Novel amphiphilic macromolecules for drug delivery applications: Design, synthesis and characterization

The focus of this dissertation is the design, synthesis, and characterization of biocompatible amphiphilic macromolecules for biomedical applications such as drug delivery and tissue engineering. The development of two macromolecular systems is described.; I. Amphiphilic scorpion-like macromolecules ( AScMs). The AScMs include three fundamental design components: (1) multi-branched hydrophobic domain; (2) hydrophilic polymer tail; and (3) functional conjugate. The branched hydrophobic domains were prepared by acylation of sugars with varying chain lengths of acyl chlorides. Poly(ethylene glycol) (PEG) was chosen as the hydrophilic polymer tail.; AScMs can self-assemble to form micelles in aqueous solution. By changing the length of both PEG and acyl chains, the physicochemical properties (e.g., HLB, and CMC) of AScMs are controlled. The unique multi-branched structure appears to enhance micellar self-assembly relative to other amphiphilic polymers. Low CMC values and nano-scale particle sizes of AScMs are appropriate and desirable for lipophilic drug delivery. Moreover, AScMs were studied as inert hydrophilic polymers for liposome vesicle stabilization.; An alternate form of AScMs was prepared in where the micellar core was cross-linkable following formation of the micelle aggregates in aqueous solution. The branched hydrophobic domain was prepared by acylation of dimethylolpropionic acid with 10-undecenoyl chloride. PEG was then conjugated onto the hydrophobic domain to form PEG-lipid-like amphiphiles. The vinylic groups at the chain ends of 10-undecenoyl acids were polymerized by cross-linking the core in the aqueous solution following micelle formation. Relative to the uncrosslinked polymeric amphiphiles as controls, the core cross-linked micelles show improved thermodynamic stability to higher temperatures and non-selective solvents, as well as increased drug loading capacity.; II. Amphiphilic star-like macromolecule systems ( ASMs). The core-shell, amphiphilic structure of ASMs are composed of pentaerythritol derivatives, mucic acid, fatty acids and poly(ethylene glycol) (PEG). ASMs are thermodynamically stable unimolecular micelles as opposed to conventional micellar systems because the structure is covalently linked with either ester, or amide bonds. The core of ASMs provides a flexible, hyperbranched, hydrophobic environment for drug encapsulation, whereas the PEG shell provides excellent water solubility. Towards active targeting drug delivery, folic acid was attached to the PEG chain ends of the hydrophilic shell.