Prospects for hypoxia-based drug delivery platforms for the elimination of advanced metastatic tumors: From 3D modeling to clinical concepts

Hypoxia is a unique characteristic of the solid tumor microenvironment. Hypoxia contributes to multi-drug resistance, metastasis and cancer relapse through numerous molecular pathways, but at the same time provides an opportunity for the development of novel drugs or modalities specifically targeting hypoxic tumor regions. Given the high significance of tumor hypoxia in therapeutic results, we here discuss a variety of hypoxia-adopted strategies, and their potential and utility in the treatment of deep-seated hypoxic tumor cells. We discuss the merits and demerits of these approaches, as well as their combination with other approaches such as photodynamic therapy. We also survey the currently available 3D hypoxia modeling systems, in particular organoid-based microfluidics. Finally, we discuss the potential and the current status of preclinical tumor hypoxia approaches in clinical trials for advanced cancer. We believe that multi-modal imaging and therapeutic hypoxia adopted drug delivery platforms could provide better efficacy and safety profiles, and more importantly personalized therapy. Determining the hypoxia status of tumors could offer a second chance for the clinical translation of hypoxia-based agents, such as hypoxia activated prodrugs (HAPs) from bench to bedside.