LnPO₄Nanoparticles Doped with Ac-225 and Sequestered Daughters for Targeted Alpha Therapy

Abstract

For targeted alpha therapy (TAT) with 225Ac, daughter radioisotopes from the parent emissions should be controlled. Here, we report on a second-generation layered nanoparticle (NP) with improved daughter retention that can mediate TAT of lung tumor colonies. NPs of La3+, Gd3+, and 225Ac3+ ions were coated with additional layers of GdPO4 and then coated with gold via citrate reduction of NaAuCl4. MAb 201b, targeting thrombomodulin in lung endothelium, was added to a polyethylene glycol (dPEG)-COOH linker. The NPs:mAb ratio was quantified by labeling the mAb with 125I. NPs showed 30% injected dose/organ antibody-mediated uptake in the lung, which increased to 47% in mice pretreated with clodronate liposomes to reduce phagocytosis. Retention of daughter 213Bi in lung tissue was more than 70% at one hour and about 90% at 24 hours postinjection. Treatment of mice with lung-targeted 225Ac NP reduced EMT-6 lung colonies relative to cold antibody competition for targeting or phosphate-buffered saline injected controls. We conclude that LnPO4 NPs represent a viable solution to deliver the 225Ac as an in vivo α generator. The NPs successfully retain a large percentage of the daughter products without compromising the tumoricidal properties of the α-radiation.

Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for 223Ra and 225Ra for targeted alpha therapy

“…This approach aims to overcome the global radiotoxicity of the parent radionuclides and associated daughters, one of the main limitations of TAT [4][5][6][7]. Inorganic nanomaterials are of interest as carriers because of their characteristic size-shape dependent properties, stable crystalline structures, and functionalizable surfaces [1,2].…”

“…Lanthanide phosphate NPs are promising candidates as carriers for α and β emitters in RIT, TAT, and imaging applications [1-4, 8, 9]. Recent investigations have been conducted to sequester the decay products of the TAT candidate a-emitting in vivo generator 225 Ac using LnPO 4 (Ln = La, Gd) core-shell nanostructures [4][5][6]. In vivo generators are parent radioisotopes that decay to one or more radioactive daughters which themselves decay quickly, thus potentially amplifying the dose from multiple emissions at a target site.…”

Radiolabeled Nanoparticles in Nuclear Oncology

“…The same group proceeded to further functionalize these nanoparticles with the monoclonal antibody 201b via the carboxylate group of discrete polyethylene glycol chains. Tumor-eradication properties of the nanoconstruct were demonstrated, with the daughter isotope 213 Bi being retained by the nanoparticles in the lung up to ~90% at 24h post-injection [124].…”

Molecular Imaging in Nanotechnology and Theranostics

“…Alpha emitters with long half-life like 225 Ac ( t 1/2 = 10 days) are the preferred radionuclides for the formulation of nanoparticles [131-132]. However, there is concern about the radioactivity of downstream decay processes.…”