The objective of the proposed research is to synthesize by a chemo-enzymatic approach a series of novel unimolecular polymeric micelles (UPMs), i.e., amphiphilic star polymers, to characterize their chemical structure, and perform in vitro tests of their ability to act as vehicles for oral or parenternal delivery of hydrophobic drugs. The molecules will consist of a polyhydric alcohol central core, with its hydroxyls covalently attached to poly(ricinoleic acid), which in turn will be convalently bonded to poly(ethylene glycol) through pH-stable ether and pH-degradable ester bonds, which will enhance the UPMs applicability for targeted delivery, e.g., to the small intestine. A chemo-enzymatic synthetic approach will involve simpler and safer synthetic processes and lower operational and materials costs compared to procedures typically employed to create UPM-, liposome-, or dendrimer-based vehicles. It is anticipated that the resultant UPMs will be very stable when encountering temperature changes, as occur during freezing and sterilization, or dilution, as occurs subsequent to introduction into the body. The objectives of the proposed research are to further refine the enzymatic synthesis of star-poly(ricinoleic acid) in order to improve the number of polymeric """"""""arms"""""""" per molecule, to covalently attach PEG though base-cleavable bonds according to published protocols, to characterize the composition, structure, geometry, and pH-controlled stability and degradability of the resultant UPMs, and to test the UPMs for hydrophobic drug solubilization, diffusional and pH-triggered release (including kinetics), and test for their storage stability. The proposed research project will allow the Principal Investigator (PI) to obtain proof-of-concept data, leading to a major """"""""Phase II"""""""" research effort examining the in vivo capabilities of the UPM materials and the relationship between UPM structure and solubilization and release properties of specific drugs. If successful, the proposed research will produce useful vehicles for delivery of drugs that are poorly soluble in water. The vehicles will be produced in a simpler and perhaps less expensive manner compared to competing technologies. They will be highly biocompatible, will allow for release to a specific organ in the body, and will be able to penetrate through common in vivo barriers to drug delivery, including the blood-brain barrier and cell membranes. ? ? ?
