We are proposing to optimize antibody-directed lipsomes as an in vivo anti- tumor drug-carrier in selected animal model systems. Our approach takes int account the two major problems of targeting any particulate matter, i.e., the endothelial barrier and the uptake by the reticuloendothelial system (RES). We are therefore proposing to develop new methods for minimizing uptake of circulating liposomes by the RES and to apply targeting of liposomes to tumor cells localized within anatomic compartments accessible to liposomes. 1. New methods for minimizing uptake by the RES. During the past few years, we have studied extensively the clearance antibody-conjugated liposomes fro the circulation. Essentially, a fast clearance indicates a predominant contribution of the liver RES in the uptake of liposomes. Thus, a major objective is the design of strategies resulting in slower clearance of liposomes, thereby increasing the liklihoo of uptake of targeted liposomes by tumor cells. Our central approach to thi goal is the design of liposomes with composition and biophysical properties that would reduce their affinity for the RES and increase their stability (absence of leakage of contents) during prolonged circulation times. In addition, we have proposed adjuvant methods of reversible RES inactivation. 2.Targeting to tumor cells. We have selected several murine tumor models: locally implanted SC tumors; systemically disseminated leukemia and lymphom models; and liver metastases models. We plan also to use a human colon carcinoma derived cell line with liver-metastasizing ability when grown in nude mice. All these tumor cell lines display targetable surface markers. Targeting will be assessed with liposome-encapsulated radiotracers and fluorofores developed in our laboratory both at the primary tumor site and at the metastatic site, the liver. A complementary aspect of this strategy would be to increase the permeability of the endothelial barrier to liposomes. We plan to examine whether the endothelial damage caused by low dose radiation therapy will increase the access of targeted will increase the access of targeted liposomes to the vicinity of tumor cells. Following optimization of the targeting system, therapeutic experiments will be performed to evaluate the efficacy of anti-tumor drugs encapsulated in targeted liposomes on liver metastases and on systemic disease.
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