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52 PHARMACIA, vol. 63, No. 4/2016 D. Aluani, V. Tzankova, Y. Yordanov, A. Zhelyazkova, E. Georgieva, K.

Yoncheva

QUERCETIN: AN OVERVIEW OF BIOLOGICAL EFFECTS AND RECENT


DEVELOPMENT OF DRUG DELIVERY SYSTEMS
Denitsa Aluani1, Virginia Tzankova1, Yordan Yordanov1, Albena Zhelyazkova1, Elena Georgieva1,
Krassimira Yoncheva2
1
Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy,
Medical University of Sofia
2
Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy,
Medical University of Sofia

Abstract. The numerous beneficial pharmacological properties of quercetin justify its future
clinical application. Nevertheless, the use of quercetin as a safe and effective therapeutic agent
in the treatment of various diseases is limited because of the poor water solubility and membrane
permeability, low bioavailability and instability. Several approaches have been undertaken to im-
prove the bioavailability of quercetin, including the loading in different drug-delivery systems
such as different types of micro and nanoparticles, nanocrystals, polymeric micelle, liposomes,
microemulsions, etc. This review summarizes the beneficial biological properties of quercetin,
discusses the problems of its bioavailability and clinical use, and provides an overview of possible
ways to overcome these problems by its loading in perspective drug-delivery systems.

Key words: quercetin, bioavailability, drug delivery systems, nanoparticles.

Introduction water-soluble drugs could be improved by de-


Flavonoids are a large group of phenolic creasing crystallinity or incorporation in com-
compounds that are widely spread in different pexes using compounds such as cyclodextrines.
plant foods. There are many classes of flavo- Encapsulating quercetin in nano-sized drug de-
noids, for example flavones, flavonones, iso- livery systems, such as polymeric micro- and
flavones, flavonols, flavanonols, and anthocy- nanoparticles, liposomes, micelles, phospholip-
anins. Quercetin (3,3′,4′,5,7-pentahydroxyfla- id complexes are novel approaches to enhance
vone) is a common dietary flavonol with a wide the solubility and permeability and to resolve
range of pharmacological activities including the pharmacokinetics and some safety problems
antioxidant, antiplatelet, antiinflammatory, neu- (1). Therefore, we focus our review on discuss-
roprotective, antimutagenic, anticarcinogenic, ing the promises of quercetin use, the problems
antiangiogenic, antibacterial, antitumor, antivi- in bioavailability and the new approaches to re-
ral, antianxiety and hepatoprotective. The ben- solve them.
eficial biological properties of quercetin make
it a promising therapeutic agent. Nevertheless, Biological effects of quercetin
the pharmacokinetic studies show that poor Antioxidant effects. The beneficial effects of
absorption and rapid metabolism are the ma- quercetin are closely related to its antioxidant ac-
jor problems and reasons for its low bioavail- tivity by the following mechanisms: scavenging
ability. A possible approach to overcome this reactive oxygen and singlet oxygen species (2),
problem is loading of quercetin in appropriate inhibiting enzymes (xanthine oxidase, protein
drug delivery systems. The solubility of poor kinase C, cyclooxygenase, glutathione S-trans-
Quercetin: an overview of biological effects and recent... PHARMACIA, vol. 63, No. 4/2016 53

ferase) or chelating trace elements, upregulating led to significant lactate dehydrogenase (LDH)
or protecting antioxidant defenses (3). Quercetin leakage and intracellular glutathione depletion,
has been reported to have antioxidant activity in respectively affecting cell viability. Thus, de-
several in vivo studies. It has been found to in- pending of the dose, the apparent antioxidative
hibit the oxidative stress caused by streptozoto- protection offered by quercetin could be trade-
cin-induced diabetes in rats (4), to show antiox- off with other type toxicity.
idant effects against lipid peroxidation, induced Protection in neurodegenerative disorders.
by tert-butylhydroperoxide in human sperm cells Because of its antioxidant property, increased
(5), and to reduce effectively oxidative damage glutathione levels and antioxidant enzyme func-
caused by an industrial compound CCl₄ using tion, quercetin has been reported to increase
methanolic extract of Heterotheca inuloides con- the intracellular GSH levels in many diseases,
taining quercetin (6). Despite of the well-known including Alzheimer‘s disease (8, 9). Querce-
antioxidant activity of quercetin, in certain cir- tin has been reported to reduce oxidative stress
cumstances it may act as a pro-oxidant (Fig. 1). induced by 6-hydroxydopamine in the striatum
This phenomenon, better-known as “quercetin and reduced the dopaminergic neuronal loss in
paradox” is first explained by Boots et al. (7). the rat model of Parkinson’s disease (9). How-
When quercetin scavenges free radicals, it is ever, prolonged use of quercetin should be better
chemically converted into oxidation products evaluated and studied.
(such as ortho-quinone/quinone methide inter- Cardiovascular protection. Cardioprotective
mediates). These products display a high reactiv- properties of quercetin have been reported in pa-
ity towards thiols and this can be a reason to the tients. The beneficial effects were supported by
loss of some protein functions. Boots et al. found several studies completed in cellular and animal
that quercetin pre-treatment can protect DNA models (10). It has been shown to decrease blood
from oxidative damage. However, it was found pressure and heart rate in spontaneously hyper-
that quercetin, in presence of hydrogen peroxide, tensive rats (11), to prevent calcium chloride in-

