Calixarenes containing supramolecular vehicles for drug delivery

Calixarenes containing supramolecular vehicles for drug delivery

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Sougata Jana⁎, Kishor Kumar Suryavanshi†, Sabyasachi Maiti‡, Subrata Jana† ⁎ Department of Pharmaceutics, Gupta College of Technological Sciences, Asansol, India, † Department of Chemistry, Indira Gandhi National Tribal University, Amarkantak, India, ‡ Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, India

17.1 Introduction The in vivo therapeutic effectiveness of a drug molecule depends on its physicochemical properties. A drug molecule will function properly in vivo once it reaches the targeted site without losing its desirable properties. In general, the drug molecules reach the specified site after administration, and during their passage, they interact with different biomolecules and biochemical fluids. During this process, many drug molecules are deactivated and as a consequence lose their efficiency. Many potent drug molecules fail at preclinical stage due to their poor solubility, stability, and toxicity. Besides, different criteria have been empirically proposed, based on structure-activity profile for the screening of successful and nonsuccessful drug candidates for their efficient cellular uptake via diffusion through the cell membrane [1]. There is a need for perfect delivery vehicles to surmount the problems of solubility and bioavailability problems of poorly soluble drug as well as to direct an exact amount of drug to the intended target site. A number of drug-delivery approaches have been reported so far to overcome this transport problem [2–11]. In recent years, smart supramolecular architectures-based drug-delivery approaches are being utilized for precise delivery to the targeted location [12, 13]. In this approach, drug molecules interact with carrier through different noncovalent forces such as electrostatic interactions, hydrogen bonding, cation-π, π-π stacking, and metalligand binding. Besides, weak van der Waals attraction and solvent reorganization also play a crucial role in drug-host carrier interaction [14–16]. The concept of supramolecular chemistry has led to the development of different drug carrier systems, which have shown a tremendous potential toward their practical application in the field of drug delivery [17,18]. This approach is useful in that it can enhance the solubility of nonpolar drug as well as promote the delivery of drug molecules through cellular barrier. The drug molecules also remain safe in terms of crucial stereochemical aspects in the supramolecular host system. Now cage-type molecules are being incorporated to nanoparticulate drug carriers, which could further enhance the drug entrapment efficiency by forming strong host-guest interactions, and reduce the ­possibility of

Polysaccharide Carriers for Drug Delivery. https://doi.org/10.1016/B978-0-08-102553-6.00017-9 Copyright © 2019 Elsevier Ltd. All rights reserved.

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u­ ncontrolled drug release (phenomenon called burst effect) due to a lack of affinity between the drug and its carrier [19,20]. Many molecules and its synthetic modified forms have been studied as molecular hosts for the recognition of wide range of guest molecules that include crown ethers, cavitands, cyclodextrins, cucurbiturils, calixarenes, cryptophanes, spherands, cryptands, carcerands, clathrates, dendrimers, metalloporphyrins, and metal-organic frameworks [21–31]. All these class of supramolecular hosts find massive application in the field of drug delivery. Calix[n]arenes are macrocycles-containing polyphenolic units that have received lot of attention from the scientific community for their diverse applications in the fields of material science, drug-delivery technology, and biomedical engineering [32,33]. The word “Calixarene” originates from calix or chalice because this type of molecule resembles a vase and the word “arene” refers to the aromatic building block (macrocyclic or cyclic oligomers) and is formed by the condensation of aldehydes and phenols [34,35]. In this chapter, we focus on the drug-delivery aspects using calix[n]arene-based supramolecular system.

