Visualization and treatment of the HIF-1-active microenvironments in tumors: Drug design and application of oxygen-dependent degradable probes for molecular imaging of HIF-1-active microenvironments

A tumor-specific microenvironment is characterized by hypoxia, a condition inwhich the oxygen tension is considerably lower than that existing in normal tissues. Insuch hypoxic regions, the transcription factor, hypoxia-inducible factor-1 (HIF-1), isexpressed. HIF-1 is a master transcriptional activator of various genes related to glucosemetabolism, angiogenesis, invasion, and metastasis; therefore, HIF-1-active regionscontribute to tumor malignancy and treatment failures. Thus, we believe that noninvasivevisualization and effective treatment of HIF-1-active microenvironments will provideuseful information for the development of novel strategies for cancer treatment; thedevelopment of such techniques will prove beneficial. HIF-1 is a heterodimer consistingof an oxygen-sensitive a-subunit (HIF-1α) and a constitutively expressed ß-subunit(HIF-1β).HIF-1α is degraded in an oxygen-dependent manner under normoxic conditions;however, under hypoxic conditions, it is stable and controls HIF-1 transcriptionalactivity. Because the oxygen-dependent degradation of HIF-1α is regulated by a unique domain, called the oxygen-dependent degradation domain (ODD), present in HIF-1α,probes containing the ODD and that are degraded in a similar manner as HIF-1α can beused to evaluate HIF-1 activity In Vivo. Furthermore, by conjugating a cytotoxic proteinto the ODD, a targeted therapy for HIF-1-active microenvironments can be developed. In this chapter, we review probes that contain the ODD and selectively function in HIF-1-active microenvironments for the purpose of imaging and treating HIF-1-active tumors.