Comparative studies on the therapeutic benefit of targeted α-particle radiation therapy for the treatment of disseminated intraperitoneal disease

Abstract

Identification of the appropriate combination of radionuclide, target and targeting vehicle is critical for successful radioimmunotherapy. For the treatment of disseminated peritoneal diseases such as pancreatic or ovarian cancer, α-emitting radionuclides have been proposed for targeted radiation therapy. This laboratory has taken a systematic approach investigating targeted α-radiation therapy, allowing comparisons to now be made between 211At, 227Th, 213Bi and 212Pb. Herein, trastuzumab radiolabeled with 211At and 227Th was evaluated for therapeutic efficacy in the LS-174T i.p. tumor model. A dose escalation study was conducted with each radioimmunoconjugate (RIC). Therapeutic benefit was realized with 211At-trastuzumab with doses of 20, 30 and 40 μCi. At doses > 40 μCi, toxicity was observed with greater weight loss and 2-fold higher decrease in the platelet counts. Following a second study comparing the effect of 20, 30 and 40 μCi of 211At-trastuzumab, 30 μCi was selected as the dose for future studies. A parallel study was performed evaluating 0.25, 0.5, 1.0, 2.0 and 5.0 μCi of 227Th-trastuzumab. The 0.5 and 1.0 μCi injected dose resulted in a therapeutic response; a lower degree of weight loss was experienced by the mice in the 0.5 μCi cohort. When the data is normalized for comparing 211At, 227Th, 213Bi and 212Pb, the choice of radionuclide for RIT is perhaps not entirely based on simple therapeutic efficacy, other factors may play a role in choosing the “right” radionuclide.

Stabilization of hydrated AcIII cation: the role of superatom states in actinium-water bonding

“…[1][2][3] However, recent discoveries tend to support its reassignment as an actual fblock element. [4][5][6][7] All isotopes of actinium are unstable and highly radioactive. Specifically, the Ac isotope 225 Ac, as a promising anticancer therapeutic agent, makes targeted radionuclide therapy a powerful cancer treatment strategy.…”

“…Specifically, the Ac isotope 225 Ac, as a promising anticancer therapeutic agent, makes targeted radionuclide therapy a powerful cancer treatment strategy. [5][6][7][8][9] The main reasons are that (a) the short half-life of 10 days matches the pharmacokinetics of the final radioactive drug, (b) the isotope is a pure α-emitter with a high energy (100 keV/μm) and short distance (<100 μm) in biological tissue, (c) the final product ( 209 Bi) from the 225 Ac decay chain leaves with small accumulated energy of 28 meV and is innocuous in vivo. Despite these advantages, many basic science problems are surrounding the coordination and solution chemistry of actinium, and the biological delivery of the 225 Ac isotope remains unresolved.…”

Targeted Radium Alpha Therapy in the Era of Nanomedicine: In Vivo Results

“…Within the alpha-emitting radionuclide domain, a broad set of isotopes are available for TRT usage, including, for instance, Radium-223 ( 223 Ra), Radium-224 ( 224 Ra), Actinium-225 ( 225 Ac), Thorium-227 ( 227Th ), Bismuth-212 ( 212 Bi), Bismuth-213 ( 213 Bi), Lead-212 (212Pb), and Astatine-211 ( 211 At) [16]. Figure 1 provides statistics from the current clinical trials and the number of preclinical and clinical publications on 223 Ra, 224 Ra, 225 Ac, 227Th , 212 Bi, 213 Bi, 212 Pb, and 211 At isotopes. A,B) and the number of preclinical and clinical publications (C,D) on 223 Ra, 224 Ra, 225 Ac, 227Th , 212 Bi, 213 Bi, 212 Pb, and 211 At isotopes.…”

“…Figure 1 provides statistics from the current clinical trials and the number of preclinical and clinical publications on 223 Ra, 224 Ra, 225 Ac, 227Th , 212 Bi, 213 Bi, 212 Pb, and 211 At isotopes. A,B) and the number of preclinical and clinical publications (C,D) on 223 Ra, 224 Ra, 225 Ac, 227Th , 212 Bi, 213 Bi, 212 Pb, and 211 At isotopes. (A) The percentage distribution (%) of different alpha-emitting radionuclides in clinical studies-available to date-investigating the anti-tumor efficacy of alpha radiation: 223 Ra (84%), 224 Ra (0%), 225 Ac (6%), 227Th (0%), 212 Bi (0%), 213 Bi (1%), 212 Pb (2%), and 211 At (7%).…”

211At-labeled immunoconjugate via a one-pot three-component double click strategy: practical access to α-emission cancer radiotherapeutics

“…Radionuclides that decay by emitting alpha particles can damage targeted cancer tissue within a few cell diameters, thereby minimizing off-target damage. α-Emitters, including 225 Ac, with a half-life of 10 days, 223 Ra, with a half-life of 11.4 days, and 227 Th, with a half-life of 18.7 days, are favored for use in radiotherapy techniques involving targeted molecules, such as radioimmunoconjugates, because of their long half-lives 11. Efficient chelators of these radionuclides must be developed before such applications may be realized 12,13…”