The primary aim of this research is to fine-tune selected polymerized vesicle systems that appear most promising as drug carriers, and to perform an extensive pharmacological evaluation of their efficacy as adjuncts for the chemotherapeutic treatment of neoplastic disease. A secondary objective of this program is to devise chemical means for controlling vesicle uptake by the reticuloendothelial system through surface modification. Specific chemical objectives that are detailed in this proposal are: (1) to prepare and characterize polymerized VETs (vesicles by extrusion technique) of 1,2-bis(12-(lipoyloxy)-dodecanoyl)-sn- glycero-3-phosphocholine (DLL), 1-palmitoyl-2-(12-(lipoyloxy)- dodecanoyl)-sn-glycero-3-phosphocholine (MLL-2), and various mixtures of DLL and MLL-2; (2) to synthesize a polymerizable disulfide-based sterol and to incorporate it into vesicles of DLL and DLL + MLL-2; (3) to examine the feasibility of preparing polymerized vesicles from preformed phospholipid polymers; (4) to study the action of Phospholipases A2, C and D on polymerized disulfide-based vesicles; (5) to prepare radiolabelled analogs of those vesicles which, from pharmacological studies, appear promising for cancer chemotherapy; and (6) to prepare nonpolymerized and polymerized vesicles that have polyethylene glycols """"""""tethered"""""""" to their surface. Specific pharmacological objectives include: (1) an evaluation of the in vitro and in vivo stability of drug-containing polymerized liposomes; (2) an investigation of the toxicity and efficacy of polymerized liposomes containing antitumor of anti-infectious drugs in appropriate murine models of neoplastic and infectious disease processes; and (3) a study of the interactions of surface modified polymerized liposomes with the cells of the reticuloendothelial system both in vitro and in vivo.
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