Mitochondria-targeting multifunctional nanoplatform for cascade phototherapy and hypoxia-activated chemotherapy

• Published in: Journal of nanobiotechnology Vol. 20; no. 1; pp. 42 - 16
• Main Authors: Lv, Jie, Wang, Shuangling, Qiao, Duo, Lin, Yulong, Hu, Shuyang, Li, Meng
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21.01.2022; BioMed Central; BMC
• Subjects: Ablation; Animals; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Cancer; Cancer therapies; Care and treatment; Cell Hypoxia - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Chemotherapy, Combination; Combination therapy; Copper sulfides; Cytotoxicity; Dopamine; Drug carriers; Drug delivery; Drug delivery systems; Drug Delivery Systems - methods; Drug resistance; Drugs; Efficiency; Female; Heat resistance; Hypoxia; Hypoxia-activated prodrug; In vivo methods and tests; Irradiation; Lasers; Light therapy; Methods; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Mitochondria-targeting; Nanomaterials; Nanoparticles; Nanoparticles - chemistry; Nitroimidazoles - chemistry; Nitroimidazoles - pharmacokinetics; Nitroimidazoles - pharmacology; Patient outcomes; Phosphoramide Mustards - chemistry; Phosphoramide Mustards - pharmacokinetics; Phosphoramide Mustards - pharmacology; Photochemotherapy; Photochemotherapy - methods; Photodynamic therapy; Phototherapy; Prodrugs; Prodrugs - chemistry; Prodrugs - pharmacology; Tissue Distribution; Tumor cells; Vehicles; Iran; Beijing China; China; Japan; Hypoxia-activated prodrug; Drug delivery; Combination therapy; Mitochondria-targeting; Phototherapy
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-022-01244-9

Despite considerable progress has been achieved in hypoxia-associated anti-tumor therapy, the efficacy of utilizing hypoxia-activated prodrugs alone is not satisfied owing to the inadequate hypoxia within the tumor regions. In this work, a mitochondrial targeted nanoplatform integrating photodynamic therapy, photothermal therapy and hypoxia-activated chemotherapy has been developed to synergistically treat cancer and maximize the therapeutic window. Polydopamine coated hollow copper sulfide nanoparticles were used as the photothermal nanoagents and thermosensitive drug carriers for loading the hypoxia-activated prodrug, TH302, in our study. Chlorin e6 (Ce6) and triphenyl phosphonium (TPP) were conjugated onto the surface of the nanoplatform. Under the action of TPP, the obtained nanoplatform preferentially accumulated in mitochondria to restore the drug activity and avoid drug resistance. Using 660 nm laser to excite Ce6 can generate ROS and simultaneously exacerbate the cellular hypoxia. While under the irradiation of 808 nm laser, the nanoplatform produced local heat which can increase the release of TH302 in tumor cells, ablate cancer cells as well as intensify the tumor hypoxia levels. The aggravated tumor hypoxia then significantly boosted the anti-tumor efficiency of TH302. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional hypoxia-associated chemotherapy. This work highlights the potential of using a combination of hypoxia-activated prodrugs plus phototherapy for synergistic cancer treatment.