Abstract

Targeted radiotherapy or endoradiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor while sparing normal tissues. Radionuclides that decay by the emission of a-particles such as the heavy halogen astatine-211 ( 211 At) offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Herein, the radiobiological advantages of alpha-particle targeted radiotherapy will be reviewed, and the rationale for using 211 At for this purpose will be described. The chemistry of astatine is similar to that of iodine; however, there are important differences which make the synthesis and evaluation of 211 At-labeled compounds more challenging. Perhaps the most successful approach that has been developed involves the astatodemetallation of tin, silicon or mercury precursors. Astatine-211 labeled agents that have been investigated for targeted radiotherapy include ( 211 At)astatide, 211 At- labeled particulates, 211 At-labeled naphthoquinone derivatives, 211 At-labeled methylene blue, 211 At-labeled DNA precursors, meta-[211 At]astatobenzylguanidine, 211 At-labeled biotin conjugates, 211 At-labeled bisphosphonates, and 211 At-labeled antibodies and antibody fragments. The status of these 211 At-labeled compounds will be discussed in terms of their labeling chemistry, cytotoxicity in cell culture, as well as their tissue distribution and therapeutic efficacy in animal models of human cancers. Finally, an update on the status of the first clinical trial with an 211 At-labeled targeted therapeutic, 211 At-labeled chimeric anti-tenascin antibody 81C6, will be provided.

Keywords: Astatine 211 labeled radiotherapeutics, Targeted alpha particle radiotherapy, Targeted radiotherapy, Endoradiotherapy, Cacer treatment, Antibody fragments, Radiation therapy, Particle Emitting Radionuclides, Bismuth 213, Bismuth 212, Astatide, Intracaity applications, Naphthoquinone, Methylene blue, Trimethylstannyl precursor TMSUdR, Synthesis, Biotin, Conjugates for pretargeting, Biosphosphonates, In vitro cytotoxicity, In vivo studies, mABs Fragments, mAB Fragments