Cyclodextrins and their derivatives as carrier molecules in drug and genedelivery systems

(1)

Cyclodextrins and their derivatives as carrier molecules in drug and gene delivery systems

Article in Current Organic Chemistry · June 2019

DOI: 10.2174/1385272823666190627115422

CITATION

1

READS

137 2 authors:

Some of the authors of this publication are also working on these related projects:

ynthesis and Charactrerization of CuII (N2O2)/X ClY X=Bi,Ba and Y=3,2) complexes with tetradentate Schiff Base ligand N, N'-bis (salicylidene)-1,4-Butanediamine.View project

paclitaxel production using Taxus tissue cultureView project Ramin Karimian

Chemical Injuries Research Center, Systems biology and poisonings institute, Baqiya…

32PUBLICATIONS 164CITATIONS SEE PROFILE

Milad Aghajani University of Mazandaran 10PUBLICATIONS 36CITATIONS

SEE PROFILE

All content following this page was uploaded by Ramin Karimian on 14 August 2019.

The user has requested enhancement of the downloaded file.

(2)

1266 Current Organic Chemistry, 2019, 23, 1266-1279

REVIEW ARTICLE

1385-2728/19 $58.00+.00 © 2019 Bentham Science Publishers

Cyclodextrins and their Derivatives as Carrier Molecules in Drug and Gene Delivery Systems

Ramin Karimian

^a

and Milad Aghajani

^a,*

aChemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran

Abstract: Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides containing six (α-CD), seven (β-CD), eight (γ-CD) and more glucopyranose units linked with α-(1,4) bonds, having a terminal hydrophilic part and central lipophilic cavity. α-, β- and γ-CDs are widely used in many industrial products, technologies and analytical methods owing to their unique, versatile and tunable characteristics. In the pharmaceutical industry, CDs are used as complexing agents to enhance aqueous solubility, physico-chemical stability and bio-availability of administered drugs. Herein, special attention is given to the use of α-, β- and γ-CDs and their derivatives in different areas of drug and gene delivery systems in the past few decades through various routes of administration with a major emphasis on the more recent developments.

A R T I C L E H I S T O R Y

Received: February 08, 2019 Revised: May 24, 2019 Accepted: May 30, 2019 DOI:

10.2174/1385272823666190627115422

Keywords: Cyclodextrins, host-guest complexation, drug carriers, drug release, drug delivery systems, gene delivery systems.

1. INTRODUCTION

Development of drugs has encountered many problems such as poor aqueous solubility, lack of efficacy and toxicity of the drug. A feasible strategy to overcome these problems is using the water- soluble carriers, enabling encapsulation of hydrophobic drugs in colloidal structures to provide the desirable drug pharmacokinetics and drug interactions to target specific tissue [1, 2]. Among various carriers, CDs have shown great attention since they are valuable carrier for loading the drugs owing to their unique properties [3].

CDs take place the most important and promising macrocyclic hosts category because they are inexpensive, non-toxic, readily functionalized and commercially available. Moreover, they improve the solubility and stability of drugs through the formation of inclusion complexes, enhancing the transdermal absorption of drugs which protects the drug release from the vehicle and undesirable side effects [4]. CDs and their derivatives have a wide variety of practical applications including pharmacy, medicine, formulation of deter- gents, foods, fibers and paper industry, cosmetics, toiletries, cataly- sis, biotechnology, textile industry, etc [5, 6]. However, just a limited number of modified CDs are currently used mainly as pharmaceutical excipients (put reference). Nowadays, many efforts have been undertaken to survey the usability of CDs in novel drug delivery system, controlling the drug release and gene delivery system.

Several pharmaceutical products containing CDs have currently produced and are available commercially as well as some of the drugs formulated with them are listed in Table 1.

*Address correspondence to this author at the Chemical Injuries Research Center, Systems biology and poisonings institute, Baqiyatallah University of Medical Sciences, Tehran, Iran; E-mail: [email protected]

Although many studies have been performed on CDs-based carriers in delivery systems [7-9], however, among them, there are a few recent review articles that discuss CDs and their pharmaceutical applications, specifically, the control release and targeting delivery of anticancer drugs for cancer treatment. According to this, we focus on the current pharmaceutical applications of natural and modified CDs in drug and gene delivery through different delivery routes, in the last decades. In the beginning, we briefly discussed about the structure, properties and toxicological considerations of CDs. Secondly, we outlined the utility of CDs and their derivatives in the development of novel drug and gene delivery systems. In the last section, the recent progress in the anticancer drug delivery systems based on CDs for targeting therapy of tumor by presenting the results of several in vivo and in vitro experiments is presented.

2. HISTORY

For the first time, CDs were discovered in 1891 by Villiers, when he isolated about 3 g of crystalline substance from 1000 g of bacterial digest and determined its composition as (C6H10O5)2·3H2O [10, 11]. The substance has been shown the resistance against the acid hydrolysis which was named “Cellulosine” by Villiers. Later on, in 1903, the Austrian microbiologist Franz Schardinger published an article where he isolated two crystalline materials from the bacterial digest of potato starch which was called dextrins A and B, with a lack of power [12]. Schardinger suggested that “crystalline dextrin” would be a better name than “cellulosine” to identify these compounds. Thereafter, he changed their names to α-dextrin and β-dextrin. Freudenberg and co-workers in the 1930s identified γ-CD (cyclomaltooctaose) and suggested that larger CDs could be existed [13]. They showed that CDs are cyclic oligosaccharides, which are formed by glucose units. Subsequently, the basic physi-

Milad Aghajani

(3)

co-chemical characteristics of CDs including reactivity, cavity size, chemical structure, solubility and their ability to form inclusion complexes with guest molecules were described by Cramer in his book “Einschlussverbindungen” [14]. From 1970s onwards, after many reliable toxicological studies, α-, β- and γ-CDs use as suc- cessful novel pharmacological excipients, right now. Interestingly, the X-ray structures of α, β and γ-dextrins were elucidated in 1942 and 1948, respectively [11].

3. CHEMICAL STRUCTURE, PROPERTIES, AND PRO- DUCTION OF CDS

CDs belong to the family of cyclic oligomers, which are composed of !-(1,4)-linked glucopyranose units in ⁴C1 chair confor- mation [15]. Due to the chair formation of the glucopyranose units, CDs are doughnut-shape molecules consisting of glucopyranose monomers with a hydrophilic terminal moiety and a partly lipo- Table 1. Examples of marketed drugs containing CDs with general uses.

