| Abstract: |
Targeted α-particle emitters are promising therapeutics for micrometastatic disease. Actinium-225 has a 10-day half-life and generates a total of four α-particles per parent decay rendering 225Ac an attractive candidate for α-therapy. For cancer cells with low surface expression levels of molecular targets, targeting strategies of 225Ac using radiolabeled carriers of low specific radioactivities (such as antibodies) may not deliver enough α-particle emitters at the targeted cancer cells to result in killing. We previously proposed and showed using passive 225Ac entrapment that liposomes can stably retain encapsulated 225Ac for long time periods, and that antibody-conjugated liposomes (immunoliposomes) with encapsulated 225Ac can specifically target and become internalized by cancer cells. However, to enable therapeutic use of 225Ac-containing liposomes, high activities of 225Ac need to be stably encapsulated into liposomes. In this study, various conditions for active loading of 225Ac in preformed liposomes (ionophore-type, encapsulated buffer solution, and loading time) were evaluated, and liposomes with up to 73 ± 9% of the initial activity of 225Ac (0.2-200 μCi) were developed. Retention of radioactive contents by liposomes was evaluated at 37°C in phosphate buffer and in serum-supplemented media. The main fraction of released 225Ac from liposomes occurs within the first two hours of incubation. Beyond this two hour point, the encapsulated radioactivity is released from liposomes slowly with an approximate half-life of the order of several days. In some cases, after 30 days, 225Ac retention as high as 81 ± 7% of the initially encapsulated radioactivity was achieved. The 225Ac loading protocol was also applied to immunoliposome loading without significant loss of targeting efficacy. Liposomes with surface-conjugated antibodies that are loaded with 225Ac overcome the limitations of low specific activity for molecular carriers and are expected to be therapeutically useful against tumor cells having a low antigen density. © 2008 American Chemical Society. |
