Prostate-specific membrane antigen (PSMA) is a promising target to achieve a selective delivery to prostate cancer.¹⁾ Even though its significance in cancer pharmacology is scarce, radiopharmaceuticals have been taken it as the target for the therapy and diagnostic purposes. PSMA targeting is the legendary story of radiopharmaceutical discovery and development and it is of high values to take a close look at for the better understanding of radiotherapy.

In PSMA, glutamate carboxypeptidase II (GCPII), targeted radiotherapeutics development, three radionuclides, ¹⁷⁷Lu, ²²⁵Ac and ²¹³Bi, have been playing invaluable roles. ⁶⁸Ga and ¹⁸F have also contributed for the diagnosis purpose in PET. We would like to focus here on the therapeutic side of PSMA-targeted radiotherapeutics.

The concept of radiotherapy for prostate cancer is rather simple. A radiolabeled PSMA binder is supposed to be targeted to the tumor cells derived from PSMA-related prostate cancer. The decay of radionuclide emits a high energy particle (a or b^-) or radiation (g) that inflict DNA strand and drive the tumor cells to death.

¹⁷⁷Lu, ²²⁵Ac and ²¹³Bi have been used because of their reliable properties in terms of the y sequence and the resulting emission of locally targetable a and/or b^- particles.

¹⁷⁷Lu is a b^- emitter and allows relatively local invasion. The energy of the b^- particle depends on the decay pathway to¹⁷⁷Hf and the distribution is analyzed to be 497 KeV (78.6 %), 384 keV (9.1 %) and 176 keV (12.2 %). The decays also involve low-energy g photons with energies of 113 keV (6.6 %) and 208 keV (11 %).^{2) 177}Lu’s decay emits low-penetrative particle with mean distance of 0.67mm.³⁾ The cellular uptake of ¹⁷⁷Lu-based radiopharmaceuticals allows cancer lesion-selective damages on the DNAs in the for single or double strand breaks. The half-life 6.6 days.⁴⁾

²²⁵Ac undergoes a decay to emit a particles with the energy of 5.8 to 8.4 MeV.^5),6) The a ray of ²²⁵Ac travels within the distance of 0.085mm in tissues. It means ²²⁵Ac selectively shows strong invasive effects on the cells just around the nuclide considering the general radius of a cancel cell is 0.01mm or a bit more. ²⁵⁵Ac has a half-life of 9.9 days.

²¹³Bi is a mixed a and b^- emitter with a half-life of only 45.6 minutes.⁷⁾ In spite of the difficulty in the supply of the short-lived ²¹³Bi, there is a report of clinical application to a patient of prostate cancer.⁸⁾

It is worth considering that ²¹³Bi are present in the decay cascade of ²²⁵Ac. The sequence of decays from ²²⁵Ac to the stable nuclide, ²⁰⁵Tl, is below.

²²⁵Ac-a-²²¹Fr-a-²¹⁷At-a-²¹³Bi-b^--²¹³Po-a- or -a-²⁰⁹Tl-b^--²⁰⁹Pb-b^--²⁰⁹Bi-a-²⁰⁵Tl

The half-lives of the nuclides except for ²⁰⁹Bi (2x10¹⁹ years) after the a decay of ²²⁵Ac are within hours to micro seconds, and hence ²²⁵Ac actually emits 4 a particles and 2 b^- particles.

¹⁷⁷Lu has been the major nuclide in PSMA-targeted radiopharmaceutical therapies.⁹⁾ However, application of ²²⁵Ac in the same scheme is an intense focus of area because of its ability to emit multiple a particles that allows more local irradiation and hence expected less adverse effects on non-cancer cells.¹⁰⁾

The approaches for radiopharmaceuticals developments are different from the other drug discovery and developments. There is orthogonality in target identification and approach for drug improvement, which we did not discuss here deeply. It is worth keep eyes on radiopharmaceuticals in cancer therapy to see the possibility of opening up their opportunity.

1. https://doi.org/10.3390/bioengineering11070714
2. https://doi.org/10.1007%2Fs13139-014-0315-z
3. https://www.fda.gov/
4. https://doi.org/10.1016/j.apradiso.2011.04.021
5. https://doi.org/10.1007/s00259-014-2978-1
6. https://doi.org/10.2967%2Fjnumed.123.265763
7. https://doi.org/10.1016/j.semcancer.2015.07.003
8. https://doi.org/10.1158/1541-7786.mcr-23-0075
9. https://doi.org/10.7150/thno.93249
10. https://doi.org/10.21037/atm-23-1842