Type of CDs Drug Name Administration Route Trade Name Market

!-CD Cefotiam hexetil hydrochloride Oral Pansporin T Japan

!-CD Benexate hydrochloride Oral Ulgut, Lonmiel Japan

!-CD Dexamethasone Dermal Glymesason Japan

!-CD Nitroglycerin Sublingual Nitropen Japan

!-CD Omeprazole Oral Omebeta Europe

!-CD Nimesulide Oral Nimedex, Mesu Europe

!-CD Piroxicam Oral Brexin Europe

SBE-!-CD Ziprasidone maleate Intramuscular Geodon, Zeldox Europe, USA

SBE-!-CD Voriconazole Intravenous Vfend Europe, USA

HP-!-CD Cisapride Rectal Propulsid Europe

HP-!-CD Indomethacin Eye drop Indocid Europe

HP-!-CD Itraconazole Oral Sporanox Europe, USA

HP-!-CD Mitomycin Intravenous Mitozytrex USA

HP-!-CD Diclofenac sodium Eye drop Voltaren Europe

SBE-β-CD= Sulfobutylether !-cyclodextrin HP-β-CD= 2-Hydroxypropyl-!-cyclodextrin HP-γ-CD= 2-Hydroxypropyl-!-cyclodextrin

Fig. (1). The chemical structure of !-, !-, and !-CDs.

O

HO HO

OH

2 1 3

4 6 5

O

n

n=6, α-CD n=7, β-CD n=8, γ-CD

(4)

philic central cavity. The outside of the molecular cavity is lined by these hydrophilic groups and the inner surface is lined by ether namely anomeric oxygen atoms [16]. Based on the number of glucose units, CDs contain three different types of mean α, β and γ, including six, seven, and eight glucopyranose units, respectively (Fig. 1) [17].

They grow in two main types of crystal packing including channel and cage structures, depending on the type of CD and guest compound. There is a hydrogen bonding between the 2-OH and 3- OH groups around the outer moiety in which these bonds are weak- est in α- and strongest in γ-CD. Using the specific precipitation agents including n-octanol, toluene, and cyclohexa dec- 8-en-1-one for α-, β- and γ-CD, respectively, they can be separated from the reaction mixture with high purity. However, higher oligomers might be separated by chromatographic methods because of the missing precipitation agents availability [16].

The solubility of α-, β- and γ-forms in water was determined to be 145, 18.6 and 232 mg/mL, respectively. Because of intramolecu- lar hydrogen bond formation, !-form has the lowest water solubility than others. This low water solubility limits their applications since the complex formation with lipophilic compounds frequently results in the precipitation of solid CD complexes, thus, a number of strategies have been reported to improve the physiological solubility of this polysaccharide [18, 19]. However, the aqueous solubility of natural CDs is often much lower than the linear or branched dextrins. The central cavity of CDs is relatively hydrophobic, whereas the outer surface shows a hydrophilic behavior. The inner diameter of the cavity in unmodified CDs ranges from ~ 4.7 to 8.3

Å, depending on the ring-size which is around 8 Å in depth [20].

These unique dimensions allow for the inclusion of several guest molecule types bearing appropriate size to form inclusion complexes. In contrast with γ-form, the natural α- and β-forms cannot be hydrolyzed by human salivary and pancreatic amylases. The main properties of natural CDs are summarized in Table 2. As a result of its molecular shape, structure and properties, CD exhibits the unique ability to trap a guest molecule inside its cavity and act as a molecular container.

In aqueous solutions, CDs are able to form inclusion complexes with many drugs by taking up the drug molecule or some lipophilic moieties of the molecule, into the central cavity [21]. No covalent bonds are formed or broken during the complex formation and the drug molecules in complex are in rapid equilibrium with free molecules in the solution. The ability of a guest molecule to enter a CD cavity depends on several factors, including the cavity dimensions, the binding forces involved and the composition of the aqueous complexation media. The ratio of “host-guest” complex is mostly 1:1, 1:2, 2:1 or 2:2 [22, 23]. The most common modes of inclusion complexation are shown in Fig. (2).

The reaction between starch and amylase from Bacillus macer- ans yields a mixture of α- (∼60%), β- (∼20%) and γ- CD (∼20%) together with small amounts of CD with more than eight glucose units[5]. The above mixture was very difficult to purify and it often contains several other linear and branched dextrins together with small amounts of proteins and other impurities. As another ad- vanced method that accomplished in the 1970s, CDs are obtained by the action of enzymes like CGTase and α-amylases on starch. In Table 2. Physical properties of the natural CDs.

!-CD !-CD !-CD

Other names - Cyclohexaamylose

- !-Schardinger dextrin - Cyclomaltohexaose

- Cycloheptaamylose - !-Schardinger dextrin

- Cyclomaltoheptaose

- Cyclooctaamylose - !-Schardinger dextrin

- Cyclomaltooctose

Physical appearance white powder white powder white powder

Number of glucose units 6 7 8

Empirical formula C36H60O30 C42H70O35 C48H80O40

Molecular weight (g/mol) 972 1135 1297

Solubility in water (mg/mL) at 25 ^oC 145 18.5 232

Outer diameter (Å) 14.6 15.4 17.5

Cavity diameter (Å) 4.7-5.3 6.0-6.5 7.5-8.3

Height of torus (Å) 7.9 7.9 7.9

Cavity volume (Å³) 174 262 427

Hydrolysis by !-amylase Negligible Slow Rapid

(5)

this way, starch is firstly liquefied by heating or adding α-amylase.

This step is followed by the addition of CGTase, synthesizing all forms of CDs in different ratios that are dependent on the kind of used enzyme. Finally, the three forms of CDs can be easily purified and separated by utilizing their different aqueous solubility. The α- form can be easily separated by crystallization since it has very low water solubility. The other two forms purify by chromatography or addition of complexing agents like toluene and ethanol [5].

4. TOXICOLOGICAL EVALUATIONS

All toxicity studies have demonstrated that hydrophilic CDs are considered non-toxic when administered in low to moderate doses by oral and intravenous routes due to the lack of absorption from the gastrointestinal tract. The α-form is well-tolerated when administered orally and is not associated with significant adverse effects.

However, a small fraction of the α-form is absorbed intact from the gastrointestinal tract and is chiefly excreted unchanged in the urine following intravenous administration [24]. The β-form cannot be used in parenteral formulations because of its low aqueous solubility and nephrotoxicity. However, it is nontoxic when administered orally [25]. Acute toxicity studies after oral, subcutaneous, intravenous and intraperitoneal administration of γ-form in animal exhibited no signs of toxicity and it does not cause genetic damage, lead- ing cell mutations and cancer. As well as, the toxicity after ophthalmic, dermal and pulmonary administration revealed that γ-form is safe [26]. Short-term toxicity investigation after intravenous administration of γ-form revealed fully reversible pulmonary histio- cytosis, partially reversible hyperplasia of the urinary bladder mucosa and reversible absorption vacuolation in the renal tubular epithelium. The increase of serum creatinine suggests that high dose of intravenously administered γ-form may cause a slight impairment of the renal function [26]. Hence, the recommended dose for daily intravenous administration of γ-form without adverse effects is ca.

120-200 mg/kg.

5. USE OF CDS AND THEIR DERIVATIVES IN DRUG DE- LIVERY SYSTEMS

Drug delivery is the method of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals.

