Synthesis of dendrons, dendrimers, and dendronized polymers as scaffolds for drug delivery

Recently, polymers have exhibited promise as scaffolds for the next generation of anti-cancer therapeutics. Because of the size-dependant interactions between compounds in the bloodstream and adjacent tissues, drug-polymer conjugates can be designed to passively accumulate within cancerous tissues. Although linear polymers have been the primary focus for macromolecular therapeutics, dendritic polymers offer a number of advantages. Unlike linear polymers, but similar to biological macromolecules, dendritic polymers can be prepared as essentially monodisperse molecules with well-defined size and shape. In addition, the synthetic versatility and multivalency associated with dendrimers should enable the attachment of a high drug payload.; The design and preparation of dendritic drug carriers involves a number of distinct stages: first, polymers with narrow polydisperisty and the appropriate size must be synthesized. Secondly a mechanism for attaching the desired drug via a cleavable linker must be developed. And finally the drug-polymer conjugates must undergo a series of trials to determine their effect in vitro and in vivo. This dissertation focuses primarily on the first stage: development of synthetic techniques for biorelevant dendritic polymers. Characterization of these materials has suggested these materials have the appropriate size narrow polydispersity, water solubility, and synthetic versatility to act as a viable scaffold for drug delivery.; After an overview of dendrimer syntheses, dendritic hybrids, and their potential application as scaffolds for drug delivery vectors, the discussion will focus on the synthesis and some preliminary biological evaluation of a variety of dendritic structures. Chapter 2 details the convergent synthesis and peripheral functionalization of chemically rugged aliphatic polyether dendrons. Chapter 3 evaluates the synthetic versatility of these structures through exploring a series of hybrid structures with hetereogenous protecting groups. The utility of these structures is probed via an orthogonal modification of a dendron's end groups. Chapter 4 explores the synthesis of dendrimers and the ability to modify functionalities at their core.; Because the aliphatic polyether dendrons proved to be more synthetically demanding and less compatible with biological systems than similar divergently prepared dendritic polyesters, the remaining chapters explore the synthesis and biological viability of materials prepared in a divergent fashion. Chapter 5 investigates a new divergent dendronization strategy that yields dendronized poly-(p-hydroxystyrene) with unprecidently high molecular weights and low polydispersity. Chapter 6 explores the synthesis of a more biodegradable dendronized caprolactone polymer and compares the divergent dendronization and macromonomer approaches.