Fig. 1. Dual anti-oxidant and pro-oxidant effects of quercetin.

In absence of quercetin, cell viability is decreased its oxidized thiol reactive form. The excessive
by ROS – induced oxidative stress cell damages. dose of quercetin (<100 µM) leads to increased
Quercetin, used in low concentrations, scaveng- GSH consumption, increase in products of lipid
es free radicals and protects cells (6, 32). However, peroxidation (MDA) and lactate dehydrogenase
during this process quercetin is converted into (LDH) leakage.
54 PHARMACIA, vol. 63, No. 4/2016 D. Aluani, V. Tzankova, Y. Yordanov, A. Zhelyazkova, E. Georgieva, K. Yoncheva

duced abdominal aortic aneurism (12), to reduce relation between total flavonoid intake (a major-
the levels of total cholesterol, triglycerides and ity of which quercetin ~95%), and overall cancer
free fatty acids, serum phospholipids, as well as incidence, as well as the incidence of lung can-
reduced levels of serum LDL and significantly cer. Quercetin possesses a good safety profile.
increased serum HDL in a model of isoprotere- Clinical and epidemiological studies of products
nol cardiotoxicity in rats (13) . containing a standardized quercetin indicate
Anticancer and antiviral activity. It is consid- that the flavonol is well-tolerated in humans; no
ered that quercetin inhibits the growth and pro- significant severe adverse events were reported
liferation of cancer cell lines of different origin, during the studies (24-26).
induces senescence, inhibits telomerase, induces
autophagy in cancer cells, possesses anti-angio- Pharmacokinetic properties and problems in
genic activity and it can also activate immune bioavailability
destruction (10). Quercetin has been reported as As it was discussed in a previous section,
a potent antiviral agent in in vitro studies (14). quercetin possesses a good efficacy, intrinsic ac-
This effect is probably related to its ability to re- tivity and has a strong potential as a therapeu-
duce viral growth, inhibit DNA fragment of in- tic agent. Despite quercetin’s efficacy and safe-
fected cells regardless of its antioxidant activity ty, some pharmacokinetic limitations, like poor
(15), inhibit viral polymerase and bind viral nu- bioavailability, continues to be mentioned as a
cleic acid or viral capsid proteins. major concern of it’s use in a clinical practice.
Anti-inflammatory activity. Quercetin can In generally, the main reasons for reduced bio-
inhibit several enzymes that are activated in availability of biologically active substances are
certain inflammatory conditions. Quercetin has poor absorption, low intrinsic activity, high rate
been shown to inhibit nitric oxide production, of metabolism, inactivity of metabolic products
iNOS expression, inflammatory causing agents and/or rapid elimination and clearance from the
like NO synthase, reactive C-protein, and cyclo- body (27). Several studies have revealed querce-
oxygenase (COX-2) in several in vivo and in vi- tin’s poor absorption and rapid metabolism.
tro studies (16). The water-solubility of quercetin is very low:
Hepatoprotective activity. It is considered that about 1µg/mL in water, 5.5µg/mL in simulated
quercetin has beneficial effects on liver damage. gastric fluid and 28.9 µg/mL in simulated intes-
Quercetin has been reported to protect hepato- tinal fluid. Chen et al. (2002) reported that, only
cytes against oxidative stress via phosphonoside 20% of the radiolabeled quercetin was absorbed
3-kinase activation and to maintain Ca2+  level following administration of an oral dose to male
in the endoplasmic reticulum in mice (17). Fur- rats (28). In experimental pharmacokinetic study,
thermore quercetin decreases oxidative damage male Sprague-Dawley rats were treated with
induced by ethanol in rat hepatocytes (18). quercetin in a dose 50 mg/kg body weight, p.o.,
once daily. The plasma concentration of the free
Clinical applications and safety quercetin was found to be 0.27 μg/mL; 93% of
There are some in vivo human studies show- the active substance was metabolized after one
ing that quercetin improve endothelial function hour (29). Low concentrations of free quercetin
in patients with hypertension and cardiovascular were identified in liver and kidney tissues (i.e.,
diseases (19), inhibit LDL oxidation after in vivo less than 8% of total quercetin) following p.o.
supplementation (20) and was effective in pre- treatment of rats.
vention and therapy of allergic and inflammatory A study in ileostomy patients showed that
diseases (21, 22). Quercetin showed beneficial 24% of total quercetin was absorbed following
effects in cancer prevention. Experimental data ingestion of 100 mg of the quercetin aglycone
suggest its role in breast cancer and prostate can- (30), while in healthy subjects provided 100 mg
cer, known to have hormone sensitive compo- of radiolabeled quercetin, up to 53% of the total
nent. Knekt et al. (23) demonstrated an inverse administered radioactivity was absorbed (31).
Quercetin: an overview of biological effects and recent... PHARMACIA, vol. 63, No. 4/2016 55

