CYCLODEXTRIN BASED NANOCARRIERS IN ANTICANCER THERAPY: A

REVIEW

INTRODUCTION

Chemotherapy for cancer has a limited therapeutic efficacy, especially for recurrent and
metastasizing disease. Long-standing challenges in the treatment of cancer include limited
aqueous solubility (hydrophobicity), degradation in gastrointestinal fluids, insufficient in vitro
stability (shelf life), low bioavailability, brief in vivo stability (half-life), affinity for intestinal
and liver cytochrome P450 (CYP3A4) and P glycoprotein (P-gp) in the intestinal barrier, poor
intestinal permeabilities, and potent dose-dependent side effects [34].Short blood circulation
times and a lack of selectivity, which can result in a variety of hazardous side effects, are other
significant problems [35].

A significant obstacle is the limited therapeutic index of some anticancer medications and the
fact that these cytotoxic medications harm both healthy and normal tissue in addition to cancer
cells. Another significant issue is multidrug resistance, which results from increased efflux
pumps like P-glycoprotein (Pgp) in the cell membrane, which transfer the majority of anticancer
medications outside of the cell [36, 37].

Low solubility and rapid rate of dissolution are two crucial variables that influence medication
formulation and development and restrict their use in therapy [1] Drug delivery via various
routes, particularly for those that are poorly soluble fall within classes II or IV of the
biopharmaceutical classification system, provides a significant problem [2].It is also noteworthy
that the majority of anticancer medications fall under BCS class IV, which includes compounds
with low apparent permeability and low solubility in aqueous fluids [3].The solubility,
bioavailability, and dissolving qualities of drugs can be improved by a number of approaches,
including the following .

Physical Modifications. Particle size reduction like micronization and

nanosuspension,modification of the crystal habit like polymorphs, amorphous form and
cocrystallization, drug dispersion in carriers like eutectic mixtures, solid dispersions, solid
solutions and cryogenic techniques.

Chemical Modifications. Change of ph, use of buffer, derivatization, complexation, and salt
formation.

Miscellaneous Methods. Super critical fluid process, use of adjuvant like surfactant, solubilizers,
cosolvency, hydrotrophy
An approach that generated a lot of interest is cyclodextrin (CD) complexation [10, 11].The idea
of using a dual approach (cyclodextrin and nanotechnology) has arisen as an unique strategy to
address such formulation issues in the twenty-first century [12–14]. In recent years, the
combined use of cyclodextrin complex with nanocarriers like liposomes, noisomes, polymeric
micelles etc., is considered as a novel method in improving the solubility of drugs thus allowing
the transfer of medicaments from BCS classes II and IV to class BCS class I.

Cyclodextrins are capable of overcoming some of the above-mentioned limitations of anticancer

medications. The physicochemical properties of the drugs are improved through the formation of
inclusion complexes with harmless substances.To enhance or improve the effectiveness of the
majority of anti-cancer medications, cyclodextrin and its derivatives have been used. By using
cds Solubility and stability are improved, bioavailability and dissolution are increased, toxicity is
decreased, and physicochemical properties are changed [38–49].Due to the breakdown of the
membrane, doxorubicin complexation with -CD and HP—CD increased permeability across the
blood brain barrier [50].Similar to this, chlorambucil was more soluble in the -CD-PEG folic
acid combination. The anticancer activity of 9-nitrocamptothecin was significantly increased
with minimal toxicity when it was complexed with HP-CD [38].

CYCLODEXTRINS

Cyclodextrins (CDs) are sugar polymers that are non-toxic [15, 16] and stable in water and some
organic solvents. CDs are cyclic oligosaccharides that do not reduce and are composed of a
succession of α -D-glucopyranose subunits connected by -1,4-glycosidic linkages.CDs can be
identified geometrically by their hydrophilic circular truncated cone shape.This cone-shaped
structure contains a 7.9Å-deep hydrophobic hollow conical chamber. The introduction of
adequately sized hydrophobic guest molecules is permitted in this cavity [15,17-19].

