Synthesis and Evaluation of Dendritic Polymer Carriers for Chemotherapeutic and Imaging Applications.

摘要

Among the multitude of compounds capable of exerting a potentially therapeutic effect on a diseased biological system, only a very select few happen to possess the stringent pharmacokinetic profile required to be used in practice. In addition to being biologically active, a potential drug candidate must also have good solubility in biological systems, reach its target destination in adequate quantities to bring about the desired effect, and not cause a substantial degree of harm to nontargeted areas of the body through toxicity or side reactions. These requirements also apply to biological agents used in conjunction with treatment, such as molecular diagnostic tools used for disease imaging and marking. Rather than simply discount agents lacking ideal pharmacokinetics, polymeric drug delivery attempts to mask these deficiencies by incorporating these small molecules into their structure, and in doing so create a conjugate structure in which the favorable pharmacokinetic properties of the carrier mask the unfavorable properties of the drug. In this work, the design, synthesis and potential uses and benefits of a specific family of these carriers, pegylated