Nitroimidazole derivative incorporated liposomes for hypoxia-triggered drug delivery and enhanced therapeutic efficacy in patient-derived tumor xenografts

Abstract Hypoxia is not merely a tumor microenvironment byproduct, but rather an active participant in tumor development, invasion, and metastasis. Hypoxia contributes to poor outcomes in tumor treatment and has currently emerged as an important therapeutic target. In this work, a facile hypoxia-responsive liposomal drug delivery system was developed by incorporating derivatized nitroimidazole into liposome membranes. Under hypoxic conditions, hypoxia-induced reductive metabolism of the nitroimidazole derivative facilitated disassembly of the liposomes for triggered drug release. The liposomes showed high sensitivity to hypoxia, even at the cellular level, and could release payload in an oxygen-dependent manner, leading to high cytotoxicity in hypoxic conditions. In vivo fluorescence imaging revealed that there was a selective release of the liposomes at the hypoxic tumor site. As a result, the liposomes exhibited enhanced therapeutic efficacy in treating a hypoxic tumor in both cell line-derived and clinically relevant patient-derived xenograft models. Thus, hypoxia-responsive liposomes are a promising drug delivery system for hypoxia targeted tumor therapy. Statement of Significance 1. A facile but smart hypoxia-responsive liposomal drug delivery system is developed by incorporating nitroimidazole derivative, one of representative hypoxia-responsive moieties, into phospholipid bilayer of the liposomes. 2. The liposomes show extremely high sensitivity to hypoxia and can selectively release payload in hypoxic cells and hypoxic tumor. 3. The liposomes show enhanced therapeutic efficacy not only in cell line-derived xenograft model but also in clinically relevant patient-derived xenograft model, indicating their promising prospect in clinical application.