Nanoparticles that target the mitochondria of tumor cells to restore oxygen supply for photodynamic therapy: Design and preclinical validation against breast cancer

• Published in: Journal of controlled release 2023-10, Vol.362, p.356-370
• Main Authors: Bai, Xiaosheng, Lin, Yan, Gong, Lingyi, Duan, Junfeng, Sun, Xiaoduan, Wang, Changguang, Liu, Zerong, Jiang, Jun, Zhou, Xiangyu, Zhou, Meiling, Zhang, Zhirong, Liu, Zhongbing, Jing, Pei, Zhong, Zhirong
• Format: Article
• Language: English
• Subjects: 5-Aminolevulinic acid; Breast cancer; Folic acid; Nanoparticles; Photodynamic therapy
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2023.07.064

Photodynamic therapy, in which photosensitizers locally generate cytotoxic reactive oxygen species, can treat tumor tissue with minimal effects on surrounding normal tissue, but it can be ineffective because of the anoxic tumor microenvironment. Here we developed a strategy to inactivate the mitochondria of tumor cells in order to ensure adequate local oxygen concentrations for photodynamic therapy. We conjugated the photosensitizer 5-aminolevulinic acid to the lipophilic cation triphenylphosphine, which targets mitochondria. Then we packaged the conjugate into nanoparticles that were based on biocompatible bovine serum albumin and coated with folic acid in order to target the abundant folate receptors on the tumor surface. In studies in cell culture and BALB/c mice bearing MCF-7 xenografts, we found that the nanoparticles helped solubilize the cation-photosensitizer conjugate, prolong its circulation, and enhance its photodynamic antitumor effects. We confirmed the ability of the nanoparticles to target tumor cells and their mitochondria using confocal laser microscopy and in vivo assays of pharmacokinetics, pharmacodynamics, and tissue distribution. Our results not only identify a novel nanoparticle system for treating cancer, but they demonstrate the feasibility of enhancing photodynamic therapy by reducing oxygen consumption within tumors. Schematic diagram of FA-BAT-NPs for targeting the mitochondria of breast cancer cells to restore oxygen supply for photodynamic therapy. BAT, Boc-ALA-TPP; BSA, bovine serum albumin; BAT-NPs, BAT-loaded nanoparticles; FA-BAT-NPs, folic acid modified BAT-NPs; FR, folate receptor. [Display omitted] •Inactivating mitochondria of tumor cells to ensure adequate local ROS for photodynamic therapy.•Targeting nanoparticles to the mitochondria of tumor cells to restore oxygen supply for PDT.•Increasing local levels of oxygen by destroying mitochondria within tumor cells.•Triphenylphosphine as a mitochondrial-targeting molecule was conjugated with photosensitizer.•Converting photosensitizer photodynamically into additional ROS.