The pKa values of the natural CDs range between 12.1 and 13.5 [17], and they exhibit
remarkable stability under alkaline environment. CDs are vulnerable to acid hydrolysis at low
pH, which leads to ring opening and the generation of different linear oligosaccharides and
glucose units [18].
Hydrogen bonding and water solubility of cyclodextrin
As previously mentioned, CDs are lined with primary and secondary hydroxyl groups. this
Hydroxyl groups can form hydrogen bonds with water molecules and other polar chemicals.
The number of hydrogen bond donors/acceptors for each α-CD, β-CD, and γ-CD is very high
[42],Table3.Numerous hydrogen bond donors and acceptors in cyclodextrin molecules leads
to a large negative LogPo/w [42], which is the logarithm of octanol/water.
partition coefficient [102

Despite comparable numbers of hydrogen bond donors and acceptors, α-CD, β-CD, and γ-CD
differ significantly in water solubility from the other two. The maximum amount of cyclodextrin
that can be dissolved at 25⁰C and 1 atm is 14.5, 1.85 23.2 g in 100 ml of water for α-CD, β-CD,
or γ-CD [103]. The values are similar even at elevated temperatures (Table 4) [103].

Table 4. Water solubility of the three native cyclodextrins *. Data taken from [103].
Temperature (α-CD) (β-CD) (γ-CD)

Among the naturally occurring cyclodextrins β-CD is the least soluble in water. Despite this
anomaly, β-CD and its derivatives are most commonly used in drug research due to their
convenient size of Internal cavities [71,104]. Some investigators believe that the unusual
solubility of β-CD is attributed to its molecular stiffness [105]. In particular, C2 and C3
secondary hydroxyls groups of β-CD form hydrogen bonds with each other, creating a rigid
structure, yet complete secondary belt. This complete 'belt' limits the ability of β-CD to form
hydrogen bonds with surrounding water molecules [4]. In contrast, both α-CD and γ-CD possess
Higher water solubility than β-CD due to incomplete hydrogen bonding belt and non-coplanar
structures [42].The low water solubility of CDs poses a major challenge for its Pharmaceutical
application. To overcome this obstacle, the CD hydroxyl group ( secondary and/or primary) can
be chemically modified. The use of synthetic derivatives of cyclodextrin Improves the water
solubility of the hydrophobic drugs and enhances their applicability diversity[9,73,74,106–
108].For example, the water solubility of β-CD increases to >1200 mg/mL (>80-fold).
When the 2-hydroxy group is replaced by a 2-hydroxy propyl group (HP-β-CD) [47].

albendazole and fenbendazole, two imidazole-based drugs [109] used to treat alveolar
echinococcus had significant differences in their Water solubility after complexation with β-CD
and HP-β-CD [110] (see Table 5). From Table 5 it is clear that the introduction of chemical
modifications can leads to enormous effect in the solubility of the drug in water.

