The in vivo fate of 225Ac daughter nuclides using polymersomes as a model carrier

TLDR

Personalized tumour therapy increasingly relies on α‑emitters, which deliver high‑linear‑energy‑transfer radiation over short ranges, but recoil of daughter nuclides can detach them from carriers and lead to off‑target accumulation in normal tissues. This study investigates whether polymersomes can retain recoiling daughters of 225Ac in vivo and evaluates their suitability as therapeutic agents. Vesicles loaded with 225Ac were injected intravenously into healthy mice and intratumourally into tumour‑bearing mice, and the biodistribution of released 213Bi was monitored in various organs. Intratumoural injection of 225Ac‑polymersomes resulted in no tumour‑related deaths over 115 days and showed low renal toxicity, yet significant redistribution of daughter nuclides throughout the body, underscoring the need for careful assessment in targeted α‑therapy.

Abstract

Abstract Increasing attention is given to personalized tumour therapy, where α-emitters can potentially play an important role. Alpha particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon the emission of an α particle the daughter nuclide experiences a recoil energy large enough to ensure decoupling from any chemical bond. These ‘free’ daughter nuclides are no longer targeted to the tumour and can accumulate in normal tissue. In this paper, we used polymersomes as model carrier to evaluate the retention of recoiling daughters of 225 Ac in vivo , and assessed their suitability as therapeutic agents. Vesicles containing 225 Ac were injected intravenously in healthy mice, and intratumourally in tumour-bearing mice, and the relocation of free 213 Bi was assessed in different organs upon the injection [ 225 Ac]Ac-polymersomes. The therapeutic effect of 225 Ac-containing vesicles was studied upon intratumoural injection, where treatment groups experienced no tumour-related deaths over a 115 day period. While polymersomes containing 225 Ac could be suitable agents for long-term irradiation of tumours without causing significant renal toxicity, there is still a significant re-distribution of daughter nuclides throughout the body, signifying the importance of careful evaluation of the effect of daughter nuclides in targeted alpha therapy.