Polysaccharides as potential materials for the delivery of therapeutic molecules

Polysaccharides as potential materials for the delivery of therapeutic molecules

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Sougata Jana*,†, Sabyasachi Maiti‡, Subrata Jana§ ⁎ Department of Pharmaceutics, Gupta College of Technological Sciences, Asansol, India, † Department of Health and Family Welfare, Directorate of Health Services, Kolkata, India, ‡ Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, India, § Department of Chemistry, Indira Gandhi National Tribal University, Amarkantak, India

5.1 Introduction The delivery of therapeutic molecules to the specific target site has been a major problem for the treatment of several diseases. Conventional drug delivery systems pose several limitations such as poor bio-distribution, less effectiveness, acid hydrolysis, short biological half-life, dose dumping, side effects, and poor pharmacokinetics. These drawbacks can be overcome by developing controlled drug delivery systems [1,2]. The biopolymers are used to design and develop various drug delivery systems for the delivery of therapeutics. These biopolymeric systems are safe and attractive to achieve sustained drug-release profiles, desired pharmacokinetics, and consequently better therapeutic effect [3,4]. The pharmaceutical and biomedical use of biopolymers has been found advantageous in terms of their nontoxicity, biodegradability, biocompatibility, and ecological safety [5,6]. Biopolymers are generally carbohydrate molecules, composed of repeating monosaccharide units linked together by glycosidic bonds [7]. Maximum carbohydrate materials in nature are obtained in the form of polysaccharides. Polysaccharides as natural macromolecules are composed not only of glycosidically linked sugar residues but also some materials linked via covalent bonds to proteins, peptides, amino acids, etc. It is also called glycans and structurally composed of monosaccharide and their derivatives. If polysaccharide is made up of only one kind of monosaccharide molecule, then it is called homoglycan or homopolysaccharide. When polysaccharide contains more than one kind of monosaccharide units, they are called heteropolysaccharides. Due to presence of a variety of functional groups, the polysaccharides can be easily modified by chemical pathway and therefore, the polysaccharide-based systems have received much attention for the delivery of therapeutics [8]. Among various polysaccharides, chitosan (CS) and alginate (Alg) have been the extensively studied biomaterials for the design of drug delivery carriers. CS is a natural polysaccharide, chemically composed of α-1,4-linked 2-amino-2deoxy-α-d-glucose (N-acetyl glucosamine). According to the United States Food and Drug Administration (USFDA), it is Generally Recognized as Safe (GRAS) material Functional Polysaccharides for Biomedical Applications. https://doi.org/10.1016/B978-0-08-102555-0.00005-4 Copyright © 2019 Elsevier Ltd. All rights reserved.

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and finds versatile application in pharmaceutical as well as biomedical fields including drug delivery, tissue engineering, and food technology [9–11]. Alg is a linear, anionic polymer, obtained from brown algae, and chemically composed of α-l-guluronic acid (G) and β-d-mannuronic acid (M) residues, linearly linked by 1,4-glycosidic linkages [12–15]. It is biodegradable, biocompatible, nontoxic, readily available, low cost, and nonimmunogenic biomaterial [16–18]. In this chapter, CS- and Alg-based systems are discussed in detail for the delivery of therapeutics.

