An overview of targeted alpha therapy

Abstract

The effectiveness of targeted α-therapy (TAT) can be explained by the properties of α-particles. Alpha particles are helium nuclei and are ~8,000 times larger than β(-)-particles (electrons). When emitted from radionuclides that decay via an α-decay pathway, they release enormous amounts of energy over a very short distance. Typically, the range of α-particles in tissue is 50-100 μm and they have high linear energy transfer (LET) with a mean energy deposition of 100 keV/μm, providing a more specific tumor cell killing ability without damage to the surrounding normal tissues than β(-)-emitters. Due to these properties, the majority of pre-clinical and clinical trials have demonstrated that α-emitters such as (225)Ac, (211)At, (212)Bi, (213)Bi, (212)Pb, (223)Ra, and (227)Th are ideal for the treatment of smaller tumor burdens, micrometastatic disease, and disseminated disease. Even though these α-emitters have favorable properties, the development of TAT has been limited by high costs, unresolved chemistry, and limited availability of the radionuclides. To overcome these limitations, more potent isotopes, additional sources, and more efficient isotope production methods should be addressed. Furthermore, better chelation and labeling methods with the improvements of isotope delivery, targeting vehicles, molecular targets, and identification of appropriate clinical applications are still required.

Embryos of the zebrafish Danio rerio in studies of non-targeted effects of ionizing radiation

“…However, there were few studies on the role of the RIBE in the clinical setting [169]. Another advancement in the medical application is called targeted atomic nanogenerators [170] or targeted alpha therapy (TAT) [171]. This technique involves targeting molecular-sized generators of alpha-particle emitting radionuclides into cancer cells, by coupling carefully chosen parent radionuclides to internalize monoclonal antibodies to form the bioconjugates.…”

“…Despite all these advantages, the RIBE in the non-targeted normal tissues surrounding the targeted cancer cells is not fully understood. In particular, if the alpha-particle emitting daughter radionuclides in the decay chain of the nanogenerators are not sequestered at the target site, then these daughter radionuclides can migrate and deliver a potentially toxic dose to non-targeted tissues as well [171]. The volume of normal tissues that are affected by RIBE from these runaway radionuclides will become even larger.…”

The development of immunoconjugates for targeted cancer therapy

“…102 Limitations to the use of targeting α-therapy include high costs and radionucleotide availability, which could be addressed in the future with the development of additional sources and more-efficient production, but also through improved isotope delivery. 103 Table 2 summarizes the radionucleotide immunoconjugates that have been approved for use or are undergoing investigation. In the wake of the discontinuation of iodine tositumomab production, it remains unclear if such agents will have a greater use in the treatment of human cancers.…”

Fractionated intravesical radioimmunotherapy with213Bi-anti-EGFR-MAb is effective without toxic side-effects in a nude mouse model of advanced human bladder carcinoma

“…Accordingly, a-particles efficiently eradicate single tumor cells and small cell clusters. [15][16][17] Moreover, irradiation with a-particles can stimulate adaptive immunity. 18 Because the epidermal growth factor receptor (EGFR) is overexpressed in 86% of urothelial carcinomas, 19 it represents an ideal target for locoregional radioimmunotherapy.…”