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
Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China; Department of Pharmacy, Longquanyi District of Chengdu Maternity and Child Health Care Hospital, Chengdu, Sichuan 610100, China.
Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.
J Control Release. 2023 Oct;362:356-370. doi: 10.1016/j.jconrel.2023.07.064. Epub 2023 Sep 4.
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.
光动力疗法利用光敏剂在局部产生具有细胞毒性的活性氧，能够治疗肿瘤组织，同时对周围正常组织的影响最小，但由于肿瘤微环境缺氧，该疗法可能无效。在此，我们开发了一种策略来使肿瘤细胞的线粒体失活，以确保光动力疗法有足够的局部氧浓度。我们将光敏剂5-氨基乙酰丙酸与靶向线粒体的亲脂性阳离子三苯基膦偶联。然后，我们将该偶联物包装到基于生物相容性牛血清白蛋白并涂有叶酸的纳米颗粒中，以便靶向肿瘤表面丰富的叶酸受体。在细胞培养以及携带MCF-7异种移植瘤的BALB/c小鼠的研究中，我们发现这些纳米颗粒有助于使阳离子-光敏剂偶联物溶解，延长其循环时间，并增强其光动力抗肿瘤作用。我们使用共聚焦激光显微镜以及药代动力学、药效学和组织分布的体内试验，证实了纳米颗粒靶向肿瘤细胞及其线粒体的能力。我们的结果不仅确定了一种用于治疗癌症的新型纳米颗粒系统，而且还证明了通过减少肿瘤内的氧消耗来增强光动力疗法的可行性。