5.2 Polysaccharides-based systems for delivery of therapeutics 5.2.1 Insulin and protein delivery Insulin is the most important therapeutic materials to maintain blood glucose levels in our body system. Currently oral delivery of insulin is attractive for the diabetic patient to avoid painful injection. Polysaccharide-based insulin delivery systems have been tested to control the release of insulin at the target site. Sajeesh and Sharma [19] synthesized poly (methacrylic acid-vinyl pyrrolidone)-CS and poly (methacrylic acid)-CS microparticles by ionic-gelation technique. They evaluated mucoadhesive property of the prepared microspheres in rat intestinal tissue by ex vivo adhesion technique. The systems were found to be nontoxic on Caco 2 cell line. Tahtat et al. [20] synthesized insulin-loaded Alg/CS beads for oral insulin delivery. The hydrogel beads were fabricated by the Ca2+ and glutaraldehyde (GA) cross-linking method. In vitro results showed that the hydrogel carriers released ~72% insulin in pH 6.5 simulated intestinal fluid (SIF) at 6 h [20]. In another investigation, Mukhopadhyay et al. [21] developed insulin-loaded Alg/CS polyelectrolyte complex for oral delivery. Particle size range and encapsulation efficiency of nanoparticles (NPs) was 100–200 nm and ∼85%, respectively. In SIF, about 79%–84% of entrapped insulin was released at 24 h. Polyurethane-Alg/CS core-shell NPs were prepared by Bhattacharyya et al. [22] for oral insulin delivery. Particle size range of the NPs was 90–110 nm as examined by scanning electron microscopy (SEM) and transmission electron microscopic (TEM) analyses. In vitro release studies are represented in Fig. 5.1. The release of insulin from polyurethane-Alg/CS NPs was 50% in pH 6.8 at 10 h and 98% in pH 7.4 at 20 h. Lim et al. [23] developed Alg-κ-carrageenan hydrogel beads by Ca2+ cross-linking (Fig. 5.2) for insulin oral delivery. The prepared beads were characterized by FESEM, FTIR, and swelling studies. In vitro insulin release from Alg-κ-carrageenan beads were performed in both simulated gastric fluid (SGF) (pH 1.2) and SIF (pH 7.4). Chang and Xiao [24] investigated N-(2-hydroxyl) propyl-3-trimethyl ammonium CS chloride NPs and CS/gelatin thermosensitive blend hydrogels by in situ gelation method for delivery of a model protein bovine serum albumin (BSA). In  vitro release study showed sustained release of the protein. In another study, Kim et  al. [25] developed BSA loaded Alg-CMC (carboxymethyl cellulose) beads by Fe3+ ion cross-linking method. The surface roughness of the micro beads was evaluated by

Polysaccharides as potential materials for the delivery of therapeutic molecules175

pH 1.2

Cumulative release percentage (%)

100

pH 7.4

pH 6.8

80

60

40

20

PU-ALG/CS NPs ALG/CS NPs PU-ALG NPS

0 –2

0

2

4

6

8

10 12 Time (H)

14

16

18

20

22

Fig. 5.1  In vitro insulin release study from PU-ALG/CS, ALG/CS, and PU-ALG nanoparticles at different pH. Reproduced with permission from Bhattacharyya A, Mukherjee D, Mishra R, Kundu PP. Preparation of polyurethane–alginate/chitosan core shell nanoparticles for the purpose of oral insulin delivery. Eur Polym J 2017;92:294–313. Copyright (2017), with permission from Elsevier.

the SEM analysis. About 70% BSA was released in pH 7.4 buffer in 24 h. Further, Yang et  al. [26] synthesized Alg-mPEG-g-CMCS [methoxy poly (ethylene glycol) grafted carboxymethyl CS] interpenetrating polymer network (IPN) system for oral BSA delivery. The IPN beads were fabricated by the Ca2+ ion cross-linking method. The IPN beads prevented the burst release of BSA in acidic medium (pH 1.2), however, sustained the release of BSA (~90% at 9 h in pH 7.4). Omera et al. [27] prepared Alg-AmCS (Alg-aminated CS) microbeads for oral delivery of BSA. In vitro release of BSA from Alg-AmCS beads were evaluated in three different pH such as pH 1.2, pH 6.8, and pH 7.4. In vitro results stated that the formulated beads were stable in simulated colonic fluid (SCF) (pH 7.4). Alg-CS nanofilms were synthesized by Wen et al. [28] for BSA delivery. Coaxial electrospinning method used for the development of nanofilms. Smooth surface characteristics were evaluated by the SEM analysis. Dynamic light scattering technique was used to determine the mean diameter and polydispersity index. The same were found to be ~270.5 nm and 0.265, respectively. In vitro results showed that about 75% BSA was released in SCF at 16 h [28]. Rahmani et al. [29] developed Alg-based complex for the delivery of protein. Authors used different types of model protein, such as BSA, cytochrome C, lysozyme, myoglobin, and chymotrypsin. Ionic strength and variation of pH had an influence on in vitro release of protein from the Alg-based complex.