Current research areas of drug delivery include the development of targeted delivery, in which the drug is only active in the target area of the body and sustains release formulations and drug releases over a period of time in a controlled manner from a formulation. CDs can serve as potential candidates for efficient and precise delivery of drugs to the targeted site. They are excellent natural molecular containers due to the proper size of the cavity, non-toxicity, good water-solubility and high biological availability, which can form host-guest inclusion complex with many drugs [27-29].

In this section, the applications of CD and their derivatives in different areas of drug delivery, particularly in oral, ocular, nasal, dermal, rectal, pulmonary and other novel drug delivery systems are explained.

5.1. Oral Drug Delivery System

Since ancient times, oral route has been the most common way for designing a drug delivery system. Now, oral administration of inclusion complexes of CDs with many poorly water-soluble drugs is possible because of the fact that CD unlike γ-form cannot be hydrolyzed by human saliva [30]. The CDs are assumed to act only as a carrier and thereby help to transport the drug through an aqueous medium to the lipophilic absorption surface in the gastrointestinal tracts. Regarding, hydrophilic CDs have been particularly use- ful. In the oral delivery, the release of the drug is as following: dis- solution controlled, diffusion controlled, osmotically controlled, density controlled or pH controlled [31]. Some of the important characteristics of CD and derivatives for oral delivery purposes are:

decrement of local GI tract irritation or bitter taste of drugs and modifying their bio-availability [32, 33]. Recently, CDs as excipients have been employed widely in pharmaceutical formulations for Fig. (2). Schematic illustration of the most common inclusion complexes between CDs and guest (updated from reference [23]).

+

CD Guest

1:1 1:2

2:1 2:2

(6)

the oral delivery of various drugs including piroxicam [34], triclosan [35], flurbiprofen [36], paclitaxel [37], flavonoid diocletian [38], cilostazol [39], efavirenz [40], diclofenac [41], glibenclamide [42], etc. In the recent work, Lakkakula et al. have developed a cationic-β-cyclodextrin (Cat-β-CD) along with alginate and chitosan petals (Cat-β-CD/Alg-Chi nanoflowers) as efficient carriers for the oral delivery of 5-Fluorouracil (5-FU). In vitro release of 5- FU from the loaded nanoflowers showed controlled and sustained release compared to the inclusion complex alone (Fig. 3) [43].

CDs and their derivatives have been also used in oral hygiene products to bind large sized malodorous compounds residing in the mouth [44].

5.2. Ocular Drug DeliverySystem

In the ophthalmology field, drug formulations are used mainly for two purposes, (1) creating intraocular treatment throughout the cornea for diseases, and (2) treating the outside of the eye for infec- tions. Eye drops are the common drug dosage forms for use in ophthalmic formulations. However, the main problem in ophthalmic drug delivery is the rapid drug loss caused by drainage and high tear fluid. Another problem with eye drops is its inability to sustain high concentration of drugs. The drug must penetrate to the eye via conjunctiva, cornea or sclera membranes. These membranes are surrounded by an aqueous tear fluid and by a mucin layer. Hence, ophthalmic drugs should be water-soluble to penetrate the exterior surface of the eye, but at the same time, they should display enough lipophilicity to penetrate the ocular barrier into the eye. Based on the aforementioned, a suitable choice for this purpose is the use of CDs. They can be enabled to deliver the entrapped hydrophobic drugs directly to the ocular surface, after the passage of the mucin layer. The feasible advantages of CDs in ocular uses are increasing the solubility, stability, corneal permeability and also avoidance of incompatibilities of drugs such as irritation and discomfort [45].

Generally, 2-Hydroxypropyl-β- CD and sulfobutyl-β- CD, have shown no toxicity to the eye and are well-tolerated in aqueous eye drop formulations. For example, Granero and co-workers have reported a multicomponent complex with hydroxypropyl-β- CD and triethanolamine in order to enhance the ocular bio-availability of acetazolamide [46]. In vitro corneal permeation studies demonstrated that the acetazolamide permeation was increased. Additionally, Mahmoud et al. have developed a Chitosan/sulfobutylether-β-CD NPs for the ocular drug delivery system [47]. In this work, Econa- zole was the chosen model drug and the encapsulation efficiency was 13-45%.

5.3. Nasal Drug Delivery System

The use of nasal mucosa for transporting drugs is a novel approach for the systemic delivery of high potency drugs with a low oral bio-availability. The nasal route is one of the most efficient ways to bypass first-pass metabolism. In order to enter the systemic circulation, the drug must to dissolve in the aqueous nasal fluids [48]. In nasal formulations, CDs are mostly used to increase the penetration and aqueous solubility of lipophilic drugs. On the other hand, nasal preparations must be critically evaluated for their possible effects on the mucociliary functions. Conversely, steroids free;

the CD complexes did not present any effects on the epithelial membranes because their cavities are shielding the intrinsic toxicity of the included molecules. They can also improve the drug bio- availability and help to bypass the nasal barrier [49, 50]. Hence, the local toxicity of CDs after nasal administration is very low.

Al Omaria et al. have reported a novel inclusion complex of ibuprofen tromethamine with native CDs and 2-Hydroxypropyl-β- CD with guest-host interactions [51]. The results have shown that complexation of the drug with natural or modified CDs reduced irritant effects on the oral cavity, throat, and pharynx, while the drug without CD exhibited these unpleasant problems [51]. There- fore, promising results from nasal delivery of insulin [52], dihydroergotamine [53], benzodiazepines [54], heparins [55], and ondansetron [56] have been reported. The chemical structure of some of these compounds is presented in Fig. (4).

5.4. Dermal Drug Delivery System

Dermal drug delivery is a sophisticated and more reliable means of administering the drug through the skin, for local and systemic action, which has gained popularity in the past decade. A suitable drug with high performance should possess at least five conditions in order to be used in dermal drug delivery system [57]:

(1) it should be neutral therapeutically, (2) it should not interfere in the normal functions of the skin such as protection from heat, hu- midity, radiation and other potential insults, (3) it should not change the pH of the skin, (4) it should not interact with any component of the skin, and (5) it should not cause skin irritation.

The transdermal drug transport and release are restricted by the stratum corneum, representing the main barrier towards the administration of active compounds by this route. Hence, many ways to increase drug absorption have been assayed. In the meantime, CDs have a significant safety margin in the dermal application and can be used to optimize the transdermal delivery of drugs intended for Fig. (3). Schematic illustration of the inclusion complex (Cat-β-CD/5-FU) formation and its encapsulation within Alginate/Chitosan nanoflowers (updated from reference [43]).

