Synthesis and characterization of β-cyclodextrin-conjugated alginate hydrogel for controlled release of hydrocortisone acetate in response to mechanical stimulation

Abstract

Alginate hydrogels are a class of biomaterials that can be used as local release depots for therapeutic agents. A particular drug that can take advantage of alginate hydrogel for controlled release is hydrocortisone acetate. Hydrocortisone acetate is a widely used anti-inflammatory agent, but is limited in application due to poor solubility and lack of controlled delivery. To overcome this limitation, a mechanically responsive β-cyclodextrin-conjugated alginate (Alg-β-CD) hydrogel was synthesized and characterized for enhanced aqueous solubility and controlled release of hydrocortisone acetate. We demonstrated that mono-6-deoxy-6-ethylenediamine-β-cyclodextrin and hydrocortisone acetate formed a 1:1 inclusion complex, thus resulting in marked increase in hydrocortisone acetate solubility, while causing no significant inhibition to the growth of cultured mouse fibroblasts (L929). More importantly, the release of hydrocortisone acetate from the hydrogel system was increasingly sensitive to mechanical compression, and the mechanical responsiveness of hydrocortisone acetate release increased dramatically as the concentration of mono-6-deoxy-6-ethylenediamine-β-cyclodextrin increased from 0% to 46%, whereas the swelling rate and stiffness of the hydrogel decreased as the concentration of mono-6-deoxy-6-ethylenediamine-β-cyclodextrin increased. The mechanical responsiveness of hydrocortisone acetate release was attributable to conformational distortion of mono-6-deoxy-6-ethylenediamine-β-cyclodextrin moieties and deformation of the polymer network. Moreover, we demonstrated that the hydrogel continuously released and accumulated hydrocortisone acetate in the medium when compressed for up to 72 h, which led to increasing suppression of nitric oxide production in the lipopolysaccharide-stimulated mouse macrophages (RAW264.7), indicating desirable anti-inflammatory effect at the cell level. Hence, this hydrogel system may provide a useful platform for drug delivery, such as hydrocortisone acetate release to wound site, by intentionally generated mechanical force.

Keywords

Alginate β-cyclodextrin hydrocortisone acetate drug delivery system mechanical compression

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References

Murakami

Aoki

Nakamura

. Hydrogel blends of chitin/chitosan, fucoidan and alginate as healing-impaired wound dressings. Biomaterials 2010; 31: 83–90.

Kim

Park

Kim

. Development of polyvinyl alcohol-sodium alginate gel-matrix-based wound dressing system containing nitrofurazone. Int J Pharm 2008; 359: 79–86.

Thomas

. Alginate dressings in surgery and wound management—part 1. J Wound Care 2000; 9: 56–60.

Thomas

. Alginate dressings in surgery and wound management: part 2. J Wound Care 2000; 9: 115–119.

Gupta

Jain

Raghubir

. A time course study for the development of an immunocompromised wound model, using hydrocortisone. J Pharmacol Toxicol Methods 1999; 41: 183–187.

Gupta

Parker

Turk

. A comparison of the effects of hydrocortisone on peritoneal inflammatory exudates, the tuberculin reaction and contact sensitivity to DNFB in the guinea pig. Int J Immunopharmacol 1985; 7: 705–712.

Stephens

Hunt

Jawetz

. Effect of cortisone and vitamin A on wound inflection. Am J Surq 1971; 121: 569–571.

Greenberg

. Corticosteroid therapy for IBD: old and new. J Gastroen Hepatol 1993; 7: 127–131.

Kwon

Diestelhorst

Suverkrup

. Dosage problems in suspension eyedrops. Klin Monbl Augenheilkd 1996; 209: 144–149 (in German).

10.

Apt

Henrick

Silverman

. Patient compliance with use of topical ophthalmic corticosteroid suspensions. Am J Ophthalmol 1979; 87: 210–214.

11.

Davies

Wang

Tucker

. Evaluation of a hydrocortisone/hydroxypropyl-β-cyclodextrin solution for ocular drug delivery. Int J Pharm 1997; 156: 201–209.

12.

Kristmundsdottir

Loftsson

Holbrook

. Formulation and clinical evaluation of a hydrocortisone solution for the treatment of oral disease. Int J Pharm 1996; 139: 63–68.

