Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
Angew Chem Int Ed Engl. 2023 May 22;62(22):e202301910. doi: 10.1002/anie.202301910. Epub 2023 Apr 21.
The efficacy of photodynamic therapy (PDT) depends on the subcellular localization of photosensitizers. Herein, we report a dual-organelle-targeted nanoparticle platform for enhanced PDT of cancer. By grafting 5-aminolevulinic acid (ALA) to a Hf -based nanoscale metal-organic layer (Hf-MOL) via carboxylate coordination, ALA/Hf-MOL enhanced ALA delivery and protoporphyrin IX (PpIX) synthesis in mitochondria, and trapped the Hf-MOL comprising 5,15-di-p-benzoatoporphyrin (DBP) photosensitizers in lysosomes. Light irradiation at 630 nm simultaneously excited PpIX and DBP to generate singlet oxygen and rapidly damage both mitochondria and lysosomes, leading to synergistic enhancement of the PDT efficacy. The dual-organelle-targeted ALA/Hf-MOL outperformed Hf-MOL in preclinical PDT studies, with a 2.7-fold lower half maximal inhibitory concentration in cytotoxicity assays in vitro and a 3-fold higher cure rate in a colon cancer model in vivo.
光动力疗法（PDT）的疗效取决于光敏剂的亚细胞定位。在此，我们报告了一种双细胞器靶向纳米颗粒平台，用于增强癌症的 PDT。通过羧酸酯配位将 5-氨基酮戊酸（ALA）接枝到基于 Hf 的纳米级金属有机层（Hf-MOL）上，ALA/Hf-MOL 增强了线粒体中的 ALA 传递和原卟啉 IX（PpIX）的合成，并将包含 5,15-二-对苯甲酰基卟啉（DBP）光敏剂的 Hf-MOL 困在溶酶体中。630nm 的光照射同时激发 PpIX 和 DBP 产生单线态氧，并迅速破坏线粒体和溶酶体，协同增强 PDT 疗效。在临床前 PDT 研究中，双细胞器靶向的 ALA/Hf-MOL 优于 Hf-MOL，体外细胞毒性测定的半最大抑制浓度低 2.7 倍，体内结肠癌模型的治愈率高 3 倍。
