Poly(2-isopropenyl-2-oxazoline) Hydrogels with Biodegradable Junction Points for Drug-Delivery Applications

Poly­(2-isopropenyl-2-oxazoline) (PiPOx) is a functional and versatile polymer showing great potential in developing hydrogel materials. The postpolymerization functionalization of PiPOx with various dicarboxylic acid derivatives evidenced that the hydrophilic character and the mechanical properties of hydrogels can be tailored to address specific applications, in particular biomedical applications. In this study, we report on the synthesis of biodegradable PiPOx-based hydrogels as drug vehicles. These hydrogels were designed to enhance the efficacy and safety of drug release, undergoing hydrolysis in simulated physiological fluids. To facilitate their use in biomedical applications, the herein PiPOx-based hydrogels were obtained in a one-pot synthesis cross-linking protocol in water at a moderate temperature of 60 °C. The cross-linking reaction of PiPOx was performed with a series of nontoxic biobased amino/hydroxy-substituted dicarboxylic acids in the absence and presence of a hydrophilic drug model, propranolol hydrochloride. The chemical nature of the cross-linker influenced the degradation rate and the drug-release performance of the hydrogel materials. The water uptake, cross-linking density, and mechanical stability of the hydrogels could be easily modulated by changing the cross-linker or by altering the ratio between the 2-oxazoline pendent groups and the carboxylic acid groups. The hydrolytic degradation and the drug-release kinetics of the hydrogels were evaluated in-depth in simulated body fluids with pH values of 1.2 (pH of gastric fluid), 7.4 (pH of plasma), and 8 (pH of intestinal fluid), whereas the drug-release kinetic parameters were also assessed and discussed. The drug-release rate could be effortlessly controlled by varying both the cross-linker nature and the amount of cross-linker. Moreover, the degradability of the hydrogels under enzymatic conditions using either lipase or esterase as the hydrolysis promoter was demonstrated. Preliminary biological assays proved that the degradation products of PiPOx hydrogels are noncytotoxic, and they do not generate inflammatory responses. Additionally, hemocompatibility assays revealed that PiPOx hydrogels did not have a noxious effect on blood plasma coagulation. Considering the reported results, these hydrogels show potential use as long-term biodegradable implants in tissue engineering or controlled drug-delivery applications.