(7)

both local and systemic use. They enhance drug delivery through aqueous diffusion barriers, but not through lipophilic barriers like stratum corneum. They have been also used to reduce the permeability of compounds into the skin [58]. In recent years, various kinds of chemically modified CDs have been prepared in order to optimize the dermal delivery and increase the solubility and stability of drugs. For example, Lopez and co-workers have investigated the effect of complexation between dexamethasone as drug and 2- Hydroxypropyl-β-CD as a carrier on the in vitro permeation through hairless mouse skin and on skin metabolism [59]. The results showed that an increase in the solubility of dexamethasone without needing any tertiary agent [59]. In another example, Maes- trellia et al. have developed an efficient formulation of ketoprofen as drug and 2-Hydroxypropyl-β-CD with the combined approach of CD complexation and entrapment in liposomes [60]. Ketoprofen is an analgesic used for the treatment of osteoarthritis, but, unfortu- nately, it has low water solubility. Meanwhile, when administered by the oral path, it exhibits a gastrointestinal irritation. To overcome such problems, transdermal administration has been used as an interesting alternative [60]. As a consequence, CDs and their derivatives are appropriate carriers for the delivery of dermal drugs and due to their high molecular weights; they are not absorbed through the skin.

5.5. Use In Other Drug Delivery Systems

Application of CDs and their derivatives in various other drug delivery systems such as rectal drug delivery [61], pulmonary drug delivery [62], and design of some novel delivery systems like liposomes [63, 64], microspheres [65], microcapsules [66], osmotic

pump [67], specific site targeting [68, 69], nanogels [70], and nanoparticles [71, 72] have also been investigated. For instance, in the field of rectal drug delivery, a large number of reports have shown that rectal mucosa can be used as a potential site for delivering drugs which have a bitter and nauseous taste with a high first-pass metabolism. Rectal drug delivery is an ideal way to deliver drugs to the unconscious patients, patients with nausea, swallowing, or vom- iting, children and infants. At the same time, systems based on CD- nanoparticles are stable and suitable to provide the targeted drug delivery and to enhance the efficacy and bio-availability of poorly soluble drugs [73-75]. In the field of novel delivery systems, Gao et al., have used β-Cyclodextrin/chitosan nanoparticles (β-CD/CS NP) for oral protein delivery of ovalbumin (OVA) as a model antigen (Fig. 5) [76]. Oral protein delivery provides an alternative way for immunization with good compliance and elicits immune responses at mucosal surfaces of the intestine. In vivo assessment results showed that OVA loaded CD/CS nanoparticles could enhance its efficacy for inducing intestinal mucosal immune response [76].

It is noteworthy that research in this area is growing rapidly and it has a promising perspective. As a conclusion, the prepared novel delivery systems using CD/drug complexes would have a dual advantage containing CD complexation ability in parallel with the potential of inherent properties of the novel delivery system.

6. USE OF CDS AND THEIR DERIVATIVES IN GENE DE- LIVERY SYSTEMS

Gene delivery is a process by which outer DNA or RNA is transferred to host cells for applications such as genetic research or Fig. (4). Some of used drugs in combination with CDs in nasal delivery.

O O CH₃

OH HO

H₃N CH₃

H₃C

Ibuprofen tromethamine

R⁷ N

N R² R¹

R^2'

Benzodiazepine

Ondansetron N

O N N

dihydroergotamine N

N O

H HO O

O NH

N

H

NH O

(8)

gene therapy. Gene delivery methods could be mechanical, chemical or biological. Non-viral gene delivery was first reported on in 1943 by Avery et al. who showed cellular phenotype change via exogenous DNA exposure. Among the various non-viral carriers considered and tested for gene delivery, CDs have demonstrated great potential as a gene carrier. In recent years, dramatic ad- vancemnets have been made in the development of native CDs as gene carriers owing to their low toxicity, non-immunogenicity, excellent hydrophobic cavity, and versatile attachment sites [77- 80].As already mentioned, CDs can be appealing to gene delivery applications because not only of their binding affinity to nucleic acids [81], but also of their ability to attenuate the cytotoxicity of other gene carriers. However, due to their failure to form stable complexes with plasmid DNA [82], native CDs have limited trans-

fection efficiency. To overcome the aforementioned problems, CDs are usually derived or so-called modified prior to their use in gene transfer. In this area, a good example of CDs derivatives is polycationic amphiphilic CDs. With fine adjustment of the molecular parameters such as charge density, hydrophilic-hydrophobic bal- ance, nature of the functional groups, and spacer length, the DNA complexation capacity and transfection efficiency of polycationic amphiphilic CDs can be modulated [83, 84]. This section is mainly concerned with the latest applications of CDs in gene delivery systems.

Agrawal’s team was one of the first who investigated the use of CDs and their analogs in facilitating cellular uptake of oligonucleotides [85]. In the following, Abdou et al. evaluated the ability of various native and derivatized CDs to enhance the action of an 18- Fig. (5). The possible formulation mechanism of OVA loaded β-CD/CS nanoparticles (updated from reference [76]).

Fig. (6). linear β-CD-containing polymer and their use in nucleic-acid therapeutics. AD-PEG and AD-PEG-Tf denote adamantane conjugated to PEG and adamantane and transferrin conjugated to PEG, respectively (updated from reference [89]).

(9)

mer phosphodiester oligodeoxynucleotide (which is complementary to the initiation region of the mRNA coding for the spike protein) against viral growth in human adenocarcinoma cells [86]. Pun and Davis modified the surface β-form containing polycations and nucleic acids (plasmids, oligonucleotides) with polyethylene glycol (PEG)-containing compounds by terminating the PEG chains with adamantane (AD) that form inclusion complexes with CDs on the particle surfaces (Fig. 6) [87, 88]. This procedure has been developed for CD-grafted PEI133 and shown to produce delivery vehi- cles that can target tissues in mice with either plasmids or oligonucleotides [89].

In another work, a CD-based polymer (CALAA-01) loaded with siRNA entered phase I clinical trials by Davis for the first time, and its safety and efficacy for the treatment of solid tumors in humans was verified (Fig. 7) [90].

Alonso et al., have used chitosan CD NPs for gene delivery into the airway epithelium. In this work, the two aqueous solutions con-

sisting of chitosan solution and sulfobutylether-β- CD solution (SBE-β-CuD) were mixed under magnetic stirring. Loading of CD/TPP phase was done with pSEAP (plasmid DNA model that encodes the expression of secreted alkaline phosphatase). The particles showed a size range of 100–200 nm and very high DNA association efficiency values of more than 90%. The formation of NPs was due to the combined effect of electrostatic interaction between chitosan and CDs (oppositely charged) and the ability of chitosan to undergo a liquid-gel transition due to its ionic interaction with TPP (tripolyphosphate) [91]. However, with “host-guest chemistry”

feature of CDs, several studies have employed CD-based vectors as non-viral gene delivery systems in these days. For example, Lee et al. have investigated the host-guest concept to form a supramolecular nano-complex for targeted imaging and gene delivery (Fig. 8) [92].

According to the authors' claim, the best advantage of this strategy is that the systems are very easy to handle, do not involve tedi- Fig. (7). Schematic representations of a CD-containing polymer (CDP), a polyethylene glycol (PEG) steric stabilization agent, and human transferrin (Tf) as a targeting ligand for binding to transferrin receptors (TfR) (updated from reference [90]).

Fig. (8). Illustration of the multifunctional nanoparticles developed via host–guest interaction for targeted imaging and controllable DNA delivery (updated from reference [92]).

