Application of Pb-212 for Targeted alpha-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation

Targeted a-particle therapy (TAT), in which an alpha-particle emitting radionuclide is specifically directed to a biological target, is gaining more attention to treat cancers as new targets are validated. Bio-vectors such as monoclonal antibodies are able to selectively transport a-particles to destroy targeted cancer cells. TAT has the potential for an improved therapeutic ratio over beta-particle targeted conjugate therapy. The short path length and the intense ionization path generated render alpha-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking. Pb-212 is the longer-lived parent radionuclide of Bi-212 and serves as an in vivo generator of Bi-212. Pb-212 has demonstrated significant utility in both in vitro and in vivo models. Recent evaluation of Pb-212-TCMC-trastuzumab in a Phase I clinical trial has demonstrated the feasibility of Pb-212 in TAT for the treatment of ovarian cancer patients. This review highlights progress in radionuclide production, radiolabeling chemistry, molecular mechanisms, and application of Pb-212 to targeted pre-clinical and clinical radiation therapy for the management and treatment of cancer.