Hyaluronic Acid Nanomicelles for Photo-chemodynamic Antitumor Therapy

Cancer cell immune escape, metastasis, invasion, and recurrence are closely related to high immune-checkpoint expression and tumor hypoxia. Immune-checkpoint inhibition and tumor hypoxia regulation have therefore garnered attention in cancer therapeutics. This study found that the methyl pyropheophorbide-a (MPPa) derivative complex 31,32,7,8-tetrahydroxy-4H-MPPa-Cu2+ (HMPPa-Cu) induces apoptosis in tumor cells to activate immunogenicity. HMPPa-Cu combined with anti-programmed death ligand 1 (PD-L1) immune-checkpoint blockade (ICB) therapy not only eradicates light-irradiated primary CT26 colon cancer but also inhibits untreated distant tumors. HMPPa-Cu catalyzes hydrogen peroxide decomposition to generate oxygen in situ and increase the cellular oxygen concentration. To enable HMPPa-Cu tumor targeting and increase its cell uptake capacity, HMPPa-Cu was embedded with hyaluronic acid–cinnamaldehyde nanomicelles (NMs) to obtain HCHC NMs. Acid stimulation of the HCHC NMs released free HMPPa and Cu2+ and significantly increased the quantum yield of singlet oxygen. The tumor microenvironment and near infrared stimulation activated chemodynamic therapy (CDT) and photodynamic therapy (PDT) synergistically. Cu2+ depleted glutathione (DG) to amplify the reactive oxygen species and simultaneously underwent in situ oxygenation (ISO). HCHC NMs-mediated PDT/CDT/ISO/DG significantly improved the therapeutic effect of ICB.