PEI-‐CyD

Bioimaging FITC

Targeting moiety Others (e.g., biopharamaceuticals) 1)

2) 3)

Functional tags

+

Host-guest intractions

DNA

Targeting moiety for cellular uptake

Fluorescent dye for imaging

Light-‐regulated iinker for efficient DNA release

(10)

ous chemical reactions and can be flexibly optimized by changing the functional tags responding to a request.

In another example, Hu and colleagues modified the CD-core star-shaped pDMAEMA (as a host) nanoparticles with PEG and an adamantyl end (as a guest) called PEGylation via supramolecular assembly approach host-guest interaction. Adamantyl groups are known to form strong inclusion complexes with CDs. These de- signed polyplexes containing the p53 gene reduced tumor growth in mice, and reduced tumor weight by approximately 50% compared to the control treatment lacking PEGylation. Such supramolecular pseudo-blockcarriers would offer a new plan for designing and developing low-toxic and high-efficient in vitro and in vivo gene delivery systems. CD coating with PEG improves water solubility, reduces aggregation, serum stability and decreases the opsonization process during blood circulation [93].

CDs and theirderivatives cannot be only used directly for gene delivery after derivatization but also they have been used as linking agents or structural modifiers for the development of gene carriers [79]. One example in this field was synthesized by linking poly(ethylenimine) (PEI) with β-form by using tosyl chloride to first generate aminereactive tosyldeoxy-β-CD, which subsequently reacted with PEI to generate the CD-PEI conjugate (PEI-β-CD) (Fig. 9).

In vitro investigation indicated that PEI-β-CD was essentially non-toxic to HEK293 cells at the working concentration for pDNA delivery. Compared to unmodified PEI, PEI-β-CD induced approximately 4-fold higher luciferase expression [94].

In another case, Huang et al. cross-linked PEI by using (2- hydroxypropyl)-β- CD and (2-hydroxypropyl)-γ-CDs [95]. The two resulting polymers represented lower cytotoxicity than PEI 25 kDa, and had transfection efficiency in SKOV-3 cells. Moreover, another example of the use of CDs as structural modifiers was reported by Uekama and his research team [96]. They synthesized the starburst polyamidoamine dendrimer conjugates with α-, β-, and γ-forms, expecting the synergistic effect of dendrimer and CDs. The aforementioned conjugates could condense pDNA and protect it from DNase I-mediated degradation. In vitro studies showed that α-form conjugate had higher transfection efficiency than conjugates with β- and γ- CDs. Its transfection efficiency in NIH3T3 and RAW264.7 cells was superior to Lipofectin and was 100-fold higher than that of the unmodified dendrimer [96]. Similarly, Arima and co-workers have reported a polyamidoamine starburst dendrimer conjugate with lactose-bearing α-formwith various degrees of substitution of the lactose moiety and use it as a selective DNA carrier (Fig. 10) [97].

Fig. (9). Scheme for synthesis of cyclodextrin-EI (CD-PEI). β-CD is tosylated with tosyl chloride to yield 1. Compound 1 was then purified and reacted with 25-kDa, branched PEI to yield 2, exhibiting ~10% of amines linked to CDs (updated from reference [94]).

Fig. (10). Chemical structure of Lac-α-CD. One of the primary hydroxyl group of α-CD was covalently bound to the amino group of dendrimer (G2) (updated from reference [97]).

OH

S

O O

Cl CH₃

O S

O

CH₃ HN PEI

+

+ PEI NH₂ pH=13

4 ^oC, 5 min DMSO, TEA

RT, 24 h

CD CD CD

(HO)₅ NH

N N

RHN N

RHN NHR

N

N N RHN

RHN

N RHN NHR

N N

N N HN

RHN NHR

NHR

N

NHR

NHR N

NHR RHN

= -C₂H₄CONHC₂H₄- Dendrimer

R= H or CD

O O HO

OH

OH HO

HO

HO OH HO

Lactose

!-CD

(11)

The conjugated system exhibited higher gene transfection efficiency than unmodified polyamidoamine, lactosylated polyamidoamine and α-formin HepG2 cells.It showed negligible cytotoxicity even up to a carrier/DNA charge ratio of 150/1 and also demonstrated higher transfection efficiency in hepatocytes, 12 h after intravenous administration to mice [97].

Furthermore, Lehr and co-workers introduced a polyrotaxane with β- and α- CD rings threaded onto ionene-6,10 for the cellular delivery of polynucleotides [98]. The results show that the polyrotaxane formed stable complexes with pDNA and with a pDNA/siRNA mixture and it also enhanced cellular uptake of the nucleic acid with the lowest cytotoxicity.

Other strategies for gene delivery applications based on CDs have been reported such as pH-responsive acetylated CD [99], star- shaped nanocomplexes composed of hyaluronic acid [100], chitosan grafting with CD [101], and methylated β- CD nanoparticles [102]. Regarding the increasing knowledge of the practical potential of CDs in gene delivery applications, it is expected that CDs-based gene carriers will increase rapidly in the literature in the forthcom- ing decades.

7. CD-BASED ANTICANCER DRUG DELIVERY SYSTEMS FOR TARGETING THERAPY OF TUMOR

In this section, some of the potential findings and applications of CDs as a carrier for effective delivery of anticancer drugs are briefly discussed.

As we all know, cancers have become one of the most serious threats to human health in the world. Although many traditional drugs have good anticancer activity, they become effective for clinical treatments. Poor water solubility and low biocompatibility of chemotherapeutic agents are among the major hurdles for effective chemotherapy treatment. Also, chemotherapy can cause a series of toxic and side effects on the human body. On the other hand, alt-

hough several techniques like solubilization [103] and solid disper- sion [104, 105] can enhance solubility and bioavailability of anticancer drugs, these methods suffer from various disadvantages such as low drug loading and large dose. Hence, it is necessary to design new drug delivery systems that can convey drugs to tumor tissues safely and effectively. In this regard, an effective way is the use of the combination of CD and nanotechnology (CD-based nanocarriers) in the targeted delivery system to the site of disease [9]. New CD-based nanocarriers such as liposomes, nanosponges [106], nanogels [107], micelles [108, 109], millirods [110], macrocyclic carbohydrate polymer [111], and magnetic nanoparticles [112], are developed in this field. Some of the notable advantages of this combination include improvement in therapeutic efficacy, increasing drug release, increasing shelf life, decrease toxicity, and enhancement retention in tumor cells and drug loading capacity. Re- cently, many attempts carried out to reduce the cytotoxicity and improve the therapeutic efficacy of anticancer drugs. For example, Sol et al. in the year 2016, prepared curcumin-cyclodextrin/cellu- lose nanocrystals by ionic interaction as an anticancer drug delivery [113]. In vitro results showed that these nanocrystals demonstrated enhanced cytotoxic activity against colorectal and prostatic cancer cell lines compared to pure curcumin [113]. Kulkarni and Belgam- war in the year 2017, developed an inclusion complex of chrysin (CHR) with sulfobutyl ether-β-cyclodextrin (SBE-β-CD) [114].