17.2 Structural feature of calixarene Calix[n]arenes (CAs) are macrocyclic molecules synthesized from phenol, and each of them is linked through methylene bridges, which forms a central cavity. In CAs, ­methylene-bridged phenol units form conical cavitations having upper and lower rims and are capable of forming guest–host inclusion complexes. CAs are normally synthesized by the reaction of para-substituted phenols with formaldehyde under basic or acidic condition. In general synthetic route, p-tert-butyl-calix[n]arene is the starting material, which is then chemically modified both in lower and upper rims. CAs with n equal to 4, 6, and 8 can be prepared by one-step synthetic routes and easily be purified. It is named as calix[n]arene, where n is the number of phenol units present in the macrocyclic unit [36]. Between upper and lower rims, there are aromatic rings called central annulus. It is hydrophobic in nature and helps to recognize less polar or nonpolar part of the drug molecules. Initially tert-butyl groups present at the upper rim of CAs are easily dealkylated and different other groups can be installed as per the need in designing the host. On the other hand, lower rim has four phenolic –OH groups, which may be substituted with alkyl chain having different other functional moieties (Fig. 17.1).

R2

R2

R2

R2

Central annulus

n O R1

O R1

O R1

Upper rim

O R1

n = 1, 2, 3, 4, 5, 6

Fig. 17.1  General structure of the calix[n]arene molecule.

Lower rim

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The interesting feature of the CAs is that it can orient in four different conformations and each conformation can be functionalized either through aromatic rings and phenolic moieties based on requirement. These are cone, partial cone, 1,2-alternate, and 1,3-alternate [37,38]. In major cases, CAs are present in its cone conformation. In current form, specific synthetic modification is being carried out at both the rims. This conformation is obtained when all the phenolic hydroxyl groups remain either free or hydrogen bonded with each other [39,40]. The other way to lock the flipping of aromatic unit is O-alkylation with larger alkyl group than propyl group. These are two common protocols to lock the CA cavity in cone conformation, which are applied to synthesize supramolecular host. Other conformations are obtained during synthetic modification with smaller alkyl (methyl, ethyl, and propyl) groups in the phenolic OH groups. In some cases, selective or partial O-alkylation could be accomplished to obtain the conformations other than cone [41]. The most interesting structural feature of the common cone conformations of the CA is the bowl-shaped cavity capable of including a variety of guests (Fig. 17.2). The cavity has two openings, with the one at the lower rim, which is comparatively smaller than that of upper rim. The 4-tbutylcalix[4]arene, having four-fold symmetry with the opening at the upper rim is 10.3 Å wide, whereas the opening at the base is 3.8 Å in diameter, resulting in a hydrophobic cavity of 3.6 Å depth (Fig. 17.3) [42]. Recent theoretical calculation (optimized at B97D/631(d) level) of different calix[n]arenes with tert-butyl group reported the size of macrocyclic cavity of different calix[n]arenes. In case of 4-tbutylcalix[4]arene, the distance between two diagonal aromatic ring is 8.307 Å; whereas other large macrocyclic rings having 5,6, and 8 numbers of phenolic units are flattened. In larger CAs, phenolic –OH groups come closer

OR OR OR OR RO

Cone

OR

OR OR

Partial cone

OR OR OR RO

1,2-Alternate

Fig. 17.2  Calix[4]arene conformations.

OR

OR OR OR

1,3-Alternate

480

Polysaccharide Carriers for Drug Delivery 10.3 Å Upper rim

3.6 Å Cavity depth OH

OH

OH

HO

3.8 Å Lower rim

Fig. 17.3  Dimension of the cavity in a cone conformer of 4-t-butylcalix[4]arene.

for the formation of better intramolecular hydrogen-bonded network [43]. However, a perfect hydrophobic cavity is usually formed in case of tbutylcalix[4]arene. For this reason, scientific communities prefer calix[4]arene for synthetic modification to design different supramolecular host for specified purpose.

