The research outlined in this proposal is aimed at synthesizing several new classes of highly stable lipid vesicles and evaluating their efficacy as carriers of chemotherapeutic drugs. The basic premise which underlies this work is that conventional phospholipid bilayer vesicles (liposomes), currently under consideration by clinicians for use in cancer chemotherapy, are of somewhat limited, value due to their in vitro and in vivo instability. Specific chemical objectives which are described in this proposal focus on: (1) the synthesis of radiolabeled polymerized vesicles derived from bis [12-(methacryloyloxy) dodecanoy 1)]-L-Alpha-phosphatidylcholine (BCL) and the examination of their disposition and stability in vivo, (2) the development of efficient nonphotochemical methods for polymerizing BCL (3) the development of synthetic methods for covalently attaching proteins to the auter surface of polymerized vesicles, (4) the synthesis of ammonium and phosphate ester surfactants to be used to construct polymerized phosphatidycholine-like vesicles and to modify the permeability, loading and targeting properties of polymerized vesicles derived from BCL, (5) the synthesis of polymerized forms of phosphatidylcholine vesicles having potentially biodegradable and/or excretable backbones based on Schiff base, disulfide or poly (ethylene glycol) formation, and (6) the ionic cross-linking of polymeric- and monomeric-based vesicles employing diphosphate and polyphosphate esters. In addition, specific biological studies are proposed which will (l) define the stability of each new vesicle class prepared, and provide insight into its biophysical properties, (2) evaluate the cellular (macrophage) processing of these synthetic liposomes and measure the influence of vesicle stability on the extent and duration of macrophage activation produced by encapsulated agents, and (3) test the role of vesicle stability in a therapeutic model (systemic candidiasis) which is of great relevance to cancer treatment problems.
| Heindel, N D; Egolf, R A; Stefely, J S (1990) Effect of liposome and cyclodextrin entrapment on retardation of glutathione decomposition of nitroimidazolyl sulfones. J Pharm Sci 79:862-5 |
| Regen, S L; Jayasuriya, N; Fabianowski, W (1989) Supramolecular surfactants: amphiphilic polymers designed to disrupt lipid membranes. Biochem Biophys Res Commun 159:566-71 |