Cyclodextrin based nanocarriers of anticancer drugs

One of the greatest advantages offered by nanotechnology is the ability to target the drug
delivery to diseased sites. The goal of targeted therapy is to target and direct chemotherapy drugs
to cancer cells, ultimately reducing side effects. Active or affinity targeting involves the binding
of targeting molecules (antibodies, ligands, nucleic acids, etc.) on the nanoparticle surface to
receptors overexpressed on tumor cell surfaces [29]. In passive targeting, liposomes,
macromolecular carriers, and nanoparticles target drugs to tumors using the EPR effect, which is
a result of increased vascular permeability and decreased lymphatic function in tumors [30].
Most of the anticancer agents distribute nonspecifically throughout the body, affecting both
normal and tumor cells [31]. Abnormal vasculature plays a key role in EPR action within tumors,
targeting specific macromolecules to tissues. The EPR effect differs from the non-targeted
passive uptake of small molecules. EPR is a mechanism by which high molecular weight non-
targeted drugs/prodrugs accumulate in tissues with increased vascular permeability..
nanotechnology based delivery system can reach tumors passively through leaky vessels due to
the EPR effect. Cyclodextrin-based nanocarriers are fabricated using a dual-approach concept,
which involves combining two different approaches into a single delivery system. Anticancer
drugs are complexed with appropriate cyclodextrins and then the complexed drug is encapsulated
in a carrier. Encapsulation of anticancer drugs in specially designed polyfunctionalized
cyclodextrin-based carriers Take a step towards application success in this challenging field. For
drug delivery, entrapping cyclodextrin-complexed drugs in nanocarriers enhances the benefits of
both. Encapsulation of cyclodextrin drug complexes in carriers enhances drug loading capacity,
entrapment efficiency, prolongs drug presence in systemic circulation, reduces toxicity, and
provides controlled, sustained, or targeted release.Unique features of the optimized drug-
cyclodextrin complex include low aggregation, Better ADME properties, less toxicity, and
patient friendliness [32]. Safety is an important criterion to consider before using cyclodextrin as
a pharmaceutical excipient. Toxic effects of Cyclodextrins are based on the route of
administration. When administered orally, cyclodextrins are virtually non-toxic as they are not
absorbed from the gastrointestinal tract. This is due to their bulky, hydrophilic nature. If
absorption does occur, it is due to passive diffusion. Most hydrophilic derivatives of natural
cyclodextrins, such as 2-hydroxypropyl cyclodextrin and sulfobutyl ether cyclodextrin, are
considered safe for parenteral administration. High doses of cyclodextrin can be harmful.
Parenterally administered CD clears rapidly from the systemic circulation and is excreted intact
by the kidneys. When administered, CDs are distributed to the kidney, liver, bladder, and various
other tissues of the body. Regarding toxicity, the cyclodextrin profile is considered. Although
several in vitro studies have reported hemolytic effects of CD, the toxicological effects of in vivo
studies are considered negligible.[33]
LIPOSOMES
They are non-toxic lipid-based carriers consisting of concentric vesicles formed by one or more
phospholipid bilayers. The amphiphilic character of phospholipid molecules offers the ability to
encapsulate both hydrophilic and lipophilic compounds,[51]
In liposomes, Cyclodextrin complexation competes with liposomal Membrane binding which
mitigates the potential benefits of Conjugation to prolong hydrophobic drug retention [79].
Entrapment of water soluble cyclodextrin-drug inclusion complexes in Liposomes leads to
accumulation of insoluble drugs in aqueous phase of vesicles which results in enhanced drug to
lipid ratio , wide range of encapsulation efficiency & Targeting of the conjugate to specific sites
to reduce toxicity. Arima et al. 2006, researched the anti-tumor effect of PEGylated
Administration of DOX liposomes conjugated with 𝛾-CD By intravenous injection into the colon
containing BALB/cmice 26 tumor cells. The results reflect delayed tumor growth, Better drug
retention and better survival [59]. In another study, anti-proliferative and cytotoxic activity of
anticancer agent LPSF/AC04 in Cyclodextrin-conjugated liposomes have been improved [60].
Cui et al 2011 Developed stable PEGylated liposomal vincristine, a Potency-enhancing
preparation using sulfobutyl ether Cyclodextrin. This formulation has enhanced the circulation
half-life from 43.6 hours to 70.0 hours & decreases the Toxicity [80].

Noisomes.

Niosomes are spherical nanocarrriers made up of a lipid bilayer that can entrap water-soluble
solutes in the aqueous domains or lipid molecules in the lipid bilayer. They are made by
hydrating the mixture of cholesterol and nonionic surfactants. These are vesicular
liposome-like system, which are biodegradable, biocompatible, non-immunogenic and flexible in
their structural characterization. They take precedence over Liposomes due to their higher
chemical stability. They alter tissue distribution, cell-drug interactions
and drug plasma clearance kinetics [81]. Omen and others. 1999 prepared an niosome
containing an inclusion complex of methotrexate – beta cyclodextrin .Entrapment efficiency and
anti tumor activity is enhanced as a result of complexation. The MTX-𝛽-CD complex (84%) is
showing higher entrapment efficiency as compared to the pure drug (67%). niosomes of
MTX-𝛽-CD complex showing Relatively slow drug release of encapsulated drug conjugates
from the vesicles as compared to simply encapsulated MTX Niosomes [61].

