Hypoxia in tumor cells is characterized by a lack of oxygen resulting from reduced blood supply to
the surrounding tissue, and is a common characteristic of solid tumors as a consequence of rapid cell growth.
Hypoxia in tumors is a predictor of both resistance to chemotherapy and of a metastatic/aggressive form of
cancer, and as a result, development of cancer therapies which target hypoxia is of vital importance. One such
targeting strategy is the development of hypoxia-activated prodrugs (HAP) which can preferentially release
chemotherapeutic agents within hypoxic tumor regions. This targeting strategy is accomplished by attaching a
hypoxia activated trigger to a chemotherapeutic agent and under oxygen-poor conditions, the agent (effector)
is released into the tumor, while remaining intact in normal tissue, and leaving non-hypoxic cells undamaged.
Overall, this strategy can achieve an increased therapeutic benefit over conventional small molecule chemotherapeutic
treatments by concentrating the drugs within hypoxic tumor environments, while simultaneously
reducing the side-effects and toxicity issues that surround the systemic distribution of traditional drugs
on normoxic cells. In this review, we will describe the factors that should be considered when designing an
effective HAP, such as the mechanism of prodrug action, the elements that influence the rational design of
HAP (i.e. reduction potential), and the activating enzymes of HAP. As part of this description, we will utilize
select examples from the literature to reinforce these factors, and make a case for the intelligent design of new
HAPs, leading to the development of novel hypoxia targeting chemotherapeutic agents.