(706b) Targeted Radionuclide Therapy of Metastatic Ovarian Cancer

Metastatic ovarian cancer is initially confined to the intraperitoneal (i.p.) space and can be targeted using liposomes immunolabeled with the humanized monoclonal antibody, trastuzumab (Herceptin) that are injected directly into the i.p. cavity. The alpha-particle (α)-emitting radionuclide, actinium-225 (Ac-225) was encapsulated within these immunoliposomes as a therapeutic in an animal model of ovarian cancer metastases. This approach is more effective than the traditional delivery of chemotherapeutics by i.v. injection for a number of reasons. By using an i.p. injection, drug delivery targets tumor nodules that are not vascularized and therefore would not be reached by i.v. treatment. Using an α-emitting radionuclide as the drug of choice delivers high local energy deposition which is effective at sterilizing targeted cells, but only has a short path length, which would spare adjacent normal tissue. By encapsulating the Ac-225 within immunoliposomes, specific targeting is achieved, and it effectively decreases the toxicity associated with Ac-225's free daughters.

Previously, it has been shown that the process of actively loading Ac-225 within the liposomes can achieve high loading of the radionuclide (~80-95%) as well as stable retention (80-90% over 4 weeks). Prior to beginning therapy, fluorescent and μSPECT/CT imaging analysis demonstrated that liposomes were selectively targeted to the sites of tumor nodules. Immunoliposomes containing Ac-225 or trastuzumab directly conjugated to Ac-225 were injected into tumor-free mice in order to determine the maximal tolerated dose (MTD) prior to treatment. It was found that immunoliposomal encapsulation and delivery of the Ac-225 resulted in a 5-fold higher MTD than antibody-mediated delivery of Ac-225 alone (1300nCi vs. 250nCi). Biodistribution analysis of a sub-therapeutic dose in tumor bearing mice suggests that the tumor targeting effect of the two formulations is very similar, but there is a much higher concentration of the free daughter, Bismuth-213 in the liver and kidneys when the antibody alone is injected. This suggests that the higher MTD of the Ac-225 loaded liposomes may be due to its efficient retention of Ac-225 and its daughters at the target site, thereby decreasing their systemic toxicity. Currently underway are therapy studies in which tumor bearing mice are injected with radionuclide loaded immunoliposomes or antibody at their respective MTDs to determine the therapeutic efficacy of this approach.