Nanosponges.
Nanosponges falling under the category of microscopic particles, having the ability to
incorporate drug molecules inside their cavities and helps in the transport of drug molecules
across the aqueous media. Cyclodextrin based nanosponges are fabricated by cross linking of
carbonyl or dicarboxylate compounds with cyclodextrins.Nanosponges are capable of forming
inclusion and non-inclusion complex with variety of drug molecules and provides high
solubilizing effect. The drug loading capacity and release pattern can be improved by changing
the drug- cyclodextrin ratio. [82]. Swaminathan et al. Prepared cyclodextrin based Nanosponges
of camptothecan that encapsulate camptothecin and expand camptothecin Shelf life and drug
release. Camptothecin (CAM) has not been utilized properly due to its limited aqueous
solubility , unstable nature of the lactone ring and other serious side effects. Cyclodextrin-based
nanosponges of camptothecin posses Sufficiently high zeta potential (-20 to -25 mV), which
results in more stable colloidal Nanosuspension [62]. The results of In vitro studies showed
sustained drug release over 24 hrs and cytotoxicity studies showed that the Formulations
containing CAM are More cytotoxic than pure CAM. Mognetti et al. 2012 prepared Cyclodextrin
nanosponges loaded with paclitaxel, a water-stable
colloidal system that avoids recrystallization of paclitaxel. In vitro release studies showed
complete drug release Obtained within 2 hours without initial burst effect. Administration of
paclitaxel via nanosponges increased the quantity of paclitaxel that enters the cancer cells and
reduces paclitaxel levels IC50, enhancing its pharmacological effects [63].

Micelles.

Micelles are self-assembled Nano-sized colloidal particles with lipophilic core and a hydrophilic
outer cover. It consists of a single central and predominantly hydrophobic zone or "core"
encapsulated by a Hydrophilic layer or "shell". They are about 5 to 2000 nm range in size.It is
capable of entrapping the liphophilic drugs in the core & the hydrophilic surrounding of the
Micelles make the polymer water-soluble. Drugs are also encapsulated in polymeric micelles
either by forming covalent bonds or by physical encapsulations. Cyclodextrin Micelles (CDM)
contain derivatives of cyclodextrins including: Dimers, trimers, and polymers incorporated as
amphiphiles and forms Aggregate molecules . Liu et al. in 2012 Formulated multifunctional
pH-degradable micellar nanoparticles Made from asymmetrically functionalized 𝛽-cyclodextrin,
A Star Copolymer Covalently Linked with Doxorubicin (DOX), Folate (FA) and DOTA- Gd
units for Targeted drug delivery. Results showed improvement in drug Release due to acid
labiality of the carbamate bond [64

Polymeric Millirods.
Site-specific controlled release of cytotoxic agents from biodegradable Polymer depots are
emerging trends in cancer Chemotherapy. Drug confinement in polymer depots providing the
Added benefit of potential tuning of release kinetics and most effective dosing regimen can be
designed. Incorporation of cyclodextrin into polymeric millirods for complexing the Drugs has
provides enhanced release Kinetics with different release patterns. Millirod consists of two
functional compartments, drug-loaded inside the Monolithic milli-rod as active ingredient depot
and NaCl-impregnated depot outside the polymer membrane that controls the release rate of
medicament. The inner portion of the millirod allows entrapment of drug particles within the
matrix, providing sustained drug delivery [84]. Wang et al. 2006 synthesized 𝛽-lapachone
polymeric millirods for local delivery. Complexation with HP-𝛽-CD prevented the dissolution of
drug and led to fast release (approximately 80%) after 2 days [65].

