Tumor Microenvironment-Responsive Intelligent Nanoplatform with Oxygen Self-Supply for Synergistic Chemotherapy/photodynamic Therapy/photothermal Therapy Against Hypoxic Tumors

Nanomaterial-based multi-modal synergistic therapies are emerging as highly promising strategies for the treatment of malignant tumors. Herein, a novel nanoplatform modified with the peptide of cyclo(Arg-Gly-Asp-D-Phe-Lys (cRGD) was designed for synergistic treatment of hypoxic tumors by the combination of chemotherapy (CT)/photodynamic therapy (PDT)/photothermal therapy (PTT). Firstly, Mn@APDA nanoparticles were synthesized for PTT and oxygen (O2) supply, consisting of an L-arginine-doped polydopamine (APDA) core and a manganese dioxide (MnO2) shell. Subsequently, the liposome nanoplatform (cRGD-Lipo-MART), loaded with Mn@APDA (MA), chemotherapy drug of deoxybouvardin dodecyl ester (RA, “R” for short), and mitochondrial targeted photosensitizer of triphenylphosphine-grafted protoporphyrin IX (TPPP, “T” for short), was developed using a film dispersion method. Upon targeted delivery to tumors, the nanoplatform disintegrated in response to the acidic and hydrogen peroxide (H2O2)-rich tumor microenvironment (TME) and near-infrared (NIR) laser irradiation, thereby facilitating controlled drug release and O2 supply to overcome hypoxia. The released RA could cause DNA damage and suppress the HIF-1α expression to sensitize PDT. Simultaneously, TPPP could generate singlet oxygen (1O2) and convert L-arginine (L-Arg) into nitric oxide (NO) for PDT, while APDA could induce hyperthermia for PTT. The combination of PDT and PTT resulted in significant mitochondrial dysfunction and lysosomal damage, ultimately leading to apoptosis. Furthermore, the chemotherapeutic effect of RA could be potentiated by the enhancement of cytoplasmic delivery caused by lysosomal disruption and the blocking of DNA damage repair pathway caused by mitochondrial dysfunction. Overall, cRGD-Lipo-MART, designed with a synergistic CT/PDT/PTT strategy, showed minimal systemic toxicity and could be used as an effective treatment for hypoxic tumors.