Macromolecules for drug delivery: New dendritic architectures and pH sensitive supramolecular assemblies.

摘要

While a number of drug delivery systems based on linear polymers have previously been developed, dendrimers are interesting polymer scaffolds to explore because they possess well-defined architectures and molecular weights, as well as multiple peripheral groups that can be functionalized in a controlled manner to introduce drugs, solubilizing groups and targeting ligands. This thesis is focused on the development of novel anticancer drug delivery systems based on dendritic polymers, utilizing both covalent and non-covalent drug incorporation strategies.; Chapter 1 reviews recent progress in the application of dendrimers and dendritic polymers for drug delivery. Special attention is given to the development of biocompatible dendrimer scaffolds and to the use of these polymers for the delivery of anticancer therapeutics.; The design, synthesis and biological evaluation of poly(ethylene oxide)-polyester dendrimer "bow-tie" hybrids are described in Chapter 2. The use of the novel bow-tie architecture for the synthesis of a small library of 8 polymers with a range of molecular weights and architectures is reported.; Chapter 3 describes the preparation of dendritic bow-ties by self-assembly. A bis(adamantylurea)-glycinylurea system is used to non-covalently link the focal points of two polyester dendrons in chloroform to form a bow-tie. Investigations into the effect of the peripheral functionality on the association constant indicate that solubility can have a critical role in determining the strength of the complex.; The development of acetals as pH sensitive linkages for drug delivery is reported in Chapter 4. The syntheses of several conjugates of poly(ethylene oxide) with model drugs using acetal linkages are described. The structures of the acetal linkages are tuned to provide conjugates with half-lives ranging from 1--2 minutes to several days at mildly acidic pH.; Combining the concept of self-assembly with acetal linkages, a new approach to pH sensitive micelles for drug delivery is described in Chapter 5. These micelles, composed of block copolymers with acetals on the core-forming block, are designed to release their non-covalently encapsulated payload at mildly acidic pH upon disruption of the micelle structure following acetal hydrolysis. (Abstract shortened by UMI.)