Dendrimer-polymer hybrids for antitumor drug delivery: Synthesis and evaluation

Drug delivery systems hold promise as a means to alter advantageously the pharmacological properties of low molecular weight drugs. The ability of high molecular weight polymer-drug conjugates to passively target tumors and deliver their drug payloads has been demonstrated in animals and humans; however, the clinical application of polymeric drug delivery systems can be hampered by a lack of polymer biodegradability or by the lack of homogeneity associated with most synthetic polymers. Dendrimers offer a macromolecular architecture characterized by a highly branched and a monodisperse structure. When the proper dendrimer chemistry is chosen, biodegradable, highly-functionalizable, and homogeneous materials can be accessed, which are ideal candidates for drug delivery applications. By combining dendrimers with linear polymers, it is possible to obtain hybrid materials that possess their own unique properties while retaining some of the beneficial features of polymers with branched or linear architectures. This dissertation describes the synthesis and biological evaluation of dendrimer-polymer hybrids with different topologies for application as antitumor drug carriers.; The syntheses and biological evaluations of linear polymers with aliphatic polyester dendrimer sidechains are presented. These materials are referred to as dendronized linear polymers, and differ from both dendrimers and random coil polymers in that their shapes are typically cylindrical and their backbones are typically rigid and extended. Since macromolecular shape can have an effect on the cellular and whole body pharmacokinetics of a polymer, drug carriers based on these materials may possess activities different from those of linear polymers or dendrimers. In vitro and in vivo experiments performed with dendronized poly(4-hydroxystyrene) verified that dendronized linear polymers do not possess toxicity or pharmacokinetic profiles that preclude their use as drug carriers. The synthesis, characterization, and biological evaluation of dendronized linear polymers with backbones more suitable for biomedical applications based on poly(&egr;-caprolactone) and poly(L-lysine) are also discussed.; The synthesis and antitumor effects of dendrimer-polymer hybrids composed of a polyester dendrimer asymmetrically functionalized with the anticancer drug doxorubicin and poly(ethylene oxide) chains are described. When these star-shaped macromolecular prodrugs, referred to as bow-tie dendrimers, were administered intravenously to tumor-bearing mice, complete cures of tumors were achieved, even though the tumors were non-responsive to treatment with the free drug. The importance of subtle differences in the chemical structures of the drug-dendrimer linkages was realized in these experiments, and insights into how these structural differences manifest themselves biologically are discussed.