13.

Szejtli

. Introduction and general overview of cyclodextrin chemistry. Chem Rev 1998; 98: 1743–1754.

14.

Moses

Dileep

Sharma

. Beta cyclodextrin-insulin-encapsulated chitosan/alginate matrix: oral delivery system. J Appl Polym Sci 2000; 75: 1089–1096.

15.

Prabaharan

Gong

. Novel thiolated carboxymethyl chitosan-g-β-cyclodextrin as mucoadhesive hydrophobic drug delivery carriers. Carbohyd Polym 2008; 73: 117–125.

16.

Hyun

Moon

Park

. Strain-controlled release of molecules from arrayed microcapsules supported on an elastomer substrate. Angew Chem Int Ed Engl 2011; 50: 724–727.

17.

Lee

Peters

Anderson

. Controlled growth factor release from synthetic extracellular matrices. Nature 2000; 408: 998–1000.

18.

Lee

Peters

Mooney

. Controlled drug delivery from polymers by mechanical signals. Adv Mater 2001; 13: 837–839.

19.

Quan

Chen

Wang

. Core-shell nanosized assemblies mediated by the α-β cyclodextrin dimer with a tumor-triggered targeting property. ACS Nano 2010; 4: 4211–4219.

20.

Izawa

Kawakami

Sumita

. β-Cyclodextrin-crosslinked alginate gel for patient-controlled drug delivery systems: regulation of host-guest interactions with mechanical stimuli. J Mater Chem B 2013; 1: 2155–2161.

21.

Tan

Liu

. Stimuli-induced gel-sol transition of multi-sensitive supramolecular β-cyclodextrin grafted alginate/ferrocene modified pluronic hydrogel. Soft Matter 2012; 8: 5746–5749.

22.

Higuchi

Kristiansen

. Binding specificity between small organic solutes in aqueous solution: classification of some solutes into two groups according to binding tendencies. J Pharm Sci 1970; 59: 1601–1608.

23.

Vázquez

San Roman

Peniche

. Polymeric hydrophilic hydrogels with flexible hydrophobic chains. Control of the hydration and interactions with water molecules. Macromolecules 1997; 30: 8440–8446.

24.

Hutter

Bechhoefer

. Calibration of atomic-force microscope tips. Rev Sci Instrum 1993; 64: 1868–1873.

25.

Lin

Kim

. Measurement of the elastic modulus of polymeric films using an AFM with a steel micro-spherical probe tip. Polym Test 2012; 31: 926–930.

26.

Yan

Luo

. Thermosensitive poly(N-isopropyl acrylamide-co-N,N-dimethyl acryl amide)-block-poly(D,L-lactide) amphiphilic block copolymer micelles for prednisone drug release. J Bioact Compat Pol 2013; 28: 66–85.

27.

You

Heiman

Chen

. Novel steroid spiro enones: condensation of prednisolone derivatives with diethyl oxalate. Steroids 2000; 65: 109–115.

28.

Heiman

Hickman

D-H

. New steroidal anti-inflammatory antedrugs bind to macrophage glucocorticoid receptors and inhibit nitric oxide generation. Steroids 1998; 63: 644–649.

29.

Park

You

. Synthesis and pharmacological evaluations of new steroidal anti-inflammatory antedrugs: 9α-Fluoro-11β,17α,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16α-carboxylate (FP16CM) and its derivatives. Steroids 2006; 71: 83–89.

30.

Green

Wagner

Glogowski

. Analysis of nitrate, nitrite, and [¹⁵N] nitrate in biological fluids. Anal Biochem 1982; 126: 131–138.

31.

Zhu

Lin

. Surface engineering of poly(DL-lactic acid) by entrapment of alginate-amino acid derivatives for promotion of chondrogenesis. Biomaterials 2002; 23: 3141–3148.

32.

Hanessian

Benalil

Viet

MTP

. The intramolecular inclusion of aromatic esters within β-cyclodextrin as a function of chain length—a detailed NMR study. Tetrahedron 1995; 51: 10131–10148.

33.

Guzik

Korbut

Adamek-Guzik

. Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol 2003; 54: 469–487.