR NPs (40 mg/kg) NAR NPs ↓↓↓
Orally (treatment started when the tumor was˜8
mm3, every day)
Flavanone PVA- DMBA-induced oral Control (liquid paraffin) 14 weeks [70]
Naringenin Eudragit carcinogenesis in hamsters NAR (50 mg/kg) NAR ↓
(NAR) (NAR NPs) NAR NPs NAR NPs ↓↓↓
(90 nm) Orally (treatment started 1 week before exposure
to the carcinogen, days alternate to DMBA)
Flavanone Eudragit DMBA-induced oral Control (liquid paraffin) 14 weeks [71]
Naringenin (NAR NPs) carcinogenesis in hamsters NAR (50 mg/kg) NAR ↓↓
(NAR) (90 nm) NAR NPs NAR NPs ↓↓↓↓
Orally (treatment started 1 week before exposure
to the carcinogen, days alternate to DMBA)
Flavone PLA-PEG Xenograft: Control (PBS/PEG) 19 days [72]
Luteolin (LUT NPs) Athymic nude mice, Tu212 cells LUT (3.3 mg/kg): LUT↔
(LUT) (115 nm) LUT NPs LUT NPs ↓
Intraperitoneally (treatment started 7 days before
cells injection and alternate day for 30 days)
Flavone FITC labelled DEN and 2-AAF-induced hepato- API (20 mg/kg) API ↔ [73]
Apigenin (API NPs) carcinogenesis in rats API NPs (20 mg/kg) API NPs ↓
(API) (270 nm) Intravenously (single dose/week for 12 weeks)
Flavone PLGA BaP and UVB induced skin cancer Control (untreated) 90 days [74]
Apigenin (API NPs) in mice topical API NPs (5 lg/mouse), Topical ↓
(API) (101.3 nm) oral API NPs (6 mg/kg) Oral ↓
API NPs topical and oral topical + oral ↓↓
topical (2 lg/mouse) + oral (3 mg/kg). Dose response
topical (5 lg/mouse) +oral (6 mg/kg)
topical (8 lg/mouse) + oral (9 mg/kg)
Isoflavonoid GEN PCL Xenograft: Control (saline) 16 days [75]
Genistein (225.8 nm) BALB/c nude mice, HeLa cells pristine-GEN (50 mg/kg) pristine-GEN ↓
(GEN) GEN TPGS-b-PCL GEN PCL NPs (50 mg/kg) GEN PCL ↓↓
NPs GEN TPGS-b-PCL NPs (50 mg/kg) GEN TPGS-bPCL NPs ↓
(181.8 nm) Intraperitoneally (treatment started when tumor ↓↓
was touchable, every 2 days)
Isoflavonoid M-PLGA–TPGS Xenograft: Control (saline) 12 days [76]
Genistein (GEN NPs) Female SCID mice, liver pristine-GEN (50 mg/kg) pristine-GEN ↓
(GEN) (225.7 nm) carcinoma HepG2 cells GEN NPs (50 mg/kg) GEN NPs ↓
Intratumoral (treatment started when tumor
volume reached 50 mm3, 0, 4 and 8 days)

2-Acetylaminofluorene (2-AAF); BaP: Benzo[a]pyrene; Cy: cyanidin; Dp: delphinidin; Pt: petunidin; Pe: peonidin; Pg: pelargonidin; Mv: malvidin; DEN: diethyl
nitrosamine; DMBA: 12-dimethyl(a)benz anthracene; Eudragit: Aminoalkyl Methacrylate Copolymer E; Exosomal: isolated from bovine milk; FITC: Fluorescein
isothiocyanate; MPEG-PCL: monomethoxy poly(ethylene glycol)-poly(-caprolactone); M-PLGA–TPGS: copolymer mannitol-functionalized Poly (lactic-co-glycolic
acid) - d-α-tocopheryl polyethylene glycol 1000 succinate; PC: phosphatidylcholine; PCL: poly(ε-caprolactone); PVA: poly-vinyl alcohol; SCID: severe combined
immunodeficient; UVB: ultraviolet-B.

vivo biodistribution experiments revealed that NPs prolonged the re-
tention of drug in the whole body, reduced the accumulation in liver
and spleen, and promoted the accumulation in tumor as compared to
vital organs [52,53]. These results can account for the high anti-cancer
efficacy in the absence of toxicity. Moreover, QCT NPs reduced the
toxicity of DEN [48,50], DMBA [47], evaluated by measuring changes
in BW [47], serum ALP, AST, ALT, urea, and/or creatinine [48,50]. QCT
in soluble form reduced the oxidative stress mediated (evaluated by
measuring GSH and MDA) in kidney tissues) nephrotoxicity (increases
in serum urea, uric acid and creatinine) caused by gold NPs [129] and
QCT NPs reduced Ultraviolet B (UVB)-induced skin damage and in-
flammation, inhibiting NF-κB/COX-2 signaling pathway [130,131].
5. Other flavonoids
Table 3 summarizes the in vivo studies on anticancer effect of NPs
containing anthocyanidins (anthocyanin aglycones) from bilberry
(Antho), flavanone naringenin (NAR), flavones API and luteolin (LUT)
and isoflavone GEN. While both Antho and ExoAnthos (by oral gavage)
reduced tumor growth [67], NPs of NAR [68,69], LUT [72] and GEN
[75,76] decreased the tumor growth more than flavonoid solutions.
Higher inhibition of tumor growth were found for flavonoids NPs
compared to free compounds were also observed on DMBA-induced
oral carcinogenesis in hamsters (NAR [70,71]), on Benzo[a]pyrene
(BaP) and ultraviolet-B (UVB)-induced skin cancer of mice (API [74])