Nanoparticles
Nanoparticles are colloidal carriers made up of natural, synthetic, or semisynthetic polymers
with size ranging between 1 nm to 1000 nanometers. Cyclodextrins enhances the loading
capacity of nanoparticles. C. irpanli et al. 2009, reported Amphipathic 𝛽-cd nanoparticles
extended the duration of action of camptothecin to 12 days as compared to polymeric
nanoparticles (48 hours). It shows the superiority of CD-based nanoparticles over conventional
polymeric nanoparticles [66]. The cytotoxic potential of amphiphilic CD nanoparticles loaded
with Camptothecan was more than that of PLGA/PCL nanoparticles, and its solution in DMSO.
.
siRNA (Short Interfering RNA) Delivery System.
A small piece of nucleic acid known as siRNA, is one of the promising carriers for cancer
chemotherapy. Free siRNA are not effective therapeutically& their biological half-life is less
than 1 hour in human plasma. Therefore, non-viral vectors are employed to extend the half-life
& therapeutic efficacy . The therapy based on cyclodextrin and siRNA is currently being studied
for the treatment of cancer [90]. Synergistic therapeutic effects and modulation in tumor
pathways can be Accomplished by combining drugs with Orthogonal therapeutic entity such as
siRNA. Kimetto Al. 2011 prepared synthetic Cyclodextrin-modified dendritic polyamines for
translocation of siRNA and anticancer drugs Suberoylanilide hydroxam acid and erlotinib. Due
to the presence of 𝛽-cyclodextrin, complex formation and intracellular uptake of anticancer
agent is enhanced & the cationic polyamine skeleton Allows for electrostatic interactions with
negatively charged siRNA. Deng et al. 2011 developed a star shaped polymer for sustained
release of methotrexate. This polymer Showed higher transfection efficiency with low
cytotoxicity in fibroblasts. (92) These examples demonstrate recent advances in nanoparticle
development.with Linear and cyclodextrin-based polymers for the treatment of cancer.
Cyclodextrin-Based Monoclonal Antibody Drug-Conjugate Approach.

Many cytotoxic chemotherapeutic agents have failed in clinical trials due to its extreme effects of
Toxicity and lack of satisfactory therapeutic activity at the maximum tolerated dose (MTD).one
of the ways to improve the therapeutic activity of these anticancer Drugs consists of binding
them to antibodies. Antibody recognizes tumor-associated cell surface antigens.
Monoclonal antibodies (mAbs) represent a major class of drugs currently used to treat cancer.
Therapeutic mAbs show better pharmacokinetic parameters with Moderate or no systemic
toxicity [94]. Anticancer drugs covalently attached to a monoclonal antibody capable of
Recognizing that tumor-associated antigens are called as antibody drug Conjugate. This
conjugate combines selectivity, altered Pharmacokinetics, bio distribution and functional activity
of antibodies with high anticancer effect of the drug. A recent contribution in this regard is
antibody drug conjugate of Trastuzumab complex (ADC). Trastuzumab emtansine (T-DM1) is
an ADC consisting of an anti-HER2 mAb. Trastuzumab (Herceptin) and maytansinoid DM1
safely administered at therapeutically effective doses, HER2 is expressed in some normal tissues,
[95-98]. Recently Researchers are interested in targeting cancer stem cells Specific antigens with
antibody-drug conjugates. Unique monoclonal antibody drug conjugates have the potential of
overcoming or minimizing multidrug resistance (MDR),which is a major barrier effective
chemotherapy.[101].

Formulation Containing Cyclodextrin

An ideal drug delivery system should deliver the specific amount of the drug to the targeted site
both efficiently and exactly at the desired time. a drug molecule to be pharmacologically active
it should be partitioned between the hydrophilic and liphophilic domains of the biological
membranes for permeation across the membranes via passive diffusion. Water solubility of
drugs depends on the potency (effectiveness) and the type of formulation.[108].aqueous. Oral
administration of cytotoxic anticancer drugs eliminates the need for hospitalization, Medical aid
and infusion equipment. Cyclodextrins are Used for the encapsulation of lipophilic drugs and
Showed ability to inhibit both PGP and cytochromes P450 localized on the surface of enterocytes
[109]. PTX (paclitaxel), one of the anticancer drugs was loaded to poly(anhydride) nanoparticles
after complex formation with Cyclodextrin. Interestingly, the relative oral bioavailability was A
staggering 80% for PTX-cyclodextrin complex Oral formulation. This example demonstrates
the effective use of Cyclodextrins in oral anticancer drug delivery formulations [110].
Cyclodextrin forms inclusion complexs by encapsulating the drug molecules in their liphophilic
cavity. They are used as formulation additives Percutaneous absorption enhancer for topical
administration.