17.3 Synthetic modification of calixarenes Basic CA unit has four alkyl groups at the upper wide rim and four phenolic OH groups at the narrow lower rim. Both upper and lower rims are amenable to easy synthetic modification or functionalization to obtain specially target-oriented supramolecular host. Other aspect of the CA modification is that different conformational isomer can also be conjugated [44]. As a first step, tert-butyl groups of calix[4]arene is dealkylated for the design of CAs-based drug carriers. Subsequently, both upper rim and lower rims are modified using various methods [45]. Many groups have been introduced at the upper rim for various purposes, which include chloromethyl, nitro [46,47], sulfonato [48–50], bromo, and iodo groups [51]. Nitro groups can further be reduced to amine groups for subsequent coupling of different moieties to create strong hydrophilic zone at upper rim. Similarly, iodo and bromo groups can be targeted to introduce a wide range of aryl [52], heteroaryl, alkenyl [51], carboxyalkyl [53], cyano [54], and acyl [55] groups. The upper rim can be used to introduce different polyether and polypeptide moieties to form either open or close cavity to recognize different guests [56–58]. This can further enhance hydrophilicity of the cargo. The synthetic modifications of lower rim at the phenolic hydroxyl groups are much more common. Generally different functionalities of interest such as crown ethers [59–61], esters, amides [62], thioureas [63], sulfonates [13,64,85], and alkyl chains [65] are introduced through more efficient O-alkylation and O-acylation protocol. This functionalization can be monitored for partial or complete substitution of phenolic hydroxyl groups as per the requirement following different methods reported earlier. In this way, the cone conformation of the CAs can be maintained [66,67]. It is worthy to mention that other conformations of CAs are also achievable through partial O-alkylation and

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O-acylation and subsequent synthetic modification for different purpose. The entire synthetic route is aimed to meet the intended design of host molecules for complexation with suitable drug candidates and consequent delivery to the specific site at a controlled rate. It is also desirable that the designed supramolecular carriers must have the capability to work in a biochemical environment.

17.4 Mode of drug delivery using calixarenes In recent years, water-soluble calixarenes, especially para-sulfanato calix[n]arene and amphiphilic calixarenes, are getting immense importance in a number of biochemical studies, which include but not limited to their interaction with organic and inorganic ions, peptides, proteins, and lipids. The most important aspects of calixarene-based molecules are their nontoxicity toward different biological reactions [68]. The drug molecules can easily be complexed with the designed supramolecular host for their stimuli-responsive release at the target site (Fig. 17.4). Recent reports indicated that calixarene-based controlled drug-delivery systems could be designed in various forms such as inclusion complexes, amphiphilic self-assembled micelles, hydrogels, vesicles and liposomes, and supramolecular nanovalves on mesoporous silica nanomaterials. Calixarenes and their derivatives of water-soluble versions, in particular, show good biocompatibility and noncytotoxicity, which are important prerequisites for practical application as drug-delivery systems [33].

Fig. 17.4  Schematic representation of the formation of inclusion complexes based on CAs and drugs and their decomplexation [33]. Reprinted from Chinese Chemical Letters, 26, Zhou Y, Li H, Yang Y-W, Controlled drug delivery systems based on calixarenes, 825–828, Copyright (2015), with permission from Elsevier.

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17.4.1 Inclusion complexes The concept of supramolecular host-guest interactions have been exploited to form different types of inclusion complexes where different noncovalent interactions play important role. These inclusion complexes have unique nature of complexation and decomplexation depending upon the physiochemical nature of system [69–72]. Many research groups have successfully designed CA-based systems as carriers for drug delivery. Wang et al. [73,74] studied the complexation of topotecan and irinotecan with water-soluble CAs, where the guest drug molecules were found to form 1:1 host-guest inclusion complex [73,74]. Antibiotics of large molecular size such as norfloxacin and ciprofloxacin can be delivered using larger cargo based on calix[8]arene, which has the ability to encapsulate the drug molecules inside the larger cavity [75].

17.4.2 Micelles and hydrogels Different amphiphilic molecules can form micelles, nanogels in which the hydrophobic cores behave like a supramolecular container for a variety of drug molecules (Fig. 17.5). The drug molecules thus remain protected and can reach to the target site without being affected by biochemical fluids during transportation. The concept of supramolecular interaction has been applied to the delivery of hydrophobic chlorin e6 using PEGylated calix[4]arene-based supramolecular polymeric micelles. Interestingly, complexed drug molecules exhibited better photodynamic therapy efficacy than free chlorin e6 [76].

