Abstract
For targeted alpha therapy with 225Ac, daughter radioisotopes from the parent emissions must be controlled. Here we report on a second-generation layered nanoparticle (NP) with improved daughter retention that can mediate targeted alpha therapy of lung tumor colonies. Nanoparticles 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 antibodyñmediated 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 over 70% at 1 hour and about 90% at 24 hours post-injection. Treatment of mice with lung-targeted 225Ac NPs reduced EMT-6 lung colonies relative to cold antibody competition for targeting or PBS injected controls. We conclude that LnPO4 NPs represent a viable solution to deliver the 225Ac as an in vivo a generator. The NPs successfully retain a large percentage of the daughter products without compromising the tumoricidal properties of the a-radiation.