히알루론산 기반의 암 치료용 다자극 반응성 하이드로겔

Abstract

One of the most promising strategies for the controlled release of therapeutic molecules is stimuli-responsive and biodegradable hydrogels developed from natural polymers. Hyaluronic acid is a natural polymer which can uptake a large amount of biological fluids and has been recognized as a safe and highly biocompatible material. In this study, multi-stimuli responsive hydrogels based on hyaluronic acid were prepared for the controlled release of doxorubicin (DOX). Hydrogels were rapidly formed via a reverse electron demand Diels-Alder click chemistry by using a norbornene functionalized hyaluronic acid and a tetrazine cross-linker containing diselenide bonds. To achieve desirable properties, we prepared hydrogels with different crosslinking densities. The formulated hydrogels demonstrated high swelling ratios, good mechanical strength, and higher drug loading capacities (up to 92%). The hydrogels showed minimal DOX release in physiological mimicking buffer, however rapid and sustained release of DOX was observed in 10 mmol DTT. To further confirm the oxidation-dependent cleavage and DOX release from hydrogels, DOX release experiments were also conducted in 0.5 % H2O2, and showed the burst release of DOX. In a parallel experiment, indocyanine green (ICG) dye was encapsulated into hydrogels along with the DOX. The DOX-ICG-loaded hydrogels showed a sustained release of DOX after NIR light exposure. The cytotoxicity experiments with human embryonic kidney cells showed that HA-Nb, crosslinker, and the formulated hydrogels were highly biocompatible (> 90% cell viability). The in vitro anti-tumor assessment experiment demonstrated that DOX-loaded hydrogels induced similar anti-tumor effect as compared to that of the free-DOX. Furthermore, DOX+ICG loaded hydrogels increased the efficacy of DOX after NIR treatment owing to the combine anti-tumor and photothermal effect.