Complexation led to the increase in aqueous solubility and bioavailability of the drug. In addition, in vitro cytotoxicity assay showed appreciable improvement in the anticancer activity of complex compared to free CHR, on MCF-7 and HeLa cell lines [114].

In another work, pH-responsive glycol chitosan-cross-linked car- boxymethyl-β-cyclodextrin nanoparticles have been developed by Wang et al. for the controlled release of doxorubicin (DOX) anticancer drug in the MCF-7 breast and SW480 colon cancer cell lines [115]. Also, in another recent study, Maiti et al. grafted polyure- thane (PU) on α-CD in order to control drug release (Fig. 11) [116].

Fig. (11). Schematic representation for grafting of α-CD on PU (updated from reference [116]).

(12)

Both In vitro and in vivo animal studies confirmed the efficacy of the sustained release of drug from the graft copolymer without side effect for cell killing on melanoma tumor in mice [116].

As a result, CD-based delivery systems are expected to be used to alleviate the pain of patients in the process of cancer therapy.

8. INDUSTRIAL APPLICATIONS OF CDS

CDs and their derivatives are able to form host-guest complexes with hydrophobic molecules given the unique nature imparted by their structure. These molecules have found a number of applications in a wide range of fields [117]. Apart from pharmaceutical applications, they also have various other industrial applications, including textile dyeing and washing processes to remove the absorbed surfactants [118], food ingredients [119, 120], cosmetic products [121], agricultural [26], environmental science [122-126], removal of heavy metals [127-129], adhesive and coating industries [130, 131].

9. SOME LIMITATIONS OF DELIVERY SYSTEMS CON- TAINING DRUG- CD

As mentioned,CDs are used to enhance the aqueous solubility, physico-chemical stability, and bio-availability of drugs and also prevent drug–drug interactions, minimize gastrointestinal and ocular irritation and reduce or eliminate unpleasant taste and smell.

However, all types of drugs are not appropriate substrates for CD complexation. In order for efficient interaction between the drug (as a guest) and CD (as host) for pharmaceutical and medicinal bene- fits, the following features must not be neglected [132]:

 The melting point of the substance is below 250 °C.

 The solubility in water is less than 10 mg/mL.

 Molecular weight is about 100-400.

 The guest molecule consists of less than five con- densed rings.

 More than five atoms (C, P, S, N) form the skeleton of the drug molecule.

 Generally, inorganic compounds are not suitable for complexation.

CONCLUSION-OUTLOOK

In this review, we presented the usability of CDs and their derivatives as efficient carrier in different areas of drug and gene delivery systems in the last decades. Recently, considerable attention of the scientific community has been shifted towards the natural products for their safety and myriads of promising pharmacological effects. Along this line, CDs and their derivatives have been attract- ing more attention in recent years owing to their unique properties and negligible cytotoxic effects. CDs have desirable properties for application in drug/gene delivery systems. The most important property of CDs is the ability to enhance the aqueous solubility, physico-chemical stability, and bio-availability of drugs and encapsulation of various types of molecules through the formation of non-covalently bonded entities, both in solid and aqueous phase.

Besides, CDs and their derivatives can also prevent drug–drug and drug-excipient interactions, minimize ocular and gastrointestinal irritation, or diminish unpleasant taste and smell. It should be noted that cell assays and animal experiments proved that CDs-based targeted drug carriers can deliver antitumor agents to target sites very well. Although CDs can be found in many pharmaceutical products, they are still regarded as novel pharmaceutical excipients

in the researches, as scientific information assessed by the number of papers published on the subject, is rapidly growing.

CONSENT FOR PUBLICATION Not applicable.

AVAILABILITY OF DATA AND MATERIALS Not applicable.

FUNDING None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or other- wise.

ACKNOWLEDGMENTS

The authors acknowledge the Baqiyatallah University of Medical Sciences for financial support of this work (IR.BMSU.REC.1396.457).

REFERENCES

[1] Kumar, P.; Singh, C. A study on solubility enhancement methods for poorly water soluble drugs. Am. J. Pharmacol. Sci., 2013, 1, 67-73.

[http://dx.doi.org/10.12691/ajps-1-4-5]

[2] Singh, R.K.; Kim, H-W. Inorganic nanobiomaterial drug carriers for medicine. Tissue Eng. Regen. Med., 2013, 10, 296-309.

[http://dx.doi.org/10.1007/s13770-013-1092-y]

[3] Conceição, J.; Adeoye, O.; Cabral-Marques, H.M.; Lobo, J.M.S. Cyclodex- trins as excipients in tablet formulations. Drug Discov. Today, 2018, 23(6), 1274-1284.

[http://dx.doi.org/10.1016/j.drudis.2018.04.009] [PMID: 29689302]

[4] Valente, A.J.; Söderman, O. The formation of host-guest complexes between surfactants and cyclodextrins. Adv. Colloid Interface Sci., 2014, 205, 156- 176.

[http://dx.doi.org/10.1016/j.cis.2013.08.001] [PMID: 24011696]

[5] Loftsson, T.; Duchêne, D. Cyclodextrins and their pharmaceutical applications. Int. J. Pharm., 2007, 329(1-2), 1-11.

[http://dx.doi.org/10.1016/j.ijpharm.2006.10.044] [PMID: 17137734]

[6] Radu, C-D.; Parteni, O.; Ochiuz, L. Applications of cyclodextrins in medical textiles - review. J. Control. Release, 2016, 224, 146-157.

[http://dx.doi.org/10.1016/j.jconrel.2015.12.046] [PMID: 26796039]

[7] Rasheed, A. Cyclodextrins as drug carrier molecule: A review. Sci. Pharm., 2008, 76, 567-598.

[http://dx.doi.org/10.3797/scipharm.0808-05]

[8] Tiwari, G.; Tiwari, R.; Rai, A.K. Cyclodextrins in delivery systems: Applica- tions. J. Pharm. Bioallied Sci., 2010, 2(2), 72-79.

[http://dx.doi.org/10.4103/0975-7406.67003] [PMID: 21814436]

[9] Gidwani, B.; Vyas, A. A comprehensive review on cyclodextrin-based carriers for delivery of chemotherapeutic cytotoxic anticancer drugs. BioMed Res. Int., 2015, 2015, 198268.

[http://dx.doi.org/10.1155/2015/198268] [PMID: 26582104]

[10] Szejtli, J. Past, present and futute of cyclodextrin research. Pure Appl.

Chem., 2004, 76, 1825-1845.

[http://dx.doi.org/10.1351/pac200476101825]

[11] Crini, G. Review: A history of cyclodextrins. Chem. Rev., 2014, 114(21), 10940-10975.

[http://dx.doi.org/10.1021/cr500081p] [PMID: 25247843]

[12] Schardinger, F. Über thermophile Bakterien aus verschiedenen Speisen und Milch. Z. Unters. Nahr. Genussm., 1903, 6, 865-880.