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Table 4
Flavonoids in delivery and co-delivery systems of anticancer drugs.
Drug Flavonoid - Animal model Treatment and Tumor growth Ref.
Formulation Administration route
(mean PS)

Doxorubicin ATC Xenograft: Control (no treatment) 12 days: [77]

(DOX) DOX-delivery Balb/c nude mice, HCT-116 cells. DOX NPs (1 mg) ATC-DOX NPs↓↓
CSU ATC (1.5 mg)–DOX NPs DOX NPs↓
(ATC–DOX NPs) Intravenously (tumor volumes reached 100 mm3
(174.8 nm) before treatment, once)
Doxorubicin QCT Xenograft: DOX 21 days [78]
(DOX) Co-delivery Mice, SCC-7 cells. QCT DOX ↓↓
pPhe-pHis-PEG DOX/QCT QCT ↓
(DOX/QCT NPs) DOX-NPs DOX/QCT ↓↓↓
(82 nm) DOX/QCT NPs (5 mg/kg) DOX-NPs ↓↓↓
Intravenously (treatment started when tumor DOX/QCT NPs ↓↓↓↓
volumes reached 50 mm3, days 1, 4, and 7)
Docetaxel EGCG Xenograft: Control (untreated) 14 days [79]
(DTX) DTX Delivery Male hairless mice (HRS/J), A- DTX (30 mg/kg, 0.3%) DTX ↓
EGCG-SPC 375 human melanoma cells EGCG (0.2%) + DTX (0.3%) EGCG + DTX ↓↓
(DTX/EGCG NPs) NPs NPs ↔
(72.4 nm) DTX NPs (0.3%) DTX NPs ↓↓
EGCG NPs (0.2%) EGCG NPs ↔
DTX/EGCG NPs DTX/EGCG NPs ↓↓↓
Topically (treatment started at 14 days when tumor
volume reached 203 mm3, every 3 d)
Paclitaxel BCL Xenograft: 5 groups: day 30: [80]
(PTX) Co-delivery: Female Balb/C nude mice, MCF-7/ Control (saline) PTX ↔
PTX-CHOL and BCL-phospholipid Tax PTX (10 mg/kg), PTX/BCL ↔
(PTX/BCL NPs) PTX/BCL PTX NPs ↓
(170 nm) PTX NPs, PTX/BCL NPs ↓↓
PTX/BCL NPs
Intravenously (treatment started when tumor volume
reached 80–100 mm3, 0, 4, 8 and 12)
Paclitaxel GEN Xenograft: Control (nanoparticles) 8 days [81]
(PTX) Co-delivery Ehrlich Ascites Tumor (EAT) in mice G12P0: GEN (12 mg/kg) G0P0.2 ↓
PLGA NPs coated with a lipid G0P10: PTX (10 mg/kg) G12P0.2 ↓↓
bilayer containing GEN G0P2: PTX (2 mg/kg) G12P2 and G0P2 ↓↓↓
(150 nm) G0P0.2: PTX (0.2 mg/kg)
G12P10: GEN + PTX 12 + 10
G12P2: GEN + PTX 12 + 2
G12P0.2: GEN + PTX 12 + 0.2
Intraperitoneal (treatment started at day 1, 7/every
day)
Honokiol EGCG Xenograft: Control (2% glucose solution) 21 days [82]
(HK) HK delivery Male BALB/c Nude mice, Human liver free HK (40 mg/kg) HK ↓
EGCG functionalized CH derivative cancer cell line (HepG2) HK NPs (20 mg/kg) HK NPs 20 ↓↓
(HK NPs) HK NPs (40 mg/kg) HK NPs 40 ↓↓↓
(80 nm) Intertumoral (treatment started when tumor volume
reached 110mm^3, 3/ week)
Vincristine QCT Xenograft: Control (saline/ blank NPs) 18 days [83]
(VCR) Co-delivery BALB/c mice, Raji/VCR cells VCR VCR ↓
PLGA-CHOL-SA-PEG-DSPE (lymphoma) QCT QCT ↓
(VCR/QCT PNs) VCR/QQCT, VCR/QCT ↓↓
(115.7 nm) VCR PNs VCR NPs ↓↓
QCT PNs QCT NPs ↓↓
VCR/QCTPNs VCR/QCT NPs ↓↓↓
20 mg drug/kg
Intravenously (treatment started one week after
cancer induction)

ATC: Anthocyanin (extracted from black soy bean); CH: chitin; CHOL cholesterol; CSU: Chondroitin sulfate; PEG-DSPE: Poly(ethylene glycol)–distearoylpho-
sphatidylethanolamine; PLGA: Poly(lactic co-glycolic acid); pPhe-pHis-PEG: poly(phenylalanine)-b-poly(L-histidine) -b- poly(ethylene glycol); PS: particle size; SA:
stearic acid; SPC: soybean phosphatidylcholine.

and on DEN-induced and 2-acetylaminofluorene (2-AAF)-induced he-
patocarcinogenesis in rats (API [73]). However, in chemically induced
cancers, treatment typically started before the exposure to the carci-
nogens (Table 3), whereas in the xenografts’ models, treatment started
when tumor volume reached a defined size in most of the studies
(Table 3). The administration route in vivo was variable (Table 3) and in
vivo pharmacokinetic studies reported that nano-incapsulation im-
proved oral bioavailability of NAR [68,69] and API [74]. It has been
suggested that the presence of the bioactive molecule in the core of NPs
prevented its degradation in the gastrointestinal tract [68] and that the
increased solubilization and dissolution improved the absorption from
enterocytes [68,69], whereas enhanced endocytic activity in human
colon cancer cell line colon-26 has been suggested within the me-
chanisms involved in the higher cytotoxic effect of physical mixture
(PM) and optimized NAR NPs were found to be approximately 6/7-fold
and 16/21-fold higher as compared with pure NAR [68,69].
Self-emulsifying phospholipid pre-concentrates for oral delivery of
GEN have been tested in ex-vivo permeation study using non-everted
gut sac technique [132]. Das et al. [74] reported high efficacy for
oral + topical API NPs versusoral or topical administrations. Tumor

