A Hypoxia-Activated\nProdrug Conjugated with a BODIPY-Based\nPhotothermal Agent for Imaging-Guided Chemo-Photothermal Combination\nTherapy

Abstract

Hypoxia-activated prodrugs (HAPs) have drawn increasing\nattention\nfor improving the antitumor effects while minimizing side effects.\nHowever, the heterogeneous distribution of the hypoxic region in tumors\nseverely impedes the curative effect of HAPs. Additionally, most HAPs\nare not amenable to optical imaging, and it is difficult to precisely\ntrace them in tissues. Herein, we carefully designed and synthesized\na multifunctional therapeutic <b>BAC</b> prodrug by connecting\nthe chemotherapeutic drug camptothecin (CPT) and the fluorescent photothermal\nagent boron dipyrromethene (BODIPY) via hypoxia-responsive azobenzene\nlinkers. To enhance the solubility and tumor accumulation, the prepared <b>BAC</b> was further encapsulated into a human serum albumin (HSA)-based\ndrug delivery system to form <b>HSA@BAC</b> nanoparticles. Since\nthe CPT was caged by a BODIPY-based molecule at the active site, the <b>BAC</b> exhibited excellent biosafety. Importantly, the activated\nCPT could be quickly released from <b>BAC</b> and could perform\nchemotherapy in hypoxic cancer cells, which was ascribed to the cleavage\nof the azobenzene linker by overexpressed azoreductase. After irradiation\nwith a 730 nm laser, <b>HSA@BAC</b> can efficiently generate\nhyperthermia to achieve irreversible cancer cell death by oxygen-independent\nphotothermal therapy. Under fluorescence imaging-guided local irradiation,\nboth <i>in vitro</i> and <i>in vivo</i> studies\ndemonstrated that <b>HSA@BAC</b> exhibited superior antitumor\neffects with minimal side effects.