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

Targeted α-particle therapy (TAT), in which an α-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 α-particles to destroy targeted cancer cells. TAT has the potential for an improved therapeutic ratio over β-particle targeted conjugate therapy. The short path length and the intense ionization path generated render α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking. ²¹²Pb is the longer-lived parent radionuclide of ²¹²Bi and serves as an in vivo generator of ²¹²Bi. ²¹²Pb has demonstrated significant utility in both in vitro and in vivo models. Recent evaluation of ²¹²Pb-TCMC-trastuzumab in a Phase I clinical trial has demonstrated the feasibility of ²¹²Pb in TAT for the treatment of ovarian cancer patients. This review highlights progress in radionuclide production, radiolabeling chemistry, molecular mechanisms, and application of ²¹²Pb to targeted pre-clinical and clinical radiation therapy for the management and treatment of cancer.