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HOOC HOOC

O OH

HO O HOOC

HO

OH

O

OH O

O OH

(A)

O OH

O

Ca-alginate hydrogel matrices

HOOC

Alginate H2C

–

O3SO

CH2OH

O

O O

Ca2+

O OH

O OH

(B)

K-carrageenan

Room temperature

Insulin aspart

(C)

Ca-K-carrageenan

Insulin aspart

Fig. 5.2  Schematic diagram of the formation of insulin aspart-loaded Alg/κ-carrageenan composite hydrogel beads. Reproduced with permission from Lim H-P, Ooia C-W, Teya B-T, Chan E-S. Controlled delivery of oral insulin aspart using pH-responsive alginate/κ-carrageenan composite hydrogel beads. React Funct Polym 2017;120:20–9. Copyright (2017), with permission from Elsevier.

5.2.2 Folic acid delivery Wang et  al. [30] synthesized CS-gelatin microgels for the delivery of folic acid, a model hydrophobic drug. Microgels were characterized by the FT-IR, fluorescence staining and imaging, and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide) assay. The microgels prohibited initial burst release and prolonged the release of folic acid up to 72 h at the physiological neutral pH and temperature.

5.2.3 Anticancer drug delivery Curcumin is a hydrophobic polyphenol obtained from the turmeric rhizome Curcuma longa. It has poor bioavailability, rapid metabolism, and low solubility in aqueous medium. To increase its bioavailability, Anitha et al. [31] fabricated curcumin-loaded carboxymethyl CS NPs for delivery of chemotherapeutic molecules. The mean hydrodynamic diameter of NPs was ~150 nm. Atomic force microscopy (AFM) and SEM analyses showed that the particles had spherical size and morphology. The drug entrapment efficiency of the NPs was ~80%. The NPs liberated 30% curcumin in media of pH 7.4 and pH 4.5 within 12 h. The same increased to 50% at pH 4.5, and 49% at

Polysaccharides as potential materials for the delivery of therapeutic molecules177

pH 7.4 without lysozyme and 63% in pH 4.5 and 58% at pH 7.4 with lysozyme at the end of 126 h. MTT assay confirmed that curcumin-loaded carboxymehtyl CS NPs was nontoxic to normal cells and demonstrated specific toxicity toward cancer cells. Fluorescence microscopy and flow cytometry analyses indicated their cellular uptake capacity. Doxorubicin (DOX) is a chemotherapeutic agent which acts effectively against various types of cancer cells such as lung cancer, breast cancer, urothelial cancer, hematological malignancies. However, it exhibits various dose-dependent side effects, such as cardiotoxicity, cytotoxicity in normal tissues, inherent multidrug resistance, and myelosuppression. To minimize its side effects, various polysaccharide-based drug delivery systems were developed. Folic acid conjugated CS nanocochleates was developed by Bothiraja et al. [32] for the delivery of DOX. Prepared nanocochleates showed higher in  vitro anticancer activity in human breast cancer cell. Differential scanning calorimetry (DSC) analysis revealed amorphous nature after encapsulation of DOX into rigid nanocochleates matrix. In  vitro release of DOX from folic acid conjugated CS nanocochleates showed 36% DOX release after 144 h in pH 7.4 buffer solution. Unsoy et al. [33] synthesized doxorubicin-loaded CS coated magnetite NPs for pH-dependent drug release. The DOX-loaded CS-coated magnetite NPs delivered a significant amount of drug to the tumor site than that could be achieved with conventional chemotherapy. Jiang et al. [34] synthesized cyclosporine A loaded poly(ethylene glycol)-graftedCS (PEG-g-CS) thermosensitive hydrogels for implant drug delivery systems. Cytotoxicity studies in L929 murine fibro sarcoma cell line indicated that the system was biologically safe. In vivo result showed sustained release (~3 weeks) of drug following subcutaneous injection of the fabricated hydrogel into Sprague-Dawley rats. Currently, Antoniraj et  al. [35] formulated CS and methoxy polyethylene glycol (mPEG) NPs for the delivery of 5-fluorouracil (5-FU). The polymeric NPs were able to sustain the release of 5-FU in vitro (~88% drug release in 24 h). The internalization of NPs into cells took place by receptor-mediated transport mechanism. Ding et al. [36] designed new hybrid CS polysaccharide nanocarriers for 5-FU delivery. The hybrid nanocarriers showed their anticancer drug delivery potential. The nanocarriers had a drug loading efficiency of 44%. The drug release occurred in pH-dependent manner, and swelling and diffusion mechanism monitored the drug-release rate from these carriers. Shagholani et al. [37] developed CS-coated magnetite NPs of 10.62 nm size and exhibited their potential as stimuli-responsive drug delivery carriers.

