Sequentially pH-Responsive Drug-Delivery Nanosystem for Tumor Immunogenic Cell Death and Cooperating with Immune Checkpoint Blockade for Efficient Cancer Chemoimmunotherapy
Mingxia Jiang, Wenqiang Chen, Wenjing Yu, Zhiwei Xu, Xinyue Liu, Qingmiao Jia, Xiuwen Guan, Weifen Zhang
Abstract
Chemoimmunotherapy has anchored a new blueprint for cancer management. As a burgeoning approach, immunotherapy has shifted the paradigm of traditional chemotherapy and opened up new prospects for cancer treatment. Here, a sequentially pH-responsive doxorubicin (DOX) delivery nanosystem is designed for simultaneous chemotherapy and tumor immunogenic cell death (ICD). DOX is modified into pH-sensitive cis-aconityl-doxorubicin (CAD) for being easily adsorbed by polycationic polyethylenimine (PEI), and the PEI/CAD complexes are in situ-shielded by aldehyde-modified polyethylene glycol (PEG). The PEG/PEI/CAD nanoparticles (NPs) can keep stable in neutral physiological pH during systemic circulation but will detach PEG shielding once in slightly acidic tumor extracellular pH. The exposed positive PEI/CAD complexes are endocytosed effortlessly, and CAD is then converted back to DOX by endosomal-acidity-triggered cis-aconityl cleavage. The released DOX further elicits ICD, and the moribund tumor cells will release antigens and damage-associated molecular patterns to recruit dendritic cells and activate antitumor immunity. An excellent therapeutic effect is achieved when the immune checkpoint PD-1 antibody (aPD-1) is utilized to cooperate with the PEG/PEI/CAD NPs for blocking tumor immune escape and maintaining antitumor activity of the ICD-instigated T cells. The sequentially pH-responsive DOX delivery nanosystem cooperating with immune checkpoint blockade will provide a potential strategy for cancer chemoimmunotherapy.