We propose and study in and in vivo a new family micellar drug carriers with controlled longevity, biodistribution, and target ability. Studies on biological pharmacological properties of various micelles have revealed their high potential as drug carriers for sparingly soluble pharmaceuticals. However, routinely used micelles have insufficient stability upon dilution and in vivo, or require chemical attache of a drug to a hydrophobic moiety of a micelle-forming surfactant molecule. Based on our preliminary experiments with new highly stable micelles prepared from diacyllipidpolyethyleneoxide (PEO) conjugates, our hypothesis is that lipid-PEO-based micelles (or micelles prepared from lipid conjugates with other PEO-like hydrophilic polymers) stable at physiologic conditions may serve as an efficient delivery system for therapeutic and diagnostic agents, and that the bioavailability of micelle-incorporated poorly soluble drugs may be increased. Targeted delivery of micelle-solubilized pharmaceuticals can be achieved by covalent coupling of specific antibodies to the free ends of hydrophillic. Overall, a proposed drug delivery system should definitely benefit from: 1) properties of PEO or similar polymers as steric protective agents for particulate; 2) extreme stability of diacyllipid-PEO and similar micelles; 3) smaller size compared to other known delivery systems; 4) high solubilization of power of PEO-based surfactants; 5) possibility of targeted delivery. In the present study we propose: a) to synthesize and characterize a set of new micelle-forming copolymers; b) to prepare micelles from these polymers, and to study how micelle stability, size, and ability to retain entrapped substances depend on polymer type, size of hydrophilic block, and loading degree; c) To study the biodistribution and longevity of micelles in mice, and their ability to accumulate in areas with affected vasculature in mice and rabbits; d) to prepare targeted micelles by attachment of a corresponding antibody to a free end of a hydrophilic bloc, and to investigate the properties and target ability of immunomicelles both in vitro and in vivo in infarcted rabbits and tumor (EL4 lymphoma and Lewis lung carcinoma) -bearing mice; e) to perform preliminary experiments on micellar delivery of actual therapeutic and diagnostic agents. As a result of this proposed study we plan to introduce a new family of micellar drug carriers for sparingly soluble pharmaceuticals and to determine the optimum micelle compositions and properties for use as pharmaceutical carriers.