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Table 5
Molecular targeted nanoparticles containing flavonoids.
Target Flavonoid - Animal model Treatment and Tumor growth Ref.
Formulation Administration route
(mean PS)

ER QCT DMBA-induced breast Control (saline) 30 Days [84]

(antagonist TMX) Co-delivery carcinogenesis in rat TMX (3 mg/kg) TMX ↓
PLGA TMX/QCT (3 mg/6 mg/Kg) TMX/QCT↓
(TMX-QCT-NPs) TMX-QCT-NPs TMX-QCT-NPs ↓↓
(185.3 nm) Orally (treatment started on tumor bearing
animals, once in 3 days)
ER NAR DMBA-induced breast Control 30 days [85]
(antagonist TMX) Co-delivery carcinogenesis in rat TMX (10 mg) TMX↓
SNEDDS TMX (10 mg) /NAR (20 mg) TMX/NAR↓↓
(52-73 nm) TMX NPs TMX NPs↓↓↓
TMX/NAR NPs TMX/NAR NPs↓↓↓↓
Orally, (treatment started after 10 weeks,
repeated 1 in 3 days)
Breast tumor-homing EGCG delivery Xenograft: Control (Saline and blank nanoparticles) 18 days [86]
cell- CMS@peptide@EGCG Female Balb/c nude mice, MCF-7 100 mg/kg EGCG: EGCG↓
penetrating (150 -180 nm) breast cancer cells EGCG CMS@EGCG ↓↓
peptide CMS@EGCG CMS@peptide@
CMS@peptide@EGCG. EGCG ↓↓↓
Intravenously (treatment started when tumor
volume reached 50 mm3, 5 times at 3-day
intervals).
PSMA EGCG delivery Xenograft Control (PBS/NPs) 7-21 days [87]
small organic molecules targeting Athymic nude mice, 22Rv1 cells EGCG (1 mg/mice/day) EGCG ↓
PSMA (human prostate carcinoma). EGCG NPs (100 mg/mice/day) EGCG NPs ↓↓
(EGCG-NPs) targeted EGCG NPs (100 mg/mice/day) targeted EGCG NPs
(130-250 nm) (treatment started 24 h post cell inoculation, 5 ↓↓↓
times/week)
67LR EGCG Xenograft: Control (Saline) 14-42 Days [88]
198
Delivery Gold (Au) radioactive SCID mice, human prostate cancer EGCG AuNP-EGCG ↓
(198AuNP-EGCG) PC-3 cells. 198
AuNP-EGCG
(535 nm) Intratumoral (Single dose 1 week after cancer
induction, day 6)
67LR EGCG Xenograft: Control (PBS) 2 weeks [89]
Delivery Ruthenium SCID mice, RuBB-Loaded EGCG-RuNPs (2.5 mg/kg) RuBB-Loaded
(EGCG-RuNPs) SMMC-7721 hepatocellular Intratumoral (treatment started after the EGCG-RuNPs ↓
(73.59 nm) carcinoma (HCC) cells tumors become ˜50 mm3, every day)
EIF5A2 CAT Xenograft: Control (PBS) 24-48 days [90]
Delivery siRNA targeting EIF5A2 Athymic mice, T24 cells Mg(II)-CAT Xenograft
(Mg(II)-CAT/siEIF5A2) MNU-induced bladder cancer in rats Mg(II)-CAT/siEIF5A2 (20 mg of siEIF5A2) Mg(II)-CAT ↓
(10-20 nm) Intravenously Mg(II)-CAT/
(treatment started 12 days after T24 siEIF5A2 ↓↓
inoculation, 1/ week for 5 times) MNU-induced:
(treatment started after successful MNU tumor Mg(II)-CAT ↓
induction 16th week, 1/ week for 5 times) Mg(II)-CAT/
siEIF5A2 ↓↓
EGFR EGCG-PEG Xenograft Control (PBS/BSA-NPs) 35 days [91]
(HER)-2 Delivery anticancer protein Athymic nude mice, human breast Herceptin (0.5 mg/ ml) Herceptin-
herceptin (monoclonal antibody cancer BT-474 cells. Herceptin-NPs (0.5- EGCG 0.26 mg/ml) NPs > BSA-NPs
Trastuzumab), Intravenously (treatment started when tumours Herceptin-NPs >
(Herceptin-NPs) reached 270 mm3, twice weekly) Herceptin
(100-500 nm)
FR FA- MSN Xenograft Control (untreated) 15 Days [92]
(QCT NPs) Chicken embryos, MDAMB-231cells QCT NPs (5 μg/mL) QCT NPs ↓
(< 200 nm) Intravenously (treatment started after tumor
induction, on days 12 and 14)
FR-CD44R BCL-PTX Xenograft Control (saline) 24 days [93]
Co-delivery Kunming mice, A549/PTX human PTX (10 mg/kg) PTX ↔
FA-HA lung cancer cells BCL (50 mg/ kg) BCL ↓
(PTX-BCL NPs) PTX-BCL (10 mg/kg + 50 mg/kg) PTX-BCL ↓↓
(90 nm) PTX NPs PTX NPs ↓↓↓
BCL NPs BCL NPs ↓↓↓
PTX-BCL NPs PTX-BCL NPs ↓↓↓↓
Intravenous (treatment started when the tumor
volume reached 90–100 mm3, every 4 days)
CD44R HA-EGCG-cisplatin NPs Xenograft: Control xenograft 38 days [94]
(57 nm) athymic NCR nude mice, ovarian Cisplatin (1 mg) Cisplatin ↓
cancer cell line (SKOV-3) HA-EGCG HA-EGCG ↔
Peritoneal metastatic model: HA-EGCG-cisplatin NPs HA-EGCG-cisplatin
SCID mice, SKOV-3 cells. Intravenously (weekly/3 weeks) NPs ↓↓
metastatic model:
cisplatin ↔
(continued on next page)

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Table 5 (continued)

Target Flavonoid - Animal model Treatment and Tumor growth Ref.