17.4.3 Vesicles and liposomes Different nanocarriers have been used for drug delivery and controlled release. Among these different forms of nanocarriers, lipid vesicles and immunoliposomes showed excellent usefulness toward drug delivery. The vesicles with hollow interiors prefer encapsulation of hydrophilic drugs in contrast to micelles. A nanocarrier based on CAs with hydrophilic branched chain at upper rim and liophilic decyl chains at the lower rim has been reported by Lee et al. [77]. The p-sulfonatocalix[5]arene and

Fig. 17.5  Schematic illustration of the formation of micelles [33]. Reprinted from Chinese Chemical Letters, 26, Zhou Y, Li H, Yang Y-W, Controlled drug delivery systems based on calixarenes, 825–828, Copyright (2015), with permission from Elsevier.

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Amphiphilic guest Excess CAs Drug

Heat

Calixarene Nonamphiphilic guest

Vesicle Enzyme

Fig. 17.6  Illustration of formation of vesicles and their response to multistimuli to realize drug release [33]. Reprinted from Chinese Chemical Letters, 26, Zhou Y, Li H, Yang Y-W, Controlled drug delivery systems based on calixarenes, 825–828, Copyright (2015), with permission from Elsevier.

1-pyrenemethylaminium-based host vesicles can form complex with 1:4 molar ratio and respond to temperature for the release of doxorubicin (DOX). The formation of lipid vesicles and drug-release mechanism is illustrated in Fig. 17.6. Though there are different kinds of stimuli-responsive systems for the purpose of effective drug release, the enzyme-based systems provide an efficient biocompatible method with high specificity, accuracy, and sensitivity for targeted delivery [13,78].

17.5 Calixarenes in drug delivery 17.5.1 Hybrid liposomes The pharmacological investigations revealed that curcumin possesses potent anti-­ inflammatory, antineoplastic, and strong antioxidant activities [79–81]. Unfortunately, its clinical development has been halted due to its extremely low water solubility (11 ng/mL), extensive glucuronide and sulfate conjugation [82,83]. Therefore, curcumin suffers from poor oral bioavailability, and fails to attain desired plasma levels and accumulation in target sites. Further, the photodegradation of curcumin limits its parenteral formulations [82]. Calix[n]arenes comprises phenolic units linked by methylene or sulfur groups at the 2,6-positions. These nanomaterials have a central cavity, large enough to encapsulate small drug molecules [68,84]. To overcome the problems associated with curcumin, Drakalska and groups [85] synthesized PEOmodified tert-butylcalix[4]arene, bearing four PEO moieties (BC) as a drug-delivery carrier for curcumin. The encapsulation of curcumin: BC inclusion complex in dipalmitoylphosphatidyl choline: cholesterol hybrid liposomes improved the amount of entrapped curcumin by a factor of almost 1.5 compared to the BC-free liposomes. The addition of PEGylated calix[4]arene at a concentration exceeding its critical value of 0.24 μmoL/mL enhanced the aqueous solubility of curcumin by 568 fold. An initial burst release of ~50%, followed by a slow release over 24 h, was evident in phosphate buffer (pH 7.0). The fast release of curcumin solubilized within the hydrophobic domains of supramolecular aggregates and slow release of strongly associated curcumin