Approaches for development of quercetin de- Nanocrystals. Nanosizing of the active


livery systems substance is achieved by wet media milling,
The successful realization of quercetin’s high-pressure homogenization, precipitation or a
health benefits depends on technological ap- combination of methods. This approach allows
proaches for improving its unfavorable ADME an achievement of greater and faster dissolution
characteristics while retaining its desired phar- (34). For example, quercetin nanosuspension
macological effects. In the present review such stabilized with Tween 80, produced by combined
strategies are summarized in Table 1. bead milling and high-pressure homogenization

Table 1. Strategies for improving quercetin’s pharmacokinetics.

Biopharmaceutical Quercetin preparation (example) Major outcome


strategy
Nanocrystals SmartCrystals® stabilized with ↑↑dispersion stability
Tween® 80(35) ↑water solubility
Nanosized emulsion produced (37) ↑ Caco-2 cells permeability
Microemulsions ↑ intestinal absorption in rats
Pentamethyleter conjugate (38) ↓ water solubility
↑ permeability coeff. nude mouse skin (26
times)
Prodrug(40)
Glutamic acid conjugate(40) ↑ water solubility,
↑MDCK cells permeability
Butyl ester conjugate (39) ↑ water solubility,
↑ skin penetration
Inclusion complexes Modified β-cyclodextrin inclusion ↑↑water solubility,
complexes(43, 44) ↑dissolution rate,
↑antioxidant
Liposomes Liposomes(48, 51) Preserve antioxidant;
↑anti-inflammatory;
CNS delivery (nasal route)
Polymeric micelles MPEG-PCL micelles(54) ↑antiproliferative effects;
PEG-phosphatidylethanolamine micelles(55)  preserve antioxidant activity(60)
PEG-b-oligo(ε-caprolactone)(56)
Pluronic P123 micelles(57)
Mixed micelles(60)
PLGA(73) preserve antioxidant activity;
PLGA, mannose/folic acid conjugated (64,65) cancer ligand targeting
PLA(63) preserve antioxidant activity;
Polymer NPs
sustained release
Chitosan(68) preserve antioxidant activity;
mucoadhesive
Chitosan-alginate(70,71) ↑hypoglycaemic;
mucoadhesive
Alginate(74) Pb(II) waste water recovery;
adhesive
Inorganic NPs NH2-MSN(75) ↑antiproliferative effects
56 PHARMACIA, vol. 63, No. 4/2016 D. Aluani, V. Tzankova, Y. Yordanov, A. Zhelyazkova, E. Georgieva, K. Yoncheva

