Radiolabeled probes targeting hypoxia-inducible factor-1-active tumor microenvironments

Abstract

Because tumor cells grow rapidly and randomly, hypoxic regions arise from the lack of oxygen supply in solid tumors. Hypoxic regions in tumors are known to be resistant to chemotherapy and radiotherapy. Hypoxia-inducible factor-1 (HIF-1) expressed in hypoxic regions regulates the expression of genes related to tumor growth, angiogenesis, metastasis, and therapy resistance. Thus, imaging of HIF-1-active regions in tumors is of great interest. HIF-1 activity is regulated by the expression and degradation of its α subunit (HIF-1α), which is degraded in the proteasome under normoxic conditions, but escapes degradation under hypoxic conditions, allowing it to activate transcription of HIF-1-target genes. Therefore, to image HIF-1-active regions, HIF-1-dependent reporter systems and injectable probes that are degraded in a manner similar to HIF-1α have been recently developed and used in preclinical studies. However, no probe currently used in clinical practice directly assesses HIF-1 activity. Whether the accumulation of (18)F-FDG or (18)F-FMISO can be utilized as an index of HIF-1 activity has been investigated in clinical studies. In this review, the current status of HIF-1 imaging in preclinical and clinical studies is discussed.

Figure 1

Regulatory mechanism of hypoxia-inducible factor (HIF-1) expression. Growth factor stimulation induces HIF-1α subunit (HIF-1α) protein synthesis by activating PI3K/Akt/mTOR and Ras/MEK/ERK kinase pathways. Under normoxic conditions, HIF-1α is hydroxylated by proline hydroxylases (PHDs), triggering its interaction between von Hippel-Lindau tumor suppressor protein (pVHL), leading to its polyubiquitination and subsequent proteasomal degradation. In contrast, under hypoxic conditions, HIF-1α remains stable, enters the nucleus, and, together with HIF-1β, binds to hypoxia-responsive elements (HREs), upregulating the expression of target genes such as glucose transporters (GLUTs), vascular endothelial growth factors (VEGFs), and matrix metalloproteinases (MMPs). Ub: ubiquitin.

Figure 2

Principle underlying the imaging of HIF-1-active tumor microenvironments, using ¹²³I -IPOS. The PTD enables ¹²³I-IPOS to be delivered to all tissues. In normoxic tissues, oxygen-dependent POS degradation occurs and ¹²³I-IBB loses its binding partner and is cleared. In contrast, in hypoxic tissues, ¹²³I-IPOS escapes degradation and is retained within cells owing to its molecular size. Thus, ¹²³I-IPOS allows for specific imaging of HIF-1-active hypoxic microenvironments.

Figure 3

Principle underlying the imaging of HIF-1-active tumor microenvironments, using pretargeted POS and ¹⁸F-FBB. The PTD enables the delivery of POS to all tissues. In normoxic tissues, POS degrades in a manner similar to HIF-1α. In contrast, in hypoxic tissues, POS escapes degradation and is retained inside the cells. After allowing sufficient time for POS to degrade in normal tissues, ¹⁸F-FBB is administered. ¹⁸F-FBB enters cells by passive diffusion and binds to the SAV moiety of the POS retained in hypoxic cells; this does not occur in normoxic tissues. Therefore, pretargeting POS followed by ¹⁸F-FBB administration enables specific imaging of HIF-1-active hypoxic microenvironments.