5.2.4 Antibiotic delivery Clarithromycin is a macrolide antibiotic widely used in Helicobacter pyloriassociated peptic ulcers and upper respiratory tract infections. Adult dose of clarithromycin is 500-mg twice daily and rapidly absorbed from the gastrointestinal tract. The sustained release formulation of clarithromycin could minimize fluctuations in plasma drug concentration and effectively deliver clarithromycin. Sarojini et  al. [38] investigated albumin CS floating microparticles for delivery of clarithromycin.

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Most of the microparticles were able to float for 12 h. Vaghani et al. [39] formulated clarithromycin-loaded CS-polyvinyl pyrrolidone (PVP) hydrogels. The hydrogel were prepared by GA cross-linking method. More than 97% clarithromycin was entrapped into the particles. The hydrogels swelled more in acidic environment than in alkaline medium and showed high mucoadhesion potential. Less than 11% drug was released in pH 7.4 buffer solution at the end of 12 h. The formulation composed of 2% (w/v) CS and 4% (w/v) PVP in the ratio of 21:4 emptied its 100% content after 12 h in pH 1.2 and pH 4.5. The drug released occurred via non-Fickian diffusion mechanism. The surface morphology of CS-PVP semi-IPN showed nonporous translucent membrane. The surface morphology of CS-PVP hydrogel after dissolution at pH 1.2 showed channel-like structure. In another study, Majithiya and Murthy [40] developed CS-based microspheres for delivery of clarithromycin for the treatment of stomach ulcers. In vitro study showed higher accumulation of clarithromycin in the tissue of stomach. The bioavailability of the drug was higher than the microspheres and drug suspension. Torrado et al. [41] developed CS-poly (acrylic) acid-based gastric retentive system for antibiotic drug delivery. These polyionic complexes were prepared from different amount of CS, drug (amoxicillin), and poly (acrylic) acid. Higher swelling of polyionic complexes was noted than that of only CS formulations. The diffusion of amoxicillin from the hydrogels matrix was governed by the polymer/ drug interaction. Torre et al. [42] also prepared poly (acrylic acid) CS interpolymer complexes for stomach-controlled antibiotic delivery of amoxicillin. The amoxicillinloaded polyionic complexes could be used for local antibiotic therapy against H. pylori infection. In another, Patel and Patel [43] formulated amoxicillin loaded mucoadhesive CS microspheres for stomach-specific drug delivery by emulsification phase separation technique using GA as cross-linker. CS microspheres were investigated by ionic cross-linked method. In  vitro release of tetracycline form ionically cross-linked CS microspheres was pH-dependent and the particles were stable under different pH condition at 37°C [44]. Govender et al. [45] developed CS-based bioadhesive microspheres containing tetracycline for the periodontitis treatment. Ampicillin loaded methylpyrrolidinone CS microspheres [46] and pentasodium tripolyphosphate cross-linked CS microspheres [47] showed gastric acid resistant properties and were stable in acidic medium. Ciprofloxacin-loaded CS-pectin microspheres were fabricated by Orhan et al. [48] with a view to treat osteomyelitis. Hydrogel-based contact lenses are important as drug delivery carriers for ocular therapy. Conventional system of HEMA-NVP (hydroxyethyl methacrylate-N-vinyl pyrrolidone) hydrogels offers several disadvantages such as limited capacity to control drug loading and release, low oxygen transmissibility, protein deposition, etc. In order to increase the efficacy of hydrogel, Hu et al. [49] synthesized CS-cross-linked HEMA-NVP for the delivery of norfloxacin and timolol. The prepared hydrogel showed significant increased oxygen transmissibility. Gratieri et al. [50] developed CS and CS/poloxamer in situ gel for ophthalmic delivery of fluconazole in the treatment of fungal keratitis. In vivo studies concluded that CS and CS/poloxamer in situ gel systems had similar sustained release characteristics. Motwani et al. [51] investigated CS-NaAlg mucoadhesive NPs for ocular delivery of an antibiotic, gatifloxacin. The release of gatifloxacin was sustained up to 24 h.

