Polymer Prodrug-Based Nanoreactors Activated by Tumor Acidity for Orchestrated Oxidation/Chemotherapy

Therapeutic nanoreactors have been proposed to treat cancers through in situ transformation of low-toxicity prodrugs into toxic therapeutics in the body. However, the in vivo applications are limited by low tissue-specificity and different tissue distributions between sequentially injected nanoreactors and prodrugs. Herein, we construct a block copolymer prodrug-based polymersome nanoreactor that can achieve novel orchestrated oxidation/chemotherapy of cancer via specific activation at tumor sites. The block copolymers composed of poly(ethylene glycol) (PEG) and copolymerized monomers of camptothecin (CPT) and piperidine-modified methacrylate [P(CPTMA-co-PEMA)] were optimized to self-assemble into polymersomes in aqueous solution for encapsulation of glucose oxidase (GOD) to obtain GOD-loaded polymersome nanoreactors (GOD@PCPT-NR). GOD@PCPT-NR maintained inactive in normal tissues upon systemic administration. After deposition in tumor tissues, tumor acidity-triggered protonation of PPEMA segments resulted in high permeability of the polymersome membranes and oxidation reaction of diffused glucose and O₂ under the catalysis of GOD. The activation of the reaction generated H₂O₂, improving the oxidative stress in tumors. Simultaneously, a high level of H₂O₂ further activated PCPTMA prodrugs, releasing active CPT drugs. High tumor oxidative stress and released CPT drugs synergistically killed cancer cells and suppressed tumor growth via oxidation/chemotherapy. Our study provides a new strategy for engineering therapeutic nanoreactors in an orchestrated fashion for cancer therapy.