Formulation Administration route
(mean PS)

HA-EGCG-cisplatin
NPs ↓
CD44R BCL-DOX Xenograft BCL/DOX 21 days [95]
Co-delivery BALB/c nude mice, MCF-7/ADR DOX NPs, BCL/DOX ↓
HA decorated cells. BCL NPs, DOX NPs ↓↓
(HA-BCL/DOX NPs) HA-BCL/DOX NPs BCL NPs ↓↓↓
(103.5 nm) BCL/DOX-NPs HA-BCL/DOX NPs ↓
(treatment started when tumor volume reached ↓↓↓↓
100 mm3, weekly) BCL/DOX-NPs ↓↓↓↓
CD44R QCT-DOX Xenograft: Control (saline) 14 days [96]
Co-delivery BALB/c nude mice, SGC7901/ADR QCT + DOX (5 mg/kg +5 mg/kg) QCT + DOX ↓
HA - silica cells HA-SiLN/D (DOX 5 mg/kg) HA-SiLN/D ↓↓
(HA-SiLN/QD) HA-SiLN/Q (QCT 5 mg/kg) HA-SiLN/Q ↓↓
(100 nm) HA-SiLN/QD HA-SiLN/QD ↓↓↓
Intravenous (treatment started when the tumor
volume reached 100 mm3, every 2 days for 7
times)
TfR BCL-DOX Xenograft Control (saline/blank NPs) 21 days [97]
Co-delivery BALB/c nude mice, MCF-7/ADR DOX (20 mg) DOX ↓
Tf decorated cells. BCL (20 mg) BCL ↓↓
(Tf-D/B NPs) DOX/BCL DOX/BCL ↓↓↓
(91.8 nm) Tf-D-SLNs (DTX 10 mg) Tf-D-SLNs ↓↓↓↓
Tf-B-SLNs (BCL 10 mg) Tf-B-SLNs ↓↓↓↓↓
Tf-D/B-SLNs Tf-D/B-SLNs ↓↓↓↓↓↓
D/ B-SLNs ↓
Intravenously, (treatment started when tumor D/ B-SLNs ↓↓↓↓↓↓
volume reached 100–200 mm3, weekly)
BR QCT-DOX Xenograft: Control (saline) 21 day [98]
Co-delivery BALB/c nude mice, DOX (5 mg/kg) DOX ↓
MPEG-PCL injecting MCF-7/ADR cells. DOX + QCT, DOX + QCT ↓
(MNDQ) MN DOX MN DOX ↓↓
100.2 MN QCT, MN QCT ↔
Biotin-decorated PEG-PLC MNDQ MNDQ ↓↓↓
(BNDQ) BNDQ BNDQ ↓↓↓↓
105.8 Intravenously (treatment started when tumor
volumes reached 50 mm3, once every three
days for a total of seven doses)
IR QCT-TPT Xenograft Control (saline) 24 days [99]
Co-delivery Athymic nude mice, breast TPT (5 mg/kg) TPT ↓
(MSN-PAA-CS) carcinoma MDA-MB-231 cells QCT (5 mg/kg) QCT ↓
45–55 MSN-PAA-CS (2.5 TPT /2.5 QCT mg/kg) MSN-PAA-CS ↓↓
Arginine-glycine-aspartic acid PMSNs (2.5 TPT /2.5 QCT mg/kg) PMSNs ↓↓↓
peptide Intravenous (Treatment started after 8 days,
(PMSN) weekly)
65–75

67LR: Laminin receptor 67 kDa; BCL: Baicalein; Bovine serum albumin (BSA); BR: biotin receptor; Catechin (CAT); CD44R: CD44 receptor; CMS: colloidal meso-
porous silica; CS: Chitosan; DMBA: 7,12-dimethyl(a)benz anthracene; DOX: Doxorubicin; EGFR: Epidermal growth factor receptor; EIF5A2: Oncogene eukaryotic
translation initiation factor 5A2; ER: Estrogen receptor; FA: folic acid; FR: folate receptors; HA: hyaluronic acid; IR: integrin receptor; MNU: N-methyl-Nitrosurea;
MSN: mesoporous silica nanoparticles; MPEG-PCL: monomethoxy poly(ethylene glycol)-poly(-caprolactone); PAA: poly (acrylic acid); PEG: Polyethylene glycol; PEG-
PCL: poly(ethylene glycol)-poly(-caprolactone)PBS: Phosphate buffered saline; PLGA: Poly (lactic-co-glycolic acid); PSMA: Prostate-specific membrane antigen
PMSN: Arginine-glycine-aspartic acid peptide-MNS; PTX: Paclitaxel; QCT Quercetin; SCID: severe combined immune deficiency; SNEDDS: Self-nano-emulsifying drug
delivery system; Tf: Transferrin; TfR: Transferrin receptor; TPT: Topotecan. TMX: tamoxifen.