Polysaccharides as potential materials for the delivery of therapeutic molecules179

Recently, Sarkar et al. [52] developed vancomycin (V) loaded β-cyclodextrin/carbon quantum dot (CQD) modified Alg-hydrogel film. The drug entrapment efficiency of the hydrogel system was 96%. In vitro experiments stated that only about 56% vancomycin was released in acidic medium (pH 1.5) at 120 h.

5.2.5 Antiviral drug delivery Acyclovir, an antiviral molecule is classified as BCS III drug, that is, soluble with low intestinal permeability. Rokhade et al. [53] prepared acyclovir-loaded semiinterpenetrating polymer network (semi-IPN) microspheres. They used acrylamide-g-dextran and CS for the fabrication of semi-IPN microspheres by emulsion-cross-linking method. The drug release was sustained up to 12 h. In addition, Genta et al. [54] developed CS-microspheres for controlled ophthalmic delivery of acyclovir. In another study, Jana et al. [55] synthesized Alg and carboxymethyl derivative of tamarind gum (CTG) hydrogel containing acyclovir by Ca2+ cross-linking method. The particle surface morphology of acyclovir-loaded IPN hydrogels was analyzed by field emission scanning electron microscopy (FE-SEM). The images of the particles revealed their rough surface with spherical morphology. Energy dispersive X-ray (EDX) suggested that 2.46% calcium (Ca) and 20.34% chloride (Cl) was present in the sample (Fig. 5.3). The drug entrapment efficiency of IPN hydrogel particles was ∼70%. Only 18%– 23% acyclovir was released in acidic medium (pH 1.2) in 2 h. However, the particles gradually released acyclovir in alkaline medium (pH 6.8). Al-Ghananeem et al. [56] entrapped didanosine into CS NPs for brain delivery. The NPs were prepared by ionotropic gelation of CS with tripolyphosphonate anions. The NPs were found to be accumulated significantly in brain through intranasal delivery than intravenous administration. Dhaliwal et al. [57] developed acyclovir-loaded gastroretentive, mucoadhesive CS microparticles. The particles looked spherical having smooth surface under SEM examination. The delivery of antiretroviral drug becomes a challenge to pharmaceutical researchers due to its hydrophobicity, short half-life, and low bioavailability. Joshy et al. [58] synthesized Alg-based NPs for the delivery of zidovudine (AZT). In the hybrid NPs, AZT acted as a core, whereas Alg and stearic acid modified polyethylene glycol acted as shell. The size and zeta potential of hybrid NPs was ~407 nm and −42.53 mV respectively. Further, Joshy et al. [59] designed AZT loaded glutamic acid-Alg conjugate (AZT-GA-Alg) for oral applications. Alg-GA-AZT NPs were prepared by emulsion solvent evaporation technique, where Pluronic-F68 was used as stabilizer. The NPs discharged ~54% in pH 7.4 buffer in 24 h.

5.2.6 Antiinflammatory drug delivery Aceclofenac-loaded CS-tamarind seed polysaccharide (TSP) IPN microparticles were developed by Jana et al. [60]. The particle size range and drug entrapment efficiency of the particles was 490–621 μm and 85%–91%, respectively. In vitro studies showed that the carriers could sustain the release of aceclofenac up to 8 h. In addition, Jana et al. [61] synthesized CS-egg albumin NPs by ionic cross-linking and heat coagulation

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(B)

(A)

(C)

Element

Weight %

Atomic %

C

28.92

48.34

O

21.34

26.78

Na

12.14

10.60

Cl

20.34

11.52

Ca

2.46

1.23

Pt

14.79

1.52

Total

100.00

(D)