[http://dx.doi.org/10.1007/BF02067497]

[13] Freudenberg, K.; Cramer, F. Die konstitution der schardinger-dextrine α, β und γ. Z. Naturforsch. B: Chem. Sci., 1948, 3, 464-466.

[14] Cramer, F. Einschlussverbindungen, Berlin Springer: 1954, [http://dx.doi.org/10.1007/978-3-642-49192-4]

[15] Zhou, J.; Ritter, H. Cyclodextrin functionalized polymers as drug delivery systems. Polym. Chem., 2010, 1, 1552-1559.

[http://dx.doi.org/10.1039/c0py00219d]

[16] Zafar, N.; Fessi, H.; Elaissari, A. Cyclodextrin containing biodegradable particles: From preparation to drug delivery applications. Int. J. Pharm., 2014, 461(1-2), 351-366.

(13)

[17] Challa, R.; Ahuja, A.; Ali, J.; Khar, R.K. Cyclodextrins in drug delivery: An updated review. AAPS Pharm. Sci. Tech., 2005, 6(2), E329-E357.

[http://dx.doi.org/10.1208/pt060243] [PMID: 16353992]

[18] Szente, L.; Szejtli, J. Highly soluble cyclodextrin derivatives: Chemistry, properties, and trends in development. Adv. Drug Deliv. Rev., 1999, 36(1), 17-28.

[http://dx.doi.org/10.1016/S0169-409X(98)00092-1] [PMID: 10837706]

[19] Saokham, P.; Muankaew, C.; Jansook, P.; Loftsson, T. Solubility of cyclodextrins and drug/cyclodextrin complexes. Molecules, 2018, 23(5), 1161.

[http://dx.doi.org/10.3390/molecules23051161] [PMID: 29751694]

[20] Saenger, W.; Jacob, J.; Gessler, K.; Steiner, T.; Hoffmann, D.; Sanbe, H.;

Koizumi, K.; Smith, S.M.; Takaha, T. Structures of the common cyclodextrins and their larger analogues beyond the doughnut. Chem. Rev., 1998, 98(5), 1787-1802.

[http://dx.doi.org/10.1021/cr9700181] [PMID: 11848949]

[21] Martín, V.I.; Ostos, F.J.; Angulo, M.; Márquez, A.M.; López-Cornejo, P.;

López-López, M.; Carmona, A.T.; Moyá, M.L. Host-guest interactions between cyclodextrins and surfactants with functional groups at the end of the hydrophobic tail. J. Colloid Interface Sci., 2017, 491, 336-348.

[http://dx.doi.org/10.1016/j.jcis.2016.12.040] [PMID: 28056443]

[22] Song, L.X.; Bai, L.; Xu, X.M.; He, J.; Pan, S.Z. Inclusion complexation, encapsulation interaction and inclusion number in cyclodextrin chemistry.

Coord. Chem. Rev., 2009, 253, 1276-1284.

[http://dx.doi.org/10.1016/j.ccr.2008.08.011]

[23] Linde, G.A.; Laverde, A.; Colauto, N.B. Changes to taste perception in the food industry: use of cyclodextrins In: Handbook of Behavior, Food and Nu- trition, Victor R. Preedy, Ronald Ross Watson, Colin R. Martin; Preedy, R .V.; Watson, R.R. Martin, C.R. Ed.; Springer: 2011, 99-118.

[http://dx.doi.org/10.1007/978-0-387-92271-3_8]

[24] Jambhekar, S.S.; Breen, P. Cyclodextrins in pharmaceutical formulations I:

Structure and physicochemical properties, formation of complexes, and types of complex. Drug Discov. Today, 2016, 21(2), 356-362.

[http://dx.doi.org/10.1016/j.drudis.2015.11.017] [PMID: 26686054]

[25] Gould, S.; Scott, R.C. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD): A toxi- cology review. Food Chem. Toxicol., 2005, 43(10), 1451-1459.

[http://dx.doi.org/10.1016/j.fct.2005.03.007] [PMID: 16018907]

[26] Saokham, P.; Loftsson, T. γ-Cyclodextrin. Int. J. Pharm., 2017, 516(1-2), 278-292.

[27] Kamada, M.; Hirayama, F.; Udo, K.; Yano, H.; Arima, H.; Uekama, K.

Cyclodextrin conjugate-based controlled release system: Repeated- and pro- longed-releases of ketoprofen after oral administration in rats. J. Control. Re- lease, 2002, 82(2-3), 407-416.

[http://dx.doi.org/10.1016/S0168-3659(02)00171-2] [PMID: 12175753]

[28] abr-Milane, L.; van Vlerken, L.; Devalapally, H.; Shenoy, D.; Komareddy, S.; Bhavsar, M.; Amiji, M. Multi-functional nanocarriers for targeted delivery of drugs and genes. J. Control. Release, 2008, 130, 121-128.

[http://dx.doi.org/10.1016/j.jconrel.2008.04.016]

[29] Thiele, C.; Auerbach, D.; Jung, G.; Qiong, L.; Schneider, M.; Wenz, G.

Nanoparticles of anionic starch and cationic cyclodextrin derivatives for the targeted delivery of drugs. Polym. Chem., 2011, 2, 209-215.

[http://dx.doi.org/10.1039/C0PY00241K]

[30] Loftsson, T.; Brewster, M.E.; Masson, M. Role of cyclodextrins in improv- ing oral drug delivery. Am. J. Drug Deliv., 2004, 2, 261-275.

[http://dx.doi.org/10.2165/00137696-200402040-00006]

[31] Zhang, J.; Ma, P.X. Cyclodextrin-based supramolecular systems for drug delivery: Recent progress and future perspective. Adv. Drug Deliv. Rev., 2013, 65(9), 1215-1233.

[http://dx.doi.org/10.1016/j.addr.2013.05.001] [PMID: 23673149]

[32] Szejtli, J.; Szente, L. Elimination of bitter, disgusting tastes of drugs and foods by cyclodextrins. Eur. J. Pharm. Biopharm., 2005, 61(3), 115-125.

[http://dx.doi.org/10.1016/j.ejpb.2005.05.006] [PMID: 16185857]

[33] Carrier, R.L.; Miller, L.A.; Ahmed, I. The utility of cyclodextrins for enhancing oral bioavailability. J. Control. Release, 2007, 123(2), 78-99.

[34] Laza-Knoerr, A.L.; Gref, R.; Couvreur, P. Cyclodextrins for drug delivery. J.

Drug Target., 2010, 18(9), 645-656.

[http://dx.doi.org/10.3109/10611861003622552] [PMID: 20497090]

[35] Dinge, A.; Nagarsenker, M. Formulation and evaluation of fast dissolving films for delivery of triclosan to the oral cavity. AAPS Pharm. Sci. Tech., 2008, 9(2), 349-356.