onset, induced by UVB–BaP radiation was significantly faster in control
mice compared to mice receiving oral + topical API NPs, lowering
chromosomal aberrations and ROS, and inducing apoptosis (caspases
and bax/bcl-2 modulation) [74]. On the contrary, in a xenograft mouse
model of head and neck cancer developed by subcutaneous injection of
Tu212 cells in athymic nude mice, the efficacy of LUT NPs (in-
traperitoneally administered) was not related to apoptosis, whereas
inhibition of proliferation was observed in tumor tissue [72].
Although in 6 out of 10 studies, that investigated the anticancer
effect, NPs were orally administered (Table 3), also intraperitoneal
(LUT [72], GEN [75]), intratumoral (GEN [76]) and intravenous (API
[73]) treatments were applied.
In vivo pharmacokinetics studies in rats reported that encapsulation
increased AUC and Cmax of LUT intravenously administered [133].
Radiolabeled API NPs (20 mg/kg single i.v.) accumulations in liver,
urinary bladder as well as in the intestinal region were noticed in mice
and rats, as well as modulation of cytochrome P-450 (cyt p-450) con-
tent, glutathione-S-transferase (GST) activity in the cytosolic fraction
and, UDP-glucuronyl transferase (UDPGT) activity in the microsomal
hepatic fraction in rats [73]. Moreover, Das et al. [134] demonstrated
the ability of API NPs, injected intraperitoneally in mice, to cross the
blood-brain barrier.
The higher efficacy of nanoparticles was confirmed by in vitro ex-
periments, where reduced IC50 for proliferation, viability and/or in-
duction of apoptosis were found for encapsulated/coniugated compared
to free HES [135], API [72,73], GEN [136–138] and LUT [139]. LUT
monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL)
micelles maintained the cytotoxicity of LUT on 4T1 breast cancer cells
(IC50 6.4 μg/mL) and C-26 colon carcinoma cells (IC50 12.62 μg/mL) in
vitro [133]. ExoAnthos (Table 3) had higher anti-proliferative effects on

