Pentablock thermoresponsive hydrogels for chemotherapeutic delivery in a pancreatic cancer model

Abstract

The design of biodegradable and thermoresponsive polymeric hydrogels with tuneable properties holds immense promise for localised and sustained drug delivery. In this study, we designed and synthesised a library of novel pentablock copolymers, incorporating poly(d,l-lactide) (PLA) into methoxypoly(ethylene glycol)-poly(ϵ-caprolactone)-methoxypoly(ethylene glycol) (mPEG-PCL-mPEG, or PECE) hydrogels to enhance the hydrolytic degradation and drug release profiles. A pentablock copolymer, methoxypoly(ethylene glycol)-b-poly(d,l lactide)-b-poly(ϵ-caprolactone)-b-poly(d,l lactide)-b-methoxypoly(ethylene glycol) (mPEG-PLA-PCL-PLA-mPEG, or PELCLE), was selected based on its thermoresponsive sol-gel transition behaviour at a physiologically relevant temperature (37 °C). Physicochemical characterisation revealed that both PECE and PELCLE hydrogels self-assembled into micellar structures, with PELCLE exhibiting smaller micellar sizes compared to PECE. The incorporation of PLA led to reduced hydrogel stiffness, enhanced degradability, and decreased swelling compared to PECE. In vitro drug release studies demonstrated that both hydrogels exhibited sustained release of various anti-cancer drugs, with PELCLE generally showing slower release kinetics, highlighting its potential for prolonged drug delivery. For potential pancreatic cancer applications, we evaluated the biocompatibility and therapeutic efficacy of PELCLE hydrogels loaded with gemcitabine and oxaliplatin (GEMOX). In vitro and in vivo studies demonstrated safety and some anti-tumour efficacy of GEMOX-loaded PELCLE compared to free drug administration, attributed to enhanced tumour retention and sustained drug release. These findings highlight the potential of the PELCLE hydrogel as a versatile and effective local drug delivery platform for the treatment of pancreatic cancer and other solid tumours, warranting further investigation towards its clinical translation.