Injectable Reactive Oxygen Species-Responsive SN38 Prodrug Scaffold with Checkpoint Inhibitors for Combined Chemoimmunotherapy
Yimou Gong, Muchao Chen, Yanjun Tan, Jingjing Shen, Qiutong Jin, Wutong Deng, Jian Sun, Chao Wang, Zhuang Liu, Qian Chen
Abstract
Chemotherapeutic agents have been widely used for cancer treatment in clinics. Aside from their direct cytotoxicity to cancer cells, some of them could activate the immune system of the host, contributing to the enhanced antitumor activity. Here, the reactive oxygen species (ROS)-responsive hydrogel, covalently cross-linked by phenylboronic acid-modified 7-ethyl-10-hydroxycamptothecin (SN38-SA-BA) with poly(vinyl alcohol) (PVA), is fabricated for topical delivery of anti-programmed cell death protein ligand 1 antibodies (aPDL1). In the presence of endogenous ROS, SN38-SA-BA will be oxidized and hydrolyzed, leading to the degradation of hydrogel and the release of initial free SN38 and encapsulated aPDL1. It is demonstrated that SN38 could elicit specific immune responses by triggering immunogenic cell death (ICD) of cancer cells, a distinct cell death pathway featured with the release of immunostimulatory damage-associated molecular patterns (DAMPs). Meanwhile, the released aPDL1 could bind to programmed cell death protein ligand 1 (PDL1) expressed on cancer cells to augment antitumor T cell responses. Thus, the ROS-responsive prodrug hydrogel loaded with aPDL1 could induce effective innate and adaptive antitumor immune responses after local injection, significantly inhibiting or even eliminating those tumors.