Na

O C

Cl

Ca Cl Pt

Ca

Pt 0

2

4

6

8

10

Fig. 5.3  Field emission scanning electron microscopy (FE-SEM) image and energy dispersive X-ray (EDX) analysis of HM2 hydrogels. (A) Spherical particles, (B) surface morphology, (C) element composition, (D) EDX spectra. Reproduced with permission from Jana S, Sharma R, Maiti S, Sen KK. Interpenetrating hydrogels of O-carboxymethyl Tamarind gum and alginate for monitoring delivery of acyclovir. Int J Biol Macromol 2016;92:1034–9. Copyright (2016), with permission from Elsevier.

techniques for the delivery of aceclofenac. The drug entrapment efficiency, particle size, and zeta potential of the NPs was 96%, 352 nm, and −22.10 mV, respectively. The drug-loaded NPs were incorporated in the Carbopol 940 to form transdermal gel. The transdermal gel showed sustained permeation of aceclofenac through mouse skin. Significant antiinflammatory activity was observed in carrageenan-induced rat paw model in comparison to marketed aceclofenac gel at 4 h (Fig. 5.4). CS-boswellia gum resin complex was developed by Jana et  al. [62] for the oral delivery of aceclofenac. The drug entrapment efficiency of the complex was ∼40%. Less than 17% aceclofenac release was noted from the complex in 2 h in medium of pH 1.2. In alkaline medium (pH 6.8), the complex extended the drug release up to 7 h. In another work, Jana et al. [63] prepared Alg-based microspheres for sustained delivery of aceclofenac. The drug was entrapped into the microspheres by Ca2+ ion induced gelation method. The microspheres were of 406–684 μm size and had a drug entrapment efficiency of 59%–93%. The Alg-locust bean gum (LBG) microspheres exhibited sustained delivery of aceclofenac in pH 6.8 over a period of 8 h. In vivo antiinflammatory activity of the drug-loaded Alg-LBG microspheres was encouraging. Recently, Jana et al. [64] developed aceclofenac-loaded CS-based IPN ­nanocomposites by GA

Polysaccharides as potential materials for the delivery of therapeutic molecules181

Carbopol940 gel containing aceclofenac-loaded chitosan-egg albumin nanoparticles

100 Cumulative drug permeated (%)

90

Marketed aceclofenac gel

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1.00

2.00

3.00

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7.00

8.00

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Carbopol940 gel containing aceclofenac-loaded chitosan-egg albumin nanoparticles 50 Marketed aceclofenac gel

% Inhibition

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2.5

3

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Fig. 5.4  (A) The comparative ex vivo drug permeation from Carbopol 940 gel containing aceclofenac-loaded chitosan-egg albumin nanoparticles and a marketed aceclofenacgel through excised mouse skin (mean ± S.D.; n = 3); (B) comparative percentage inhibition profile of paw edema for Carbopol 940 gel containing aceclofenac-loaded nanoparticles and marketed aceclofenac gel at various time intervals in carrageenan-induced rat model for antiinflammatory activity evaluation. Reproduced with permission from Jana S, Manna S, Nayak AK, Sen KK, Basu, SK. Carbopol gel containing chitosan-egg albumin nanoparticles for transdermal aceclofenac delivery. Colloids Surf B Biointerfaces 2014;114:36–44. Copyright (2014), with permission from Elsevier.

cross-linking (Fig.  5.5). The particle size range of the composites was 372–485 nm. The composites entrapped ~78% drug. In alkaline medium (pH 6.8), the drug release can be prolonged up to 8 h with the use of CS/LBG blend at a ratio of 1:5. Rivera et al. [65] synthesized CS-Alg nanocapsules for sustained delivery of glycomacropeptide (GMP) and 5-aminosalycilic acid (5-ASA) in inflammatory bowel disease (IBD) patients. The nanocapsules were developed by the layer-by-layer (LbL) deposition method. 5-ASA entrapment efficiency was 70%. In another report, Duan et  al. [66] developed 5-ASA-loaded Alg-N-succinylchitosan (5-ASA-Alg-NSCS)

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Functional Polysaccharides for Biomedical Applications OH