9
P. Aiello, et al.
various cancer cell lines (breast MCF7 and MDA-MB-231; lung H1299
and A549; colon HCT116, pancreatic Panc1 and Mia PaCA2; prostate
DU145 and PC3; ovarian Ova432), compared to Anthos [67]. IC50
values are different depending on cell type, ranging from 2μM (H1299)
to 68μM (MDA-MB-231) for ExoAnthos and from 59μM (H1299) to
960μM (Mia PaCa2) for Anthos, but irrespective of the cancer cell type
ExoAnthos had significantly higher anti-proliferative effects compared
to Anthos, within the same cell type [67]. Furthermore, the anti-in-
flammatory activity in vitro, measured by the TNF-α-induced NF-kB
activity was higher for ExoAnthos compared to Anthos in H1299 [67].
Although no in vivo studies on tumor growth inhibition are available, in
vitro studies investigated the cytotoxic effect of anthocyanin nano-
particles (Tetraethyl orthosilicate Si(OC2H5)4 (TEOS), hydrolyzed si-
lica, PAMAM (Polyamidoamine) from black carrots [140] and cyanidin-
3-O-Glucoside nanoliposomes [141]. In particular, Yesil-Celiktas et al.
[140] reported differential effects on Neuro-2A brain neuroblastoma
from mouse and Vero (African green monkey kidney) normal cell lines
and reported that neither empty NPs nor anthocyanin loaded NPs were
toxic for Vero normal cells, whereas anthocyanin NPs reduced Neuro
2A cells proliferation. Similar results of selective cytotoxic effects on
cancer cells have been reported for CS encapsulated NAR towards
normal fibroblast 3T3 cells and A549 lung cancer cells and authors also
observed a free radical scavenging activity in NAR NPs [142].
Among the other potential mechanisms, there is the modulation of
the early alteration in metabolic activity in cancer cells and tissue. In
the DMBA-induced oral carcinogenesis in hamsters, by monitoring the
NADH and FAD fluorescence, Gurushankar et al. [143] reported a
greater inhibition of the increased metabolic activity of tumor tissue
with HES NPs oral treatment (dose equivalent to 40 mg/kg BW/day of
HES), starting 1 week before exposure to the carcinogen and continuing
on days alternate to DMBA for 14 weeks, than HES (40 mg/kg BW/day).
By using the same DMBA-induced oral carcinogenesis in hamsters,
Krishnakumar et al. [144] reported that oral administration of free NAR
(50 mg/kg) and NAR NPs significantly increased lipids and the gly-
cogen contents and decreased the levels of proteins and nucleic acid
contents in tumor.
When the safety profile was assessed by measuring the changes in
BW during the cancerogenesis protocol, NAR [68,69], LUT [72], API
[74] and GEN [75,76] NPs inhibited the cancer-induced BW reduction.
On the contrary, pristine-GEN solution induced BW loss in mice [76].
On the other hand, Antho was nontoxic in wild-type mice at a dose
(40 mg/kg weekly dose) higher than those used for anti-tumor study
(weekly dose of 30 mg/kg as free Anthos or 15 mg/kg in bovine milk
exosomal formulation, ExoAnthos) [67]. No effects on blood counts,
liver and kidney function enzymes were observed in the toxicity study
[67].
6. Flavonoids in delivery and co-delivery systems of anticancer
drugs
Chemotherapy for cancer treatment causes side effects on healthy
tissues and MDR of the tumor cells, which limits therapy. To address
these limitations, combination therapies based on NPs and flavonoids
administration have been suggested to both improve efficacy (through
delivering different agents simultaneously with synergistic effect) and
minimize toxicity of anticancer drugs (by targeting towards cancer cells
and by counteracting ROS-mediated damage). Combination therapies
included co-administration and co-delivery. Co-administration of QCT
NPs [64] or theaflavin-EGCG NPs [145] with cisplatin improved its
efficacy in mice.
Studies that evaluated tumor growth after treatment with flavonoids
in delivery and co-delivery systems of anticancer drugs are summarized
in Table 4.
Anthocyanins from black soy bean (ATC) [77] loaded NPs, for DOX
delivery, increased DOX NPs efficacy in vivo (Table 4). Histological
analysis revealed apoptosis after treatment with ATC–DOX NPs and that
10
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
DOX in tumor tissue was higher in ATC–DOX NPs treated mice than
those treated with DOX NPs [77]. In tumor sections, percentage of
cancer cells expressing CD31 (marker for angiogenesis and vascular
permeability) and Ki-67 (tumor proliferation marker) were significantly
lower in the DOX/QCT NPs treated group than in other groups [77],
accounting for the synergistic effect on cancer growth (Table 4). DOX/
QCT NPs did not result in BW loss in mice, whereas DOX and drug
cocktail (DOX/QCT)-treated groups experienced nearly 11% and 5%
loss of BW, respectively, indicating severe drug-related toxicity [78].
ROS are involved in DOX-mediated hepatotoxicity and cardiotoxicity
and QCT, reducing the GSH/GSSG ratio, potentiated the cytotoxic effect
of DOX on the cancer cells and in vitro data, on HCT-116 human colon
cancer cells, suggested a H2O2 dependent drug delivery and cell death
[77], whereas CSU/ATC had free radical scavenging activity in LPS
treated Hela cells [146]. The histopathologic analysis of hearts in vivo
and cellular uptake in MCF-7/Adr cells suggested that combination
therapy with EGCG and DOX in the NPs core could protect the cardi-
omyocytes from DOX-mediated cardiotoxicity and overcome MDR, re-
spectively [147]. EGCG-based NPs were used for the delivery of hon-
okiol (HK) [82] and intertumoral injection of HK NPs (40 mg/kg)
inhibited tumor growth by 83.55% (p < 0.05), which was far higher
than the 30.15% inhibition of free HK (40 mg/kg). Improved efficacy
(Table 4) and delivery of docetaxel (DTX) were reported for topic
EGCG-based NPs and pharmacokinetics after both intravenous and to-
pical dermal administrations revealed that DTX tumor exposure, as
measured by AUC of the concentration-time curve, was 2.48-fold higher
in mice receiving 30 mg/kg by topically administered DTX/EGCG NPs
than those treated with 10 mg/kg DTX by tail vein injection [79].
Moreover, the dermal administration decreased toxicity of DTX to the
liver, lung and spleen because the maximum concentrations of DTX by
dermal administration were lower than those by intravenous adminis-
tration [79]. On the other hand, in vivo tissue distribution results found
that NPs pulmonary administration enhanced the lung PTX and QCT
concentrations and decreased their concentration in other tissues, re-
ducing the clearance rate of drugs [148]. Moreover, pharmacokinetic
