Responsively aggregatable nanochelator-mediated antiangiogenesis to enhance interventional therapies for liver cancer

Abstract

Transarterial chemoembolization (TACE) requires the complete embolization of tumor vessels. However, after embolization, tumor hypoxia and angiogenesis increase, and copper ions (Cu2+) play a key role in the regulation of angiogenesis. Decreasing the undesirable release of Cu2+ into serum and tumor tissues is a major challenge in the use of TACE. In this study, we constructed an adhesive injectable thermosensitive hydrogel (poly(N-isopropylacrylamide-codopamine methacrylamide), PND) loaded with a small Cu chelator (SO-N) for use in synergistic tumor embolization; this agent is called PNDS. SO-N chelates Cu2+ in a highly selective manner and can effectively consume the biocopper that is involved in angiogenesis. In addition, the adhesive thermosensitive hydrogel rapidly formed a gel in situ, which further inhibited the local blood ny to the tumor and accelerated ischemic necrosis. Moreover, the ability of PNDS to efficiently chelate Cu2+ and inhibit angiogenesis was investigated in vitro. Our in vivo experiments demonstrated that PNDS can promote tumor necrosis, reduce tumor Cu2+ levels, inhibit angiogenesis and tumor metastasis, and greatly prolong rabbit survival. This study is the first to show elevated serum Cu2+ levels in liver cancer patients with TACE failure/refractoriness; PNDS provides a promising approach for improving the efficacy of TACE for liver cancer by regulating Cu homeostasis.