had 7.56 fold higher saturation solubility than Liposomes are lipid bilayer vesicles with
crude quercetin (35). great potential and application in clinical drug
Microemulsions (ME) are optically isotro- delivery. A major disadvantage of liposomal
pic and thermodynamically stable solutions of preparations is the high cost of industrial scale
oil, water, surfactant/s and a cosurfactant (36) and difficult aseptic manufacturing (45). There
Hädrich et al. created a nanosized emulsion by is plenty of research on liposome-loaded quer-
the hot solvent diffusion method with phase in- cetin. This approach preserves its pharmacolog-
version technique (PIT). Oral administration to ical effects (46-50). Noteworthy, Priprem et al.
rats was non-toxic and resulted in significant re- (51) suggested that such a formulation is effec-
duction of paw edema, comparable to diclofenac tive in delivering quercetin to the CNS through
(10 mg/kg, i.p.) (37). the nasal route. Based on their synergism in ad-
Prodrugs. The five hydroxyl groups of ipocyte apoptosis induction and adipogenesis
quercetin enable its conjugation with a variety inhibition, Cadena et al. proposed that encap-
of chemical moieties. However, the capping sulation of quercetin and resveratrol in sodium
of these groups may improve solubility at the deoxycholate-elastic liposomes could be an ap-
cost of decreased pharmacological activity. A proach for local fat reduction by subcutaneous
study comparing quercetin glycosides and its injection (47).
3,5,7,3’,4’-pentamethyl ether concluded that its Polymer micelles are composed of amphi-
ether was less water-soluble but had superior philic block copolymers with critical micelle
skin permeability and anti-inflammatory activity concentrations (CMC) in the order of 10-6 to
(inhibition of superoxide anion activated neutro- 10-7 M (1000 times less than classical, low mo-
phils)(38). Among acyl esters at C3, propyl and lecular weight surfactants) (52). They allow
butyl ones notably improved water solubility (9- very efficient loading of compounds of a wide
and 64-fold respectively) and penetration through lipophylicity range either incorporating them
excised human skin (enhancement factor of 3.9 in the hydrophobic core or hydrophilic corona
and 11.9 respectively) (39). The research on ami- (53). Quercetin loading in Pluronic® P104 mi-
no acids conjugates with different charge to the celles revealed that the drug could be protect-
aromatic B-ring showed that negatively charged ed from oxidation or the instantaneous phase II
aspartic and more notably, glutamic acids had metabolism in cells or plasma (52, 53). Many
increased water solubility (45,2- and 53-fold re- reports show that the incorporation of querce-
spectively) and permeability across MDCK cell tin in micelles can amplify its antiproliferative
layers (2,9- and 3-fold respectively) (40). effects on cell lines (54-59). Recent study also
Inclusion complexes. Cyclodextrins (CD) are reported that polymer micelles can preserve
capable of forming inclusion complexes with hy- quercetin from oxidation and release it in a sus-
drophobic drugs. β-CD is inappropriate for paren- tained manner (60).
teral administration due to nephrotoxicity but is Polymer nanoparticles. Polymeric nanoparti-
non-toxic when administered orally (41). Nowa- cles (NPs) are valuable drug delivery platforms
days, cyclodextrins were modified in order to ob- due to their mechanical strength, uptake by cells,
tain cyclodextrins which are safer and appropriate slow drug release and potential for multifunc-
for i.v. route (42) The complexation of querce- tional modification (1, 61). Some of the most
tin with methyl-β-cyclodextrin led to increase in studied polymers for drug delivery are poly(lac-
aqueous solubility (254-fold), dissolution rate (3- tic-co-glycolic acid) (PLGA) and poly-d,l-lac-
fold) and antioxidant activity (10%)(43). Further- tide (PLA) which are biocompatible and biode-
more, a comparison of methylated β-cyclodextrin gradable. PLGA NPs have attracted considerable
with sulfobutyl ether-β-cyclodextrin (SBE-β-CD) attention due to their approval by FDA and EMA
and hydroxypropyl-β-cyclodextrin (HP-β-CD) as parenteral drug delivery systems (62). En-
concluded that quercetin’s antioxidant activity capsulation of quercetin in PLA NPs preserved
was strongest in the SBE-β-CD complex (44). antioxidant activity and showed sustained re-
Quercetin: an overview of biological effects and recent... PHARMACIA, vol. 63, No. 4/2016 57

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 Corresponding author:
Denitsa Aluani, MPhSci
Department of Pharmacology, Pharmacotherapy and Toxicology
Medical University of Sofia, Faculty of Pharmacy
2 Dunav Str., 1000 Sofia
Tel: +35929236524
E-mail: denitsa.aluani@gmail.com