Prostat Kanserinde ²²⁵Ac-PSMA-617 ve ¹⁷⁷Lu-PSMA-617’nin Subsellüler Dozimetriye Dayalı Göreceli Etkinliği

Abstract

Objectives: Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) with alpha-emitting 225 Ac-PSMA-617 has shown clinical efficacy even in cases of failed therapy with beta-emitting 177 Lu-PSMA-617. We investigated the efficacy of 225 Ac-PSMA-617 relative to 177 Lu-PSMA-617 using subcellular dosimetry. Methods: A 3-dimensional model of prostate cancer was constructed. For each decay, the absorbed and equivalent radiation dose to the cell nuclei was calculated. The relative efficacy per administered activity was calculated by taking into account the differences in residence time and tumor uptake. Results: As the tumor size increased, the absorbed dose from 225 Ac-PSMA-617 increased linearly (R2: 0.99) and reached an asymptote near the maximum alpha range (85 µm), whereas the absorbed dose from 177 Lu-PSMA-617 continued to increase linearly (R2: 0.99). The equivalent dose per decay was 2,320, 2,900, and 823-fold higher in favor of 225 Ac-PSMA-617 compared to 177 Lu-PSMA-617 in a single cell, 100 µm-radius micrometastasis, and macroscopic tumor, respectively. Per administered activity, the relative efficacy of 225 Ac-PSMA-617 compared to 177 Lu-PSMA-617 in respective tumor sizes was at least 3,480, 4,350, and 1,230-fold higher, and possibly 11,800, 14,900, and 4,200-fold higher considering differences in tumor uptake. Conclusion: At commonly administered 1,000-fold lower activity of 225 Ac-PSMA-617 relative to 177 Lu-PSMA-617, the equivalent radiation dose deposited by 225 Ac-PSMA-617 is higher in measurable disease and much higher in microscopic disease compared to 177 Lu-PSMA-617.

Novel radionuclide therapy combinations in prostate cancer

“…By combining 177 Lu-PSMA-I&T with 225Ac-J591, alpha and beta concurrent emission could potentially treat a range of tumor lesions with variable geometry. 88…”

“…By combining 177 Lu-PSMA-I&T with 225Ac-J591, alpha and beta concurrent emission could potentially treat a range of tumor lesions with variable geometry. 88 Following on the POPSTAR I trial in oligometastatic prostate cancer demonstrating feasibility, tolerability, and preliminary efficacy, POPSTAR II (NCT05560659) is a recruiting phase II trial planned to assess biochemical PFS from SABR compared to combination SABR and two cycles of 177 Lu-PSMA-617 in 92 individuals with oligometastatic prostate cancer. 89 ROADSTER (NCT05230251) is a two-part phase II trial currently recruiting to assess the safety and feasibility of one cycle 177 Lu-PSMA-617 followed by high-dose radiation (HDR) brachytherapy to the entire prostate, or two brachytherapy treatments alone.…”

Production study of Fr, Ra and Ac radioactive ion beams at ISOLDE, CERN

“…Since they have a higher linear energy transfer (LET) than β radiation, more energy is deposited in cancer cells 4 . This is beneficial not only to patients but also to hospital staff due to a shorter radiation range and a smaller dose needed for the same treatment 5 . The demand for this radionuclide is expected to rise every year (unmatched with supply), thus finding a sustainable production way is crucial 6 .…”

Nanoparticle-Based Radioconjugates for Targeted Imaging and Therapy of Prostate Cancer

“…Moreover, therapy with [ 177 Lu]Lu-PSMA-617 is not efficient for the treatment of micrometastatic disease and circulating tumour cells because β − particles emitted from 177 Lu have a relatively long range in the soft tissue (1–10 mm), well beyond a diameter of micrometastases [ 24 ]. Radiotherapy with α-emitting radionuclides seems to be a better alternative to this based on β − particles because α particles deposit their whole energy within a few cell diameters (<100 µm), efficiently inducing DNA damage [ 25 ]. However, one of the most important obstacles associated with α-emitting radionuclides is the liberation of the recoiled daughter radionuclides rising during decay, which allows them to freely migrate in the body, causing significant toxicity to healthy tissues and decreasing the therapeutic dose delivered to the tumour [ 26 , 27 ].…”