A “Missile-Detonation” Strategy to Precisely Supply and Efficiently Amplify Cerenkov Radiation Energy for Cancer Theranostics

Cerenkov radiation (CR) from radionuclides can act as a built-in light source for cancer theranostics, opening a new horizon in biomedical applications. However, considerably low tumor-targeting efficiency of existing radionuclides and radionuclide-based nanomedicines limits the efficacy of CR-induced theranostics (CRIT). It remains a challenge to precisely and efficiently supply CR energy to the tumor site. Here, a “missile-detonation” strategy is reported, in which a high dose of p-SCN-Bn-deferoxamine-porphyrin-PEG nanocomplex (Df-PPN) is first adminstered as a CR energy receiver/missile to passively target to tumor, and then a low dose of the ⁸⁹Zr-labeled Df-PPN is administrated as a CR energy donor/detonator, which can be visualized and quantified by Cerenkov energy transfer imaging, positron-emission tomography, and fluorescence imaging. Based on homologous properties, the colocalization of Df-PPN and ⁸⁹Zr-Df-PPN in the tumor site is maximized and efficient CR energy transfer is enabled, which maximizes the tumor-targeted CRIT efficacy in an optimal spatiotemporal setting while also reducing adverse off-target effects from CRIT. This precise and efficient CRIT strategy causes significant tumor vascular damage and inhibited tumor growth.