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Polysaccharide Carriers for Drug Delivery

molecules from the interior of the calixarene residue of the inclusion complexes could be responsible for biphasic curcumin release pattern. The free curcumin and its formulations exerted concentration-dependent lowering of the cellular viability in acute promyelocyte leukemia and multiple myeloma human tumor cell lines. This caused total eradication of viable cells at concentrations >50 μM following an exposure of 3 days. As depicted in Fig. 17.7, the 24-h treatment at equitoxic concentration of curcumin led to an increase in the generation of sub-G1 fraction, indicative for apoptotic cells. The encapsulation of curcumin in inclusion complexes enhanced its proapoptotic activity, whereas liposomal entrapment of the complexes further increased the sub-G1 fraction. Overall, the inclusion complex and its liposomal formulation exerted superior antineoplastic potential compared to free curcumin. Jelezova et al. [86] reported hybrid pH-sensitive liposomes containing curcumin. Its water-soluble inclusion complex with polyoxyethylated tert-butylcalix[4]arene was subsequently encapsulated in dipalmithoyl phosphathydilcholine: cholesterol liposomal membranes, grafted with a poly(isoprene-b-acrylic acid) diblock copolymer

Fig. 17.7  Proapoptotic activity of (A) free curcumin, (B) curcumin: BC inclusion complex, (C) curcumin loaded hybrid liposomal system after 24 h treatment, and (D) curcumin-BC inclusion complex loaded hybrid liposomal system after 24 h treatment. Reprinted from Int J Pharm, 472, Drakalska E, Momekova D, Manolova Y, Budurova D, Momekov G, Genova M, Antonov L, Lambov N, Rangelov S, Hybrid liposomal PEGylated calix[4]arene systems as drug delivery platforms for curcumin, 165–174, Copyright (2014), with permission from Elsevier.ART: It is Ok and may remain same. Better quality figure will not be produced as it is copyrighted material.

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to confer pH-sensitivity. The curcumin formulation exhibited superior cytotoxic and apoptogenic effect compared to the free drug. Presumably, the potent proapoptotic effect of pH-sensitive liposomal curcumin was mediated via recruitment of both extrinsic and intrinsic apoptotic pathways in acute myelocyte leukemia-derived HL-60 cell line.

17.5.2 Solid lipid nanoparticles In the preparation of solid lipid nanoparticles (SLNs), the oily lipid of an oil/water emulsion is substituted with a solid lipid or blend of solid lipids to produce particle sizes in the range 80–1000 nm. These particles are dispersed in water or aqueous surfactant solutions [87,88]. Melt emulsification followed by a hot or cold high-pressure homogenization process is usually followed for the synthesis of SLNs. Briefly, the active ingredient is dissolved or dispersed in molten lipid phase and, subsequently, a pre-emulsion is produced in a hot surfactant solution after stirring this lipid phase. The pre-emulsion is further homogenized under high pressure to produce a hot nanoemulsion, cooled down for the lipid recrystallization and the formation of SLN suspensions [89,90]. The preparation and stability parameters of para-acyl-calix[4] arene-based SLNs came into existence in 2003 [91]. The authors explained the influence of the nature and volume of the organic solvent, the amphiphile concentration, and the presence of a cosurfactant in the organic phase on the size of the SLNs, produced by solvent displacement method. Shahgaldian et al. [92] reported the effects of cryoprotectant carbohydrate (glucose, fructose, mannose, and maltose) on the reconstitution of para-dodecanoylcalix[4]arene-based SLN suspensions after freeze-drying. All carbohydrates tested showed excellent cryoprotection and redispersion properties with the calixarene-based SLNs. The calix[n]arenes are potential class of supramolecular skeleton for the development of SLNs. The para-acyl-calix[9]arene-based SLNs of 85–215 nm size were reported by Jebors et al. [93]. In solvent displacement method, para-acylcalix[9]arene solution in THF (5 mg/mL) was diluted with water, stirred to produce a slightly milky suspension, and evaporated under reduced pressure to have SLN concentration of 0.1 g/L. No SLN aggregation was observed in the presence of human serum albumin. Ultrasonic and ultraviolet and thermal treatment of the SLN suspensions had no effect on the SLN stability. The lack of interaction with human serum albumin, coupled with the preliminary encapsulation results, opens the door for these transporters for biomedical applications. Wang et al. [94] constructed a new nanoscale supramolecular vesicle based on p-sulfonatocalix[5]arene and 1-pyrenemethylaminium by host-guest interactions, which could form 1:4 molar ratio of complex and respond to temperature to realize the release of doxorubicin. Weeden et  al. [95] designed a novel amphiphilic tetrahexyloxy-tetra-p-­ aminocalix[4]arene nanocarrier by an emulsion evaporation method for the delivery of paclitaxel, used to treat breast and ovarian cancers. The nanoparticles had a mean size of 78.7 nm and encapsulation efficiencies of 50.4%. The nanoparticles released 91% of the encapsulated amount of drug in phosphate-buffered saline supplemented with 4% bovine serum albumin at the end of 120 h. They speculated that the particles