[http://dx.doi.org/10.1208/s12249-008-9047-7] [PMID: 18431674]

[36] Tokumura, T.; Muraoka, A.; Machida, Y. Improvement of oral bioavailability of flurbiprofen from flurbiprofen/β-cyclodextrin inclusion complex by action of cinnarizine. Eur. J. Pharm. Biopharm., 2009, 73(1), 202-204.

[37] Agüeros, M.; Ruiz-Gatón, L.; Vauthier, C.; Bouchemal, K.; Espuelas, S.;

Ponchel, G.; Irache, J.M. Combined hydroxypropyl-β-cyclodextrin and poly(anhydride) nanoparticles improve the oral permeability of paclitaxel.

Eur. J. Pharm. Sci., 2009, 38(4), 405-413.

[http://dx.doi.org/10.1016/j.ejps.2009.09.010] [PMID: 19765652]

[38] Rezende, B.A.; Cortes, S.F.; De Sousa, F.B.; Lula, I.S.; Schmitt, M.; Sinis- terra, R.D.; Lemos, V.S. Complexation with β-cyclodextrin confers oral activity on the flavonoid dioclein. Int. J. Pharm., 2009, 367(1-2), 133-139.

[39] Patel, S.G.; Rajput, S.J. Enhancement of oral bioavailability of cilostazol by forming its inclusion complexes. AAPS Pharm. Sci. Tech., 2009, 10(2), 660- 669.

[40] Sathigari, S.; Chadha, G.; Lee, Y.H.; Wright, N.; Parsons, D.L.; Rangari, V.K.; Fasina, O.; Babu, R.J. Physicochemical characterization of efavirenz- cyclodextrin inclusion complexes. AAPS Pharm. Sci. Tech., 2009, 10(1), 81- 87.

[41] Miro, A.; Rondinone, A.; Nappi, A.; Ungaro, F.; Quaglia, F.; La Rotonda, M.I. Modulation of release rate and barrier transport of Diclofenac incorpo- rated in hydrophilic matrices: role of cyclodextrins and implications in oral drug delivery. Eur. J. Pharm. Biopharm., 2009, 72(1), 76-82.

[42] Lucio, D.; Martínez-Ohárriz, M.C.; Gu, Z.; He, Y.; Aranaz, P.; Vizmanos, J.L.; Irache, J.M. Cyclodextrin-grafted poly(anhydride) nanoparticles for oral glibenclamide administration. In vivo evaluation using C. elegans. Int. J.

Pharm., 2018, 547(1-2), 97-105.

[43] Lakkakula, J.R.; Matshaya, T.; Krause, R.W.M. Cationic cyclodextrin/alginate chitosan nanoflowers as 5-fluorouracil drug delivery system.

Mater. Sci. Eng. C, 2017, 70(Pt 1), 169-177.

[http://dx.doi.org/10.1016/j.msec.2016.08.073] [PMID: 27770878]

[44] Lantz, A.W.; Rodriguez, M.A.; Wetterer, S.M.; Armstrong, D.W. Estimation of association constants between oral malodor components and various native and derivatized cyclodextrins. Anal. Chim. Acta, 2006, 557, 184-190.

[http://dx.doi.org/10.1016/j.aca.2005.10.005]

[45] Anand, S.; Braga, V.M.L. Cyclodextrins in Ocular Drug Delivery In: Nano- Biomaterials For Ophthalmic Drug Delivery; Pathak, Y.; Sutariya, V.; Hira- ni, A,A, Ed.; Springer: 2016, , 243-252.

[http://dx.doi.org/10.1007/978-3-319-29346-2_12]

[46] Palma, S.D.; Tartara, L.I.; Quinteros, D.; Allemandi, D.A.; Longhi, M.R.;

Granero, G.E. An efficient ternary complex of acetazolamide with HP-ss-CD and TEA for topical ocular administration. J. Control. Release, 2009, 138(1), 24-31.

[47] Mahmoud, A.A.; El-Feky, G.S.; Kamel, R.; Awad, G.E. Chi- tosan/sulfobutylether-β-cyclodextrin nanoparticles as a potential approach for ocular drug delivery. Int. J. Pharm., 2011, 413(1-2), 229-236.

[48] Djupesland, P.G. Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review. Drug Deliv. Transl. Res., 2013, 3(1), 42-62.

[49] Asai, K.; Morishita, M.; Katsuta, H.; Hosoda, S.; Shinomiya, K.; Noro, M.;

Nagai, T.; Takayama, K. The effects of water-soluble cyclodextrins on the histological integrity of the rat nasal mucosa. Int. J. Pharm., 2002, 246(1-2), 25-35.

[50] Boulmedarat, L.; Bochot, A.; Lesieur, S.; Fattal, E. Evaluation of buccal methyl-β-cyclodextrin toxicity on human oral epithelial cell culture model. J.

Pharm. Sci., 2005, 94(6), 1300-1309.

[http://dx.doi.org/10.1002/jps.20350] [PMID: 15858859]

[51] Al Omari, M.M.; Daraghmeh, N.H.; El-Barghouthi, M.I.; Zughul, M.B.;

Chowdhry, B.Z.; Leharne, S.A.; Badwan, A.A. Novel inclusion complex of ibuprofen tromethamine with cyclodextrins: physico-chemical characterization. J. Pharm. Biomed. Anal., 2009, 50(3), 449-458.

[http://dx.doi.org/10.1016/j.jpba.2009.05.031] [PMID: 19545961]

[52] Zhang, Y.; Jiang, X-G.; Yao, J. Nasal absorption enhancement of insulin by sodium deoxycholate in combination with cyclodextrins. Acta Pharmacol.

Sin., 2001, 22(11), 1051-1056.

[PMID: 11749800]

[53] Marttin, E.; Romeijn, S.G.; Verhoef, J.C.; Merkus, F.W. Nasal absorption of dihydroergotamine from liquid and powder formulations in rabbits. J.

Pharm. Sci., 1997, 86(7), 802-807.

[http://dx.doi.org/10.1021/js960500j] [PMID: 9232520]

[54] Loftsson, T.; Gudmundsdóttir, H.; Sigurjónsdóttir, J.F.; Sigurdsson, H.H.;

Sigfússon, S.D.; Másson, M.; Stefánsson, E. Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray. Int. J. Pharm., 2001, 212(1), 29-40.

[55] Yang, T.; Hussain, A.; Paulson, J.; Abbruscato, T.J.; Ahsan, F. Cyclodextrins in nasal delivery of low-molecular-weight heparins: in vivo and in vitro studies. Pharm. Res., 2004, 21(7), 1127-1136.

[http://dx.doi.org/10.1023/B:PHAM.0000032998.84488.7a] [PMID:

15290851]

[56] Cho, E.; Gwak, H.; Chun, I. Formulation and evaluation of ondansetron nasal delivery systems. Int. J. Pharm., 2008, 349(1-2), 101-107.

[57] Bibby, D.C.; Davies, N.M.; Tucker, I.G. Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems. Int. J. Pharm., 2000, 197(1-2), 1-11.