Dual-Locked Nanophotosensitizer Harnessing Cerenkov Radiation for Deep Tumor Therapy
Huihui Liu, Jie Guo, Wu Yin, Hehua Xiong, Ling Chen, Yiling Ruan, Kai Feng, Dan Su, Yi Liu, Xiaolian Sun
Abstract
Photodynamic therapy (PDT) faces significant challenges in treating deep tumors due to the limited light penetration depth. Cerenkov radiation-induced PDT (CR-PDT) offers a potential solution by harnessing luminescence derived from radionuclides. However, the simultaneous delivery of radionuclides and photosensitizers in conventional CR-PDT systems leads to unnecessary phototoxicity of healthy tissues. Here, we present a tumor microenvironment (TME)-activated, dual-locked nanophotosensitizer ( 89 Zr-PHZ-BrCyE) that integrates 89 Zr-labeled pH-responsive polymeric micelle and a carboxylesterase (CrES)-activated photosensitizer prodrug for precise deep tumor therapy. The dual-responsive CR-PDT system demonstrated highly selective cytotoxicity toward hepatocellular carcinoma (HepG2) cells, with minimal impact on normal liver cells (L02). Upon intravenous injection, 89 Zr-PHZ-BrCyE exhibited robust tumor inhibition and excellent biosafety in both subcutaneous and orthotopic H22 tumor models. This approach holds great promise for improving the therapeutic outcomes of CR-PDT in deep-seated tumors while ensuring good biosafety, paving the way for future potential clinical applications in the future.