Radiofrequency induced UCST-type gel-sol transition of metformin-conjugated nanogels for precisely synergizing thermal ablation and blood-vessel embolization

Abstract

Transcatheter arterial chemoembolization (TACE) exhibits an important role in the treatment of some solid tumors. However, incomplete embolization and angiogenesis-induced tumor relapse and metastasis remain the biggest challenges for TACE. Here, we synthesized metformin-conjugated poly(N-acryloyl glycinamide) (pMet) nanogels for precisely synergizing TACE with radiofrequency ablation (RFA) to improve antitumor efficacy. pMet nanogels exhibited RF-heating effect and UCST-type gel-sol phase transition, with high performance of sol syringeability, gel strength and thermal stability. Meanwhile, pMet nanogels showed distinct cytotoxicity and suppression of CD24. By the synergistic efficacy with RF-heating, pMet nanogels exhibited significant tumor regression (0.37 ± 0.5) over 36 d in H22-bearing mice. pMet nanogels further down-regulated the levels of PD-1 and Tim-3 of CD8+ T cells and CD25 and CD38 of CD4+ T cells, suggesting their improvement on tumor immunosuppressive microenvironment. The blood-vessel embolization of pMet nanogels was well validated on rabbit ear vessel model. pMet nanogels provide a new paradigm for constructing RF responsive embolic platform.