and intestinal permeation studies reported high etoposide AUC after
treatment with a QCT-based NPs and the involvement of P-glycoprotein
(Pgp) [149].
Flavone baicalein (BCL) was used as MDR reversal agent in co-en-
capsulated paclitaxel (PTX) NPs and were reported synergistic effects
and improved cellular uptake in vitro [80] and inhibition of tumor
growth in vivo (Table 4). Also GEN improved PTX efficacy in vivo
(Table 4) [81].
In a co-delivery system tested for tumor growth inhibition in lym-
phoma-bearing BALB/c nude mice model (Table 4), both vincristine
(VCR) and QCT distribution of VCR/QCT PNs were higher in the tumor
tissue than VCR/QCT solution, mainly distributed in heart and kidney
[83].
7. Molecular targeted nanoparticles containing flavonoids
Molecular targeted cancer therapy mediated by NPs is a promising
strategy to overcome the lack of specificity of conventional che-
motherapeutic agents and to improve efficacy and reduce toxicity. The
estrogen receptor antagonist tamoxifen (TMX) can be considered a
“pioneer" of this approach. Kumar et al. [150] studied NPs for the de-
livery of TMX with physically adsorbed QCT (TMX-QCT-NPs), the latter
being a mild P-gp efflux inhibitor, in order to treat MDR-cancer cells
MDA-MB-231. Authors reported reduced IC50 values for TMX-QCT-NPs
compared to TMX and TMX-NPs. Moreover, the pharmacokinetic in rats
(intravenous injection) of TMX (2 mg/Kg), TMX-NPs or TMX-QCT-NPs
(equivalent to 2 mg/Kg of TMX and 10 mg/Kg of QCT) turned out high
plasma drug concentrations from TMX-QCT-NPs (AUC ng·mL−1·h
9138.36) and TMX-NPs (AUC ng·mL−1·h 7770.58) by comparison with
pure TMX (AUC ng·mL−1·h 3435.62) [150]. Jain et al. [84] in-
vestigated TMX association with quercetin in NPs. The plasma
P. Aiello, et al.
concentration time profiles of TMX and QCT after single oral adminis-
tration of free TMX (10 mg/kg), free QCT (20 mg/kg), a combination of
TMX and QCT (TMX/QCT) or TMX-QCT-NPs (equivalent to 10 mg/kg
TMX) revealed that TMX-QCT-NPs increased the bioavailability of TMX
by 5.31- and 2.69-fold as compared to free TMX and TMX/QCT. Co-
formulated NPs increased the oral bioavailability of QCT by 2.9-fold in
comparison with free QCT and its combination with free TMX. More-
over, TMX-QCT-NPs had higher in vivo antitumor efficacy (Table 5), as
well as anti-angiogenic potential measured by plasma MMP-2 and
MMP-3 after 30 days of treatment. Interestingly, TMX-QCT-NPs, but not
TMX/QCT, reduced TMX hepatotoxicity, measured by liver markers in
plasma (AST and ALT), oxidative stress markers in liver tissue (thio-
barbituric acid reactive substances (TBARS) and GSH) and liver histo-
pathology (parenchymal degeneration, lymphocyte infiltration and
apoptosis of cells) [84]. Similar results were found with TMX/NAR NPs,
with improved pharmacokinetic, reduced hepatotoxicity [85] and in-
creased efficacy (Table 5) compared to TMX in solution.
In a xenograft model of breast cancerogenesis, the anticancer effect
of EGCG was increased by loading of EGCG into colloidal mesoporous
silica (CMS) containing a breast tumor-homing cell-penetrating peptide
NPs (CMS@peptide) [86] (Table 5). On tissue sections, at 18 days after
treatment with EGCG, CMS@EGCG, and CMS@peptide@EGCG, ne-
crosis was observed in histological sections from the different treatment
groups, whereas no sign of organ damage was found [86]. The prostate-
specific membrane antigen (PSMA) targeting has been also used to se-
lectively deliver EGCG to cancer cells in vitro [151] and in vivo
(Table 5). In a tumor xenograft model EGCG NPs showed better efficacy
than native EGCG and decreased serum PSA [87].
On the other hand, in vivo studies investigated the use of the high
binding affinity of EGCG to the 67-kDa laminin receptor (67LR)
(Table 5), overexpressed in cancer cells, in order to increase the de-
livery of NPs. EGCG (used as a capping agent) improved the efficacy of
both radioactive gold NPs derived from the Au-198 isotope [88] and
ruthenium NPs [89] in xenografts models with 67LR overexpression in
human prostate cancer cells (PC-3) [88] and hepatocellular carcinoma
(HCC) [89] cells (Table 5). In vitro experiments showed that RuBB-
loaded EGCG-RuNPs accumulated in the cytoplasm of SMMC-7721
cells, where direct ROS-dependent cytotoxic and pro-apoptotic effects
were observed, with no toxic effect in normal L-02 cells [89]. Phar-
macokinetic and therapeutic studies in PC-3 xenograft SCID mice
showed 72% retention of NPs in tumors 24 h after intratumoral ad-
ministration [89] and efficacy (Table 5). Shukla et al. [88] did observe
neither EGCG therapeutic effects nor blood parameters alterations
(RBC, WBC, Hb and lymphocytes) within the tumor-bearing mice.
Analysis of radioactivity revealed that 72% NPs were retained in
prostate tumors at 24 h. Intratumoral injected NPs exhibited slow
leakage into the blood (0.06%), and variable uptakes were observed:
lungs (0.33% at 24 h), pancreas (0.22% at 24 h), kidneys (0.12% at
24 h), spleen (1.56% at 24 h), stomach (5% at 2 h, decreasing to 0.03%
at 24 h), small intestines (0.91% at 2 h, decreasing to 0.01% at 24 h)
and liver (0.51% after 30 min, increasing to 6.13% after 24 h).
Catechin [90] and EGCG containing NPs have been also used to
deliver small interfering RNA (siRNA), targeting the oncogene eu-
karyotic translation initiation factor 5A2 (EIF5A2) and herceptin
(Trastuzumab), the approved monoclonal antibody (mAb) for EGFR
(HER)-2 positive breast cancer and gastric or gastroesophageal junction
adenocarcinoma [152], into cells in vitro [90,91] and into tumor site in
vivo (Table 5).
Chen et al. [90] reported that Mg(II)-CAT/siEIF5A2 inhibited on-
cogenic PI3K/Akt signal pathway and demonstrated, in mice, effective
delivery in heart, lung, liver, kidneys, spleen, and most importantly
tumor. Accordingly, Mg(II)-CAT/siEIF5A2 had high efficacy on tumor
growth in both xenograft and N-methyl-N-nitrosourea (MNU)– induced
cancer models (Table 5).
Self-assembly of the EGCG derivative with anticancer herceptin
formed NPs, obtained by complexation of oligomerized EGCG with the
11
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
anticancer protein followed by complexation of PEG-EGCG [91], which
have greater anticancer effects in vitro and in vivo (Table 5) than the free
protein. Herceptin NPs showed the improved tumor selectivity to sur-
rounding normal organs/tissues, exhibited 2.3-fold higher accumula-
tion in tumor and 0.3-, 0.3- and 0.6-fold lower accumulation in liver,