Injections containing hydrophobic drugs mainly composed of mixture of water, organic co-
solvents and surfactants. The use of organic solvents results in precipitation of the drug at the site
of action which causes pain, inflammation, and hemolysis [111]. Isotonic aqueous solution of
cyclodextrin are considered as a suitable replacement for the Organic Solvents and Surfactants
in Injectable Formulations. Various cyclodextrins, derivatives including HP-𝛽-CD and SBE-𝛽-
CD Due to its high water solubility and minimal toxicity are widely used in parenteral
administration. The benefits of using cds in parentrals includes enhanced drug solubility ,
reducing the irritation at the site of administration Stabilization of drugs unstable in aqueous
environment, and so on [112].the use of Cyclodextrin reduces the In situ irritation due to the
direct chemical stimulation of Drugs that cause phlebitis and pain in the area injection. After
intravenous injection, the drug is released Rapidly and quantitatively from the diluted conjugate,
followed by competitive displacement and binding to tissue and plasma proteins. Cyclodextrins
have no effect. On the Pharmacokinetics of injected drugs. Horse et al. 1999 prepared Melphalan
injection formulation containing SBE-𝛽-CD and HP- 𝛽CD. This formulation showed improved
shelf life, solubility, and stability of reconstituted melphalan. In addition, Oomen et al. 2010
synthesized niosome formulation For subcutaneous administration of plumbadin. Complexation
with 𝛽-Cyclodextrin results in enhanced water solubility, stability, and efficacy and niosome-
encapsulated drug conjugates Improved anticancer activity as evidenced by enhanced anticancer
activity Volume doubling time and growth retardation [113]. Li.et al. 2011 Single- and repeated-
dose pharmacokinetics were studied using Injectable 𝛽-Cyclodextrin Oridonin Inclusion
Complex in rats. Results showed a significant increase in solubility and oridonin bioavailability
in rats. Finally hydrophilic Cyclodextrin derivatives such as hydroxypropyl-𝛽-cyclodextrin and
sulfobutyl ether 𝛽 cyclodextrin are relatively non-toxic Minimal impact on intrinsic
pharmacokinetics of medicine.
Conclusion
various nontherapeutic approaches have been developed for the Delivery of anticancer drugs. but
none of these treatments are safe, effective and could provide a complete relief. Most of these
treatments are expensive, unacceptable and Long-term use is uncomfortable or associated with
serious problems of toxicity. That's why we need to step up Using advanced technology in
combination, A strategy that takes advantage of both systems, namely, cyclodextrin
complexation and nanotechnology in single delivery system.the use of drug delivery systems,
Based on colloidal vesicles and macromolecular carriers (cyclodextrin), representing a promising
and innovative strategy that enables effective treatment with minimal side effects. However, the
biggest challenge is toxicity and Pharmacokinetic studies of these cyclodextrin-based carriers.
Most toxicity information is based on in vitro cell model. Numerous researches have been done
regarding the interaction of nanoparticles within the body. But no information is available on the
interaction of cyclodextrin complexed nanoparticles in the body. In addition, we must be
clarified regarding the route of administration and mechanism of removal of these carriers from
the body. Another important parameter is dosage of anticancer drugs and the amount of
cyclodextrin considered to be Used in formulations. Extraordinary properties of these two
systems (cyclodextrin and nanotechnology) At the same time, it offers further possibilities for
cancer treatment success. Additionally, there are requirements to take advantage of it Utility of
these cyclodextrin-based nanocarriers for use in In vivo models for tumor targeting and cancer
toxicity studies Like a life-threatening illness. In the future, cyclodextrin will be Used to modify
powerful anticancer drugs achieve effective treatment.