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

Abstract

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.