kidney and lung, respectively, as compared to free Herceptin at 24 h
post-injection and were observed throughout the extravascular space,
which was consistent with the localization of overexpressed HER2/neu
receptors on the tumor [91].
On the other hand, folic acid (FA), having high selectivity for folate
receptors (FR), which are overexpressed on the surface of cancer cells,
has been employed in the development of EGCG NPs and tested on
human breast cancer MCF-7 cells [102]. The in vivo tumor accumulation
[153] and the in vitro targeting of FA armed QCT NPs to folate-ex-
pressing cells [153], were confirmed on cancer growth in Chicken
embryos [92] (Table 5). In biodistribution experiments, QCT was co-
delivered with DTX by using hyaluronic acid (HA)-modified NPs as
tumor targeting system [154]. Dual-targeted ligands of FA and HA have
been successful employed for BCL and PTX co-delivery in a xenograft
mice model with injection of A549/PTX resistant human lung cancer
cells [93]. HA on the surface of the complex can bind to CD44 receptor,
which is overexpressed in some cancer cells [93,95,96]. HA-EGCG NPs
improved cisplatin anticancer effect in both xenograft and peritoneal
metastatic in vivo models [94], whereas orally EGCG (20 mg/kg) and
HA-based NPs (intravenously) improved DOX efficacy [155]. HA de-
corated BCL/DOX NPs reduced tumor growth induced by injection of
MCF-7/ADR resistant cells better than BCL/DOX-NPs, single drug NPs
and free BCL/DOX (Table 5) [95]. Similar results were obtained with
QCT and DOX in HA-modified silica NPs [96] and the biodistribution
study revealed that a high dose of HA intravenously injected prior to
administration of NPs to saturate CD44 receptors reduced tumor tar-
geting [96]. Tumor targeting has been reported also for HA-EGCG-cis-
platin NPs and HA-EGCG formulation inhibited cisplatin-induced liver
toxicity (ALT and AST) [94].
It has been suggested that QCT decreased the expression of Pgp,
thus reversing MDR and facilitate DOX activity against SGC7901/ADR
resistant cells [96]. On the other hand, transferrin receptor(TfR)-
mediated, biotin receptor (BR)-mediated and integrin receptor (IR)-
mediated (arginine-glycine-aspartic acid peptide) endocytosis improved
in vivo efficacy of BCL/DOX [97], DOX/QCT [98] and topotecan(TPT)/
QCT [99] co-delivery NPs, respectively (Table 5). Tumor targeting
viareceptor-mediated endocytosis has been also suggested for DOX/
EGCG NPs linked with an aptamer (DOX/EGCG NP-Apt) [156]. In a
xenograft mice model, it has been reported that DOX accumulated
preferentially in liver and kidney after free DOX intravenous injection,
whereas DOX/EGCG NPs and to a great extent DOX/EGCG NP-Apt ac-
cumulated in the tumor.
8. Discussion and conclusion
Application of nanotechnologies to cancer therapy might increase
solubility and/or bioavailability of bioactive compounds of natural or
synthetic origin and offers other potential benefits in cancer therapy,
including selective targeting [157,158]. In both xenograft and che-
mical-induced animal models of cancerogenesis, NPs (formulated with
CS, PEG, PLGA (Fig. 1) and other chemicals (Tables 1–3) of food-de-
rived flavonoids resulted in better efficacy for tumor growth than free
compounds (Tables 1–3), and synergistic effects in co-delivery systems
(both drug and flavonoid in the core, Fig. 1) have been reported
(Table 4). Besides, when EGCG [147] and BCL [80] were used as MDR
reversal agent in co-encapsulated (DOX and PTX) NPs increased bioa-
vailability and efficacy of drugs. QCT has been used as MDR reversal
agent as well [96,150]. Moreover, flavonoids’ loaded NPs for delivery
of anticancer drugs (Table 4), as well as decorated NPs targeting cancer
cells (Table 5), increased the efficacy and/or reduced the systemic
toxicity of drugs.
P. Aiello, et al.
Fig. 1. Nanodelivery and nanoparticles of dietary flavonoids.
CS: chitosan; NPs: nanoparticles; PEG: Polyethylene glycol; PLGA: Poly(lactic
co-glycolic acid); ROS: reactive oxygen species.
Furthermore, reductions in the MMPs have been reported among
molecular mechanisms [47,48,84], suggesting inhibition of invasion,
migration and angiogenesis [159].
Mechanisms of cellular uptake include diffusion, endocytosis and
specific molecular target NPs (Fig. 1). In addition to receptor-mediated
targeting, it has been reported that EGCG, due to its high binding af-
finity to the 67LR (Table 5), overexpressed in cancer cells, can be used
as capping agent. Cancer cells have lower pH and higher ROS content
and within mechanisms, ROS-dependent [77,89] and pH-dependent
[62], drug delivery and/or cell death have been suggested. pH-re-
sponsive drug carriers loaded with QCT were synthesized with CS
chemically modified with 2-chloro-N,N-diethylethylamine hydro-
chloride and dodecyl aldehyde [160] and PEG modified viaa pH-re-
sponsive coordination bond to form triphenylphosphine-QCT-PEG NPs
[62].
On the other hand, results with ROS-sensitive drug carriers, in-
cluding ATC in NPs for DOX delivery, demonstrated that higher DOX
release occurred compared to ATC-free NPs [77]. Authors suggested
that DOX was almost always released before reaching at the tumor site
in the ATC-free DOX NPs, whereas DOX was released from ATC-con-
taining NPs at the tumor site, by ROS mediated ATC degradation and
NPs destruction [77]. Similarly, it has been reported that NPs can ef-
fectively protect the carotenoid lycopene against degradation due to
EGCG's anti-oxidant property [161]. Authors applied self-assembly of
oligomerized (-)-epigallocatechin-3-O-gallate (OEGCG) for delivery of
lycopene [161].
In this context, polyphenols act as both reducing and capping agents
of green chemistry process [19,161,162] and tea [161] and Mangosteen
pericarp waste [163] extracts have been employed to produce NPs by
eco-friendly synthesis. Other suggested natural excipients include α-
tocopherol [164] and squalene [165]. On the other hand, non-flavonoid
bioactive phytochemicals, including curcumin, has been included in
nanoformulations [166] or used as a model for the synthesis of analogs
with better bioavailability and higher anti-cancer activity [167].
In conclusion, although human studies are needed, NPs obtained
from food-derived flavonoids show promising anticancer effects in vivo,
improve cancer drug efficacy and minimize their toxicity.
Declaration of Competing Interest
The authors declare that there are no conflicts of interest.
12
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
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