4.8 Article

Metal-Organic Layer Delivers 5-Aminolevulinic Acid and Porphyrin for Dual-Organelle-Targeted Photodynamic Therapy

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WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202301910

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5-Aminolevulinic Acid; Cancer Therapy; Metal-Organic Layer; Organelle Targeting; Photodynamic Therapy

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A dual-organelle-targeted nanoparticle platform was developed for enhanced photodynamic therapy (PDT) of cancer. The platform grafted 5-aminolevulinic acid (ALA) to a Hf-12-based nanoscale metal-organic layer (Hf-MOL), which improved ALA delivery and protoporphyrin IX (PpIX) synthesis in mitochondria, and trapped 5,15-di-p-benzoatoporphyrin (DBP) photosensitizers in lysosomes. By simultaneously exciting PpIX and DBP with light irradiation at 630 nm, synergistic enhancement of PDT efficacy was achieved through the damage to both mitochondria and lysosomes.
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-12-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.

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