Gelatin/carboxymethyl cellulose based stimuli-responsive hydrogels for controlled delivery of 5-fluorouracil, development, in vitro characterization, in vivo safety and bioavailability evaluation

Abstract

Current work focuses on the synthesis and characterization of novel pH-sensitive biocompatible gelatin/carboxymethyl cellulose based hydrogels by free radical polymerization technique cross-linked with glutaraldehyde. Effect of pH, polymer ratio and variable crosslinking concentrations on dynamic swelling, equilibrium swelling, porosity, sol-gel analysis and in vitro release pattern was investigated. Hydrogel structure was confirmed by FTIR, XRD, and DSC. Moreover scanning electron microscopy confirmed the porous structure of gel network. Various structure property relationships like average molecular weight between crosslinks (Mc), solvent interaction parameters, volume fraction of polymer (V_2,s) and diffusion coefficient (D) that affect the release behaviour were determined. Results showed that maximum swelling and highest release of drug occurred at pH 1.2. Porosity and gel fraction increased by increasing polymer load. The invivo absorption and pharmacokinetics evaluation in rabbit's models revealed the controlled nature of hydrogels. MTT assay confirmed the biocompatible nature of blank hydrogels against Vero cell lines and cytotoxic potential against HeLa cell lines. The preliminary safety evaluation and oral tolerability revealed that the hydrogel solution is safe up to 4000 mg/kg body weight without causing any hematological or histopathological changes in rabbits.

Keywords: 5-Flourouracil (Pubchem CID: 121997); 5-Fluorouracil; Acetic acid (Pubchem CID: 176); Carboxymethyl cellulose (Pubchem CID: 6328154); Diffusion coefficient; Gelatin (Pubchem CID: DB11242); Gelatin/CMC hydrogels; Glutaraldehyde (Pubchem CID: 3485); Histopathology; Invivo evaluation; MTT assay; Potassium bromide (Pubchem CID: 253877); Potassium dihydrogen phosphate (Pubchem CID: 516951); Sodium chloride (Pubchem ID: 5234); Sodium hydroxide (Pubchem CID: 14798).