Clinical Applications and the Roles of Transporters in Disposition, Tumor Targeting, and Tissue Toxicity of meta-Iodobenzylguanidine

Abstract

Transporters on the plasma membrane of tumor cells are promising molecular “Trojan horses” to deliver drugs and imaging agents into cancer cells. Radioiodine-labeled meta-iodobenzylguanidine (mIBG) is used as a diagnostic agent (123I-mIBG) and a targeted radiotherapy (131I-mIBG) for neuroendocrine cancers. mIBG enters cancer cells through the norepinephrine transporter (NET) where the radioactive decay of 131I causes DNA damage, cell death, and tumor necrosis. mIBG is predominantly eliminated unchanged by the kidney. Despite its selective uptake by neuroendocrine tumors, mIBG accumulates in several normal tissues and leads to tissue-specific radiation toxicities. Emerging evidences suggest that the polyspecific organic cation transporters play important roles in systemic disposition and tissue-specific uptake of mIBG. In particular, human organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K) likely mediate renal secretion of mIBG, whereas hOCT1 and hOCT3 may contribute to mIBG uptake into normal tissues such as the liver, salivary glands, and heart. This mini-review focuses on the clinical applications of mIBG in neuroendocrine cancers and the differential roles of NET, OCT, and MATE transporters in mIBG disposition, response and toxicity. Understanding the molecular mechanisms governing mIBG transport in cancer and normal cells is a critical step for developing strategies to optimize the efficacy of 131I-mIBG while minimizing toxicity in normal tissues.