The potential and hurdles of targeted alpha therapy - clinical trials and beyond

Abstract

This article presents a general discussion on what has been achieved so far and on the possible future developments of targeted alpha (α)-particle therapy (TAT). Clinical applications and potential benefits of TAT are addressed as well as the drawbacks, such as the limited availability of relevant radionuclides. Alpha-particles have a particular advantage in targeted therapy because of their high potency and specificity. These features are due to their densely ionizing track structure and short path length. The most important consequence, and the major difference compared with the more widely used β(-)-particle emitters, is that single targeted cancer cells can be killed by self-irradiation with α-particles. Several clinical trials on TAT have been reported, completed, or are on-going: four using (213)Bi, two with (211)At, two with (225)Ac, and one with (212)Pb/(212)Bi. Important and conceptual proof-of-principle of the therapeutic advantages of α-particle therapy has come from clinical studies with (223)Ra-dichloride therapy, showing clear benefits in castration-resistant prostate cancer.

Keywords: alpha emitters; cancer; dosimetry; ovarian cancer; radionuclide therapy; targeted alpha therapy.

Figure 1

The favorable geometric situation for α-particles in small-scale metastases (e.g., in the adjuvant setting) is depicted in a scanning electron microscopy micrograph of micro-metastatic clusters from ovarian cancer on the peritoneal lining (mouse). The range of the α-particles in red (here ~50–70 μm), can hardly reach the surrounding normal healthy cells other than possibly the mesothelium and its sub-layer. They cannot reach the epithelial cells of the intestinal lining. The situation for β⁻ particles on the other hand, shows that a great deal of its energy will be deposited far away from the binding site and possibly into healthy tissue as demonstrated by the white dashed line (here ~700 μm). Consequently, it may add to side effects. Bar equals 100 μm.

Figure 2

Decay chains. Alpha-particle emitters are in red boxes and stable isotopes are in green boxes. The box in light green to the far right (²⁵¹Cf) indicates that although the isotope is considered stable in medical applications (T_1/2 = 898 years), it can still decay via ²²⁷Ac to ²⁰⁷Pb (stable). The T_1/2 is shown inside each box, and between boxes the type of decay [α, β^(−/+), or EC (electron capture)], with the probability of each decay route occurring (expressed as %). In the figure are also shown three alpha-particle emitters that are not mentioned in the text: ²³⁰U, ²²⁶Th, and ²⁵⁵Fm. Studies on the feasibility of producing ²³⁰U and its daughter ²²⁶Th via proton irradiation of ²³¹Pa according to the ²³¹Pa (p, 2n) ²³⁰U reaction have been performed (29). So far, there are no published data on the use of these three nuclides for TAT, although ²⁵⁵Fm has been occasionally mentioned as a potential candidate for targeted radionuclide therapy.