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size of ­nanoparticles would avoid the mononuclear phagocyte system and, therefore, had potential to achieve targeted delivery to tumor tissues.

17.5.3 Larger calixarene-based carriers Amphoteric calix[8]arene with negatively charged upper rim and positively charged lower rim was synthesized by Xue et  al. [75]. On the base of negatively charged p-­sulfonato-calix[8]arenes, they introduced positively charged groups at the lower rims, preparing amphoteric calix[8]arenes. The drug-loading efficiencies were 17.8%–24.5%. Only 38%–42% of the loaded ciprofloxacin released after 12 h in pH 7.4 buffer. In contrast, about 82% and 86% of the loaded drug released in 12 h as the pH of release media were adjusted to 5.0 and 8.5, respectively. As shown in Fig.  17.8, a number of calix[8]arenes (AC [8]) associated into rod or tube-like structures and formed the complexes. The hydrophobic interactions between ciprofloxacin and phenol units as well as the hydrogen bonding interactions between the amide groups on ciprofloxacin and the hydroxyl groups on amphoteric calix[8]arenes could be responsible for enhanced drug loading into calix[8]arene complexes. Both the pH-dependent solubility of the drug and pH-triggered assembly and disassembly of the amphoteric calix[8]arenes influenced the drug release. Such pH-­triggered switch on-off are of great potential for diagnosis and therapeutic applications. Owing to its weak zwitterionic character (pKa ~6.2, 8.8), the poorly soluble ciprofloxacin dissolves readily in acidic and basic solution but to some extent in neutral solution [96]. However, pH was unlikely to be the exclusive factor dominating the drug release due to little difference in solubilities observed at pH 7.4 and 8.5, whereas

Fig. 17.8  Model of pH-triggered drug loading and releasing procedure. Reprinted from Colloids Surf B Biointerfaces, 101, Xue Y, Guan Y, Zheng A, Xiao H, Amphoteric calix[8]arene-based complex for pH-triggered drug delivery, 55–60, Copyright (2013), with permission from Elsevier.

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the difference in drug-release kinetics was significant. With the opposite charges at upper and lower rims of calix[8]arenes, the amphoteric calix[8]arenes formed complexes via electrostatic attraction in neutral solution. As the pH of the solution was fluctuated below a certain value, adequate H+ or OH− ions diminished the attraction among amphoteric calix[8]arenes. The complexes disassembled, resulting in the release of drug from the complexes.

17.5.4 Conjugated delivery vehicles Qin and coworkers [97] reported a supramolecular strategy to coassemble an amphiphilic antipsychotic agent chlorpromazine with p-sulfonatocalix[4]arene tetraheptyl ether (SC4AH). A drug-loading efficiency of 46% was noticed for the supramolecules having an average diameter of 192 nm. Trimethyl chitosan (TMC) as a cationic ligand could facilitate the active transport of nanoparticles via absorptive mediated transcytosis. Therefore, TMC-modified nanoparticles have been reported as a drug carrier for delivery to the brain [98]. Importantly, the calixarene-drug coassembly could provide a new direction for the development of carriers. Gallego-Yerga et  al. [99] previewed an original giant surfactant based on β-cyclodextrin (β-CD) and calix[4] arene heterodimers with the ability to self-assemble into core-shell nanosystems with the capabilities of sufficient drug encapsulation and controlled release of anticancer drug docetaxel. Mo et al. [100] reported a calix[4]arene amphiphilic supramolecular system with phospholipid-containing phosphonate/phosphonic acid at upper rim and nonpolar aliphatic group at lower rim. In calix[4]arene moiety, PEGlyted folic acid was conjugated by applying “click” ligation protocol as shown in Fig.  17.9. The NH2 O HO P HO

