The investigator proposes to prepare and to study in vitro and in vivo a new family of long-circulating polymer-modified liposomes with controlled longevity, biodistribution, and targetability. Studies on biological and pharmacological properties of amphiphilic polyethylene glycol, (PEG)-coated long-circulating liposomes have revealed their high potential as drug carriers. Based on preliminary experiments on the elucidation of molecular mechanisms underlying biological properties of PEG-liposomes, the investigator suggested a hypothesis that other amphiphilic polymers can be synthesized with properties similar to those of PEG. Such polymers can be incorporated into the liposomal membrane yielding sterically-protected long-circulating liposomes with a variety of physico-chemical and biological properties. In particular, liposome properties in vivo can be controlled by the chemical nature and charge of the distal terminal group of the liposome-grafted polymer. Sterically-protected targeted liposomes can also be prepared by simultaneous coupling of monoclonal antibodies to the liposome surface or to activated distal termini of protecting polymers. The use of new polymers for the preparation of polymer -modified liposomes will broaden the possibilities for regulating the properties of liposomal preparations in a desired way by altering their biodistribution and pharmacokinetics, thus increasing their potential as pharmaceutical carriers. The investigator proposes: a) to synthesize and characterize a set of water-soluble and flexible polymers of different molecular weights modified at one terminus with a hydrophobic residue which can be incorporated into the liposomal membrane and at another (distal) end with certain reactive groups; b) to prepare liposomes containing these polymers, and to study how liposome properties, such as permeability and stability in water solutions and in blood plasma, depend on polymer type and lipid-to-polymer molar ratio; c) to study the biodistribution and longevity of polymer-modified liposomes in mice, and their ability to accumulate in areas with affected vasculature (infarcted areas, tumors) in mice and rabbits; d) to prepare polymer-coated targeted liposomes by co-immobilization of targeting moiety (antibody) and protecting polymer on their surface (including antibody attachment to the activated distal termini of polymeric chains), and to investigate the properties and targetability of polymer-modified targeted liposomes in infarcted rabbits and tumor (EL4 lymphoma)-bearing mice, while using infarct- or tumor-specific monoclonal antibodies. As a result of this proposed study the investigator plans to determine the optimal liposome properties and composition for use as pharmaceutical carriers, and to find which liposomes will be able to provide the maximum target accumulation and maximum target-to-nontarget ratio.
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