Acid-responsive endosomolytic polymeric nanoparticles with amplification of intracellular oxidative stress for prodrug delivery and activation†

Prodrug strategy especially in the field of chemotherapy of cancers possesses significant advantages reducing the side toxicity of anticancer drugs. However, high-efficiency delivery and in situ activation of prodrugs for tumor growth suppression are still a great challenge. Herein, we report rationally engineered pH-responsive endosomolytic polymeric micelles for the delivery of an oxidation-activable prodrug into the cytoplasm of cancer cells and amplification of intracellular oxidative stress for further prodrug activation. The prepared block copolymers consist of a poly(ethylene glycol) (PEG) block and a segment grafted by endosomolytic moieties and acetal linkage-connected cinnamaldehyde groups. The amphiphilic diblock copolymers can self-assemble to form micelles in water for loading the oxidation-activable phenylboronic pinacol ester-caged camptothecin prodrug (ProCPT). The obtained micelles can release free cinnamaldehyde under acidic conditions in tumor tissues and endo/lysosomes followed by efficient endosomal escape, which further induces enhancement of intracellular reactive oxygen species (ROS) to activate the prodrugs. Simultaneously, intracellular glutathione (GSH) can be reduced by quinone methide that was produced during prodrug activation. The ProCPT-loaded micelles can finally achieve efficient tumor accumulation and retention as well as effective tumor growth inhibition. More importantly, hematological and pathological analysis of toxicity reveals that the ProCPT-loaded micelles do not cause obvious toxic side effects toward important organs of mice. A positive immunomodulatory microenvironment in tumor tissue and serum can be detected after treatment with ProCPT-loaded micelles. Therefore, the endosomolytic ProCPT-loaded micelles exert synergistic therapeutic effects toward tumors through amplification of intracellular oxidative stress and activation of the prodrugs.