O OH P OH

O HO P HO

O P OH OH

N

N

HO

N N

O O

O

O

NH NH2 N

N

HO

O

N N

1

O HO P HO

NH O HO P HO

O OH P OH N N N

O HO P HO

O

O

O O

2

O

O

H N n

NH O

O

3

OH

CuSO4 Na ascorbate

HO HO

O

N O OH N P OH N

O P

O O

O

H N n

NH

O O

OH

O

rt

4

Fig. 17.9  Model “click” reaction between the alkyne-PEG-folate reagent and P3C6N3 in the calixarene vesicle. 1, P4C6; 2, P3C6N3; 3, alkyne-PEG-folate; 4, P3C6N3-PEG-folate. From Mo, J.; Eggers, P. K.; Yuan, Z.; Raston, C. L.; Lim, L. Y., Paclitaxel-loaded phosphonated calixarene nanovesicles as a modular drug delivery platform. Sci. Rep. 6, 23,489 (2016).

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Polysaccharide Carriers for Drug Delivery

p­ aclitaxel encapsulation in the vesicles was accomplished by thin film-sonication method. This delivery system worked as a pH-responsive delivery vehicle to trigger the release of the encapsulated paclitaxel in cancer cells. It also enhanced potency against folate receptor (FR)-positive SKOV-3 ovarian tumor cells over FR-negative A549 lung tumor cells.

17.5.5 Amphihpilic calixarene carriers Zhao et al. [101] developed amphiphilic calixarene carboxylic acid derivatives (calix [6] arene hexacarboxylic acid and calix [8] arene octo-carboxylic acid) as a promising nanosize delivery carrier for paclitaxel. The spherical particles were of 180– 220 nm size. Hexa- and octo-carboxylic acid derivatives showed stability to protein solutions and buffers (pH 5–9), and found to form aggregates at critical concentrations of 5.7 and 4.0 mg/L, respectively. Increased hydrophobic chain length increased the drug entrapment efficiency of the particles from 81.6% to 90.3%. In absence of serum proteins, hexa-carboxylic acid derivatives released 33.7% drug within 30 min in phosphate buffer solution (pH 7.4) containing 1% Tween 80. The drug release at 24 h corresponded to 96.2%. However, only 18.8% drug was released from octo-­ carboxylic acid derivatives in 30 min. Overall, the drug release from octo-carboxylic acid nanoparticles was less than hexa-carboxylic acid particles in 12 h. Ignoring the burst release, a slow continuous release was evident at later stages until 24 h. This could overcome some drawbacks associated with the drug such as local toxicity and a short half-life in vivo resulting from a rapid release [102]. In presence of serum proteins, however, the release rates of paclitaxel from both nanoparticles were relatively slower. Thus, the properties of calixarene nanoparticles favor their application for tumor-targeted drug delivery. Rodik et al. [103] provided new insights for designing nonviral vectors based on macrocyclic molecules. They synthesized amphiphilic calixarenes bearing cationic choline or N-(2-aminoethyl)-N,N-dimethylammonium groups at the upper rim and alkyl chains at the lower rim. It was observed that longer alkyl chains favored the formation of small virus-sized DNA nanoparticles with low polydispersity. Moreover, longer alkyl chains, such as dodecyl groups, significantly improved the transfection efficiency with lower cytotoxicity. The amphiphilic tetrahexyloxy-p-­sulfonato calix[4]arene nanocapsules were reported by Chen et al. [104]. Nanocapsules of 206 nm diameter were prepared by film hydration method, which supported the encapsulation of paclitzxel with an efficiency of about 83%. The spherical shape of the calix[4]arene was evident without any sign of agglomeration. Taxol exhibited rapid drug release of 70% at 4 h and 85% after 24 h in phosphate buffer (pH 7.4) containing 0.1% Tween 80. In contrast, the paclitaxel-loaded amphiphilic calix[4]arene nanocapsules released 63% drug at the same duration. The formulation showed more effective cytotoxicity in human cervical cancer cell culture than commercial Taxol. These properties favored their potential application to target cancer cells by virtue of their capability of passive accumulation through enhanced permeability and retention (EPR) effect of tumors [105]. Later on, Gallego-Yerga et  al. [106] reported the preparation of self-assembled nanoparticles from the giant β-CD-CA4 giant amphiphiles using the nanoprecipitation

