Radiopharmaceutical Therapy

Abstract Radiopharmaceutical therapy involves the use of radionuclides that are either conjugated to tumor-targeting agents (e.g., nanoscale constructs, antibodies, peptides, and small molecules) or that concentrate in tumors through natural physiological mechanisms that occur predominantly in neoplastic cells. In the latter category, radioiodine therapy of thyroid cancer is the prototypical and most widely implemented radiopharmaceutical therapy. In the category of radionuclide-ligand conjugates, antibody and peptide conjugates have been studied extensively. The efficacy of radiopharmaceutical therapy relies on the ability to deliver cytotoxic radiation to tumor cells without causing prohibitive normal tissue toxicity. After some 30 y of preclinical and clinical research, a number of recent developments suggest that radiopharmaceutical therapy is poised to emerge as an important and widely recognized therapeutic modality. These developments include the substantial investment in antibodies by the pharmaceutical industry and the compelling rationale to build upon this already existing and widely tested platform. In addition, the growing recognition that the signaling pathways responsible for tumor cell survival and proliferation are less easily and durably inhibited than originally envisioned has also provided a rationale for identifying agents that are cytotoxic rather than inhibitory. A number of radiopharmaceutical agents are currently undergoing clinical trial investigation; these include beta-particle emitters, such as 177Lu, that are being used to label antisomatostatin receptor peptides for neuroendocrine cancers and also prostate-specific membrane antigen targeting small molecules for prostate cancer. Alpha-particle-emitting radionuclides have also been studied for radiopharmaceutical therapy; these include 211At for glioblastoma, 225Ac for leukemias and prostate cancer, 212Pb for breast cancer, and 223Ra for prostate cancer. The alpha emitters have tended to show particular promise, and there is substantial interest in further developing these agents for therapy of cancers that are particularly difficult to treat.