The long-term goal of the project is to design new and improved liposomal drug carrier system for the target-specific delivery of the anti-tumor drugs to tumor cells. To achieve this goal, immunoliposomes with monoclonal antibody covalently attached on the surface have been prepared. Target-specific binding of the immunoliposomes have been demonstrated. To improve the efficiency of drug delivery, two novel types of immunoliposomes are designed. The pH-sensitive immunoliposomes whose membrane- fusion activity is greatly enhanced at mildly acidic conditions (pH - 6) are useful in delivering the liposomal contents to the cytoplasm, instead of the lysosomal compartment, of the target cells, one of the significant achievements in the last funding period is the use of this novel liposome type to deliver cloned foreign genes to tumor cells in an experimental animal model. other cytotoxic drugs such as cytosine arabinoside, methotrexate and diphtheria toxin A fragment have also been delivered. The second novel immunoliposome design is the target sensitive immunoliposomes. These liposomes contain a self-destructive mechanism which is triggered by the specific binding of the immunoliposome with the target cell. Thus, the entrapped drug is released at cell surface and rapidly taken up by the target cells. Both types of liposome are designed using the principle of phospholipid polymorphism and the major lipid ingredient is the phosphatidylethanolamine (PE). The PE polymorphism will be studied in detail with the emphases of equilibrium and kinetic studies of the PE bilayer stabilization and destabilization. The possibility of using DNA as a new type of anti-tumor drug will be explored. Genes coding for toxins or the anti-sense RNA to the cellular oncogenes will be delivered to the tumor model system and this novel modality for cancer chemotherapy will be critically evaluated in a nude mouse tumor model. The use of the target-sensitive immunoliposome to deliver anti-tumor drugs will be further explored in the Rauscher erythroleukemia model both in vitro and in animals. A new project will be initiated to study the interaction of the targeted liposome with the pulmonary endothelial cells.
The aim i s to deliver antitumor drugs such as adriamycin to the metasatic lung tumor cells. Also important is to explore the possibility of liposome transcytosis by the pulmonary endothelium. Finally, liposomes with reduced affinity to the reticuloendothelial system will be designed to improve the circulation halflife and the chance of tumor targeting of the immunoliposomes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Experimental Therapeutics Subcommittee 2 (ET)
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University of Tennessee Knoxville
Schools of Arts and Sciences
United States
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