Calixarenes containing supramolecular vehicles for drug delivery489

technique reported earlier [107]. The mixture of giant surfactant species and docetaxel (1:3 molar ratios) in anhydrous methanol was dropped into an equal volume of water containing polysorbate 80 under magnetic stirring. The organic solvent was removed under reduced pressure and centrifuged to obtain nanospheres. In the preparation of nanocapsules, anhydrous methanol containing a small amount of capric/caprylic triglycerides and a nonionic surfactant, Span 80 was used. The drug-loaded nanospheres had hydrodynamic size to 20–35 nm. In contrast, drug-loaded nanocapsules had hydrodynamic diameters of 200–265 nm. The encapsulation efficiencies ranged from 83% to 89% for nanospheres and 98% to 99% for nanocapsules, the highest value reported so far for docetaxel nanoformulations [108]. The nanoparticles followed a hyperbolic release profile with an initial burst release in 6–8 h followed by a sustained release over 30–60 h. The docetaxel-loaded formulations exhibited efficient cytotoxic effects in prostate and glioblastoma cell lines. The nanoparticles obtained from giant surfactant containing four hexyl chains at the calix[4]arene demonstrated significantly slower drug-release rate compared to formulations prepared from four dodecyl chains at the CA4 component. The current commercial docetaxel formulation lack water solubility and thus requires dilution with ethanol before administration, which exacerbates the already high intrinsic docetaxel toxicity [109]. The giant amphiphile-based nanoparticle formulations efficiently incorporated/solubilized docoetaxel in water without the need for a cosolvent and entirely liberated the drug payload in a biological environment over a period of 30–60 h, yielding docetaxel concentrations sufficient to induce cancer cell death.

17.6 Conclusion The current chapter focuses on the recent advancement of CAs-based supramolecular drug-delivery system. Considering its huge applications in drug delivery as well as in other biomedical fields, CAs-based macrocyclic supramolecular systems have gained popularity in last few decades. Major advantage of CAs-based system is that core structure of CAs can be modulated as per the requirement. Both hydrophilic and liophilic terminals can easily be attached to either upper rim or lower rim by synthetic modifications. By this way, suitable hosts can be designed and synthesized. Though the cavity size of CAs is fixed depending on the ring size, still it can encapsulate and deliver larger drug or molecules with biological importance, provided both the rims have suitable groups. These types of hosts can act as carrier for the drug molecules of both hydrophobic and hydrophilic nature. Not only that, CAs-based delivery system may anchor with polymer or other nanoparticles for efficient delivery of drugs. The major advantage of CAs is the nontoxicity of core moieties. Thus, research progress of host-guest supramolecular systems in biomedical applications has huge scope to address not only drug-delivery aspects but also for gene delivery, bioimaging, and photodynamic cancer therapy. The reversible nature of supramolecular inclusion complexes, formed via host-guest interactions, made them popular devices for controlled drug release. Many types of CA-based smart nanocarriers, i.e., micelles, hydrogels, vesicles, liposomes, and nanovalves, have shown promising toward the stability,

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s­ ensibility, specific targeting, and high loading efficiencies of drug molecules. Despite remarkable progress in the field of calixarene-based drug delivery, further works are required for successful clinical application.

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