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

Abstract

Targeted alpha-particle therapy using radionuclides with alpha emission is a rapidly developing area in modern cancer treatment. To selectively deliver alpha-emitting isotopes to tumors, targeting vectors, including monoclonal antibodies, peptides, small molecule inhibitors, or other biomolecules, are attached to them, which ensures specific binding to tumor-related antigens and cell surface receptors. Although earlier studies have already demonstrated the anti-tumor potential of alpha-emitting radium (Ra) isotopes-Radium-223 and Radium-224 (^223/224Ra)-in the treatment of skeletal metastases, their inability to complex with target-specific moieties hindered application beyond bone targeting. To exploit the therapeutic gains of Ra across a wider spectrum of cancers, nanoparticles have recently been embraced as carriers to ensure the linkage of ^223/224Ra to target-affine vectors. Exemplified by prior findings, Ra was successfully bound to several nano/microparticles, including lanthanum phosphate, nanozeolites, barium sulfate, hydroxyapatite, calcium carbonate, gypsum, celestine, or liposomes. Despite the lengthened tumor retention and the related improvement in the radiotherapeutic effect of ^223/224Ra coupled to nanoparticles, the in vivo assessment of the radiolabeled nanoprobes is a prerequisite prior to clinical usage. For this purpose, experimental xenotransplant models of different cancers provide a well-suited scenario. Herein, we summarize the latest achievements with ^223/224Ra-doped nanoparticles and related advances in targeted alpha radiotherapy.

Keywords: Radium-223/224 (223/224Ra); nanoparticles; preclinical; targeted alpha-particle therapy; xenotransplants.

Figure 1

Statistical analysis of the clinical trials (A,B) and the number of preclinical and clinical publications (C,D) on ²²³Ra, ²²⁴Ra, ²²⁵Ac, ^227Th, ²¹²Bi, ²¹³Bi, ²¹²Pb, and ²¹¹At isotopes. (A) The percentage distribution (%) of different alpha-emitting radionuclides in clinical studies—available to date—investigating the anti-tumor efficacy of alpha radiation: ²²³Ra (84%), ²²⁴Ra (0%), ²²⁵Ac (6%), ^227Th (0%), ²¹²Bi (0%), ²¹³Bi (1%), ²¹²Pb (2%), and ²¹¹At (7%). Data obtained from clinicaltrials.gov. (B) Detailed status analysis of the clinical trials using the investigated alpha-emitting radionuclides. Data obtained from clinicaltrials.gov. (C) Distribution of the published preclinical and clinical scientific papers in the field of alpha-emitting radionuclide therapies in the last 10 years. Data obtained from pubmed.ncbi.nlm.nih.gov. (D) The number of preclinical and clinical publications on targeted alpha radionuclide therapies from the last 5 and 10 years. Data obtained from pubmed.ncbi.nlm.nih.gov. ²²³. Ra: Radium-223, ²²⁴Ra: Radium-224, ²²⁵Ac: Actinium-225, ^227Th: Thorium-227, ²¹²Bi: Bismuth-212, ²¹³Bi: Bismuth-213, ²¹²Pb: Lead-212, ²¹¹At: Astatine-211.

Figure 2

Decay scheme of Radium-223 and Radium-224. Panel (A) presents the decay scheme of Radium-223. Panel (B) demonstrates the decay scheme of radium-224.