HO-responsive polymer prodrug nanoparticles with glutathione scavenger for enhanced chemo-photodynamic synergistic cancer therapy.

The combination of chemotherapy and photodynamic therapy (PDT) based on nanoparticles (NPs) has been extensively developed to improve the therapeutic effect and decrease the systemic toxicity of current treatments. However, overexpressed glutathione (GSH) in tumor cells efficiently scavenges singlet oxygens (O) generated from photosensitizers and results in the unsatisfactory efficacy of PDT. To address this obstacle, here we design HO-responsive polymer prodrug NPs with GSH-scavenger (Ce6@P(EG--CPBE) NPs) for chemo-photodynamic synergistic cancer therapy. They are constructed by the co-self-assembly of photosensitizer chlorin e6 (Ce6) and amphiphilic polymer prodrug P(EG--CPBE), which is synthesized from a hydrophilic alternating copolymer P(EG--PD) by conjugating hydrophobic anticancer drug chlorambucil (CB) via an HO-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA). Ce6@P(EG--CPBE) NPs can efficiently prevent premature drug leakage in blood circulation because of the high stability of the PBA linker under the physiological environment and facilitate the delivery of Ce6 and CB to the tumor site after intravenous injection. Upon internalization of Ce6@P(EG--CPBE) NPs by tumor cells, PBA is cleaved rapidly triggered by endogenous HO to release CB and Ce6. Ce6 can effectively generate abundant O under 660 nm light irradiation to synergistically kill cancer cells with CB. Concurrently, PBA can be transformed into a GSH-scavenger (quinine methide, QM) under intracellular HO and prevent the depletion of O, which induces the cooperatively strong oxidative stress and enhanced cancer cell apoptosis. Collectively, such HO-responsive polymer prodrug NPs loaded with photosensitizer provide a feasible approach to enhance chemo-photodynamic synergistic cancer treatment.