OH H

H

OH

OH

H

O

O

H

O

H

N

n

OH

OH

OH

H

H

N

O

OH

Locust bean gum

O

H

OH H H

N

H

o

OH n OH

n

Chitosan

OH Glutaraldehyde

OH

H OH

o

H

H OH H

N H

O

OH n OH

Fig. 5.5  The reaction mechanism of GA crosslink CS-LBG IPN. Reproduced with permission from Jana S, Sen KK. Chitosan—Locust bean gum interpenetrating polymeric network nanocomposites for delivery of aceclofenac. Int J Biol Macromol 2017;102:878–84. Copyright (2017), with permission from Elsevier.

microspheres by Zn2+ ion cross-linking method. Treenate and Monvisade [67] fabricated CS-Alg hydrogels for the delivery of paracetamol. The hydrogels were developed using different ionic cross-linkers such as Ca2+, Zn2+, and Cu2+. Ca2+ ion cross-linked hydrogel provided the highest stability than other formulation.

5.2.7 Hormone delivery Alg-based nanocapsules were developed by Jana et  al. [68] using emulsification cross-linking techniques for testosterone delivery. Testosterone encapsulation efficiency was 30%. Size and zeta potential of the nanocapsules was 34 nm and −5 mV, respectively. In  vivo results suggested favorable pharmacokinetic properties such as AUC0–24 (~317 ng mL−1 h−1), Cmax (~38 ng mL−1), and Tmax (2 h) in female rats, compared to nanocapsules, pure testosterone, and marketed testosterone injection (Fig. 5.6).

5.2.8 Gene delivery The polycationic polysaccharide CS has been investigated as potential gene delivery material [69]. Lameiro et al. [70] developed adenovirus loaded CS-bile-salt microparticles for mucosal vaccination. The systems showed delayed release of adenovirus and beneficial properties. Yun et  al. [71] incorporated DNA into PEG-g-CS composites by emulsion solvent evaporation method. The composites showed higher transfection efficiency and prolonged release of DNA. The IL-2-encoding geneencapsulated CS microspheres could be an interesting strategy for the delivery of cytokine gene into cells. Akbuga et al. [72] developed IL-2 loaded plasmid for genebased immunotherapy.

Polysaccharides as potential materials for the delivery of therapeutic molecules183 Control

Plasma conc. (ng/mL)

45

Testosterone-loaded alginate nanocapsules

40

Pure testosterone

35

Commercial testosterone injection

30 25 20

15 10 5 0

0

10

20

30

Time (h)

Fig. 5.6  Testosterone plasma concentration vs time curve. Reproduced with permission from Jana S, Gangopadhaya A, Bhowmik BB, Nayak AK, Mukherjee A. Pharmacokinetic evaluation of testosterone-loaded nanocapsules in rats. Int J Biol Macromol 2015;72:28–30. Copyright (2015), with permission from Elsevier.

5.3 Conclusion This chapter reviewed CS- and Alg-dependent novel materials for drug delivery applications. The drug carriers can be prepared under mild, eco-friendly environment. The entrapment of therapeutic molecules was dependent on the method of preparation and solubility of the active moieties. These polysaccharides have been extensively investigated for the delivery of insulin, proteins, antiinflammatory drugs, anticancer drugs, antiviral drugs, antibiotics, hormones, and genes. It was noticed that CS- and Alg-based materials could control the release of entrapped drug in pH-dependent manner under simulated gastrointestinal conditions. However, in vivo studies on the polysaccharide-based drug carriers reported so far are limited. Future studies should focus on evaluation of therapeutic activity of these carriers in vivo and toxicity of the modified materials in order to make them useful clinically.

References [1] Assa  F, Jafarizadeh-Malmiri  H, Ajamein  H, Vaghari  H, Anarjan  N, Omid Ahmadi  O, Berenjian  A. Chitosan magnetic nanoparticles for drug delivery systems. Crit Rev Biotechnol 2017;201(37):492–509. [2] Jana S, Sen SO, Sen KK. In: Jana S, Jana S, editors. Introduction to novel therapeutic carriers, particulate technology for delivery of therapeutics. Singapore: Springer Nature Singapore Pte Ltd; 2017. p. 1–24. [3] Maiti S, Jana S, Jana S. Bio-composites in therapeutic application: current status & future. In: Jana S, Maiti S, Jana S, editors. Biopolymer-based composites: drug delivery and biomedical applications. UK: Woodhead Publishing; 2017. p. 1–29.

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