Block copolymer prodrugs (BCPs) have emerged as one of the most promising anticancer drug delivery strategies, which can self‐assemble into nanoparticles with optimal physicochemical properties including sizes, morphologies, surface properties, and integration of multifunction for improved in vivo applications. Moreover, the utility of stimuli‐responsive linkages to conjugate drugs onto the polymer backbones can achieve efficient and targeting drug release. Several BCP micellar delivery systems have been pushed ahead into the clinical trials, which showed great promising potentials for cancer therapy. In recent years, various novel and more efficient BCP systems have been developed for better in vivo performance. In this focus article, we focus on the recent advances of BCPs including the synthesis, self‐assembly, and applications for cancer therapy. The synthetic methods are first introduced, and the self‐assembly of BCPs for in vivo anticancer applications is discussed along the line of varying endogenous stimuli‐responsive linkages including amide or ester bonds, pH, reduction, and oxidation‐responsive linkages. Finally, conclusions along with the brief future perspectives are presented. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

Immunotherapeutic efficacy of tumors based on immune checkpoint blockade (ICB) therapy is frequently limited by an immunosuppressive tumor microenvironment and cross-reactivity with normal tissues. Herein, we develop reactive oxygen species (ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody (αPDL1) and glucose oxidase (GOx). GOx and αPDL1 were complexed with oligomerized (−)-epigallocatechin-3-O-gallate (OEGCG), which was followed by chelation with Fe 3+ and coverage of the ROS-responsive block copolymer, POEGMA-b-PTKDOPA, consisting of poly(oligo(ethylene glycol)methacrylate) (POEGMA) and the block with thioketal bond-linked dopamine moieties (PTKDOPA) as the side chains. After intravenous injection, the nanocomplexes show prolonged circulation in the bloodstream with a half-life of 8.72 h and efficient tumor accumulation. At the tumor sites, GOx inside the nanocomplexes can produce H 2 O 2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals (•OH) which further trigger the release of the protein cargos through ROSresponsive cleavage of thioketal bonds. The released GOx improves the production efficiency of •OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy (CDT). The enhanced immunogenic cell death (ICD) can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released αPDL1, which significantly suppresses primary and metastatic tumors. Thus, the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via combination with CDT.

Although there is a strong correlation between multinucleated cells (MNCs) and cancer chemo-resistance in variety of cancers, our understanding of how multinucleated cells modulate the tumor micro-environment is limited. We captured multinucleated cells from triple-negative chemo-resistant breast cancers cells in a time frame, where they do not proliferate but rather significantly regulate their micro-environment. We show that oxidatively stressed MNCs induce chemo-resistance in vitro and in vivo by secreting VEGF and MIF. These factors act through the RAS/MAPK pathway to induce chemo-resistance by upregulating anti-apoptotic proteins. In MNCs, elevated reactive oxygen species (ROS) stabilizes HIF-1α contributing to increase production of VEGF and MIF. Together the data indicate, that the ROS-HIF-1α signaling axis is very crucial in regulation of chemo-resistance by MNCs. Targeting ROS-HIF-1α in future may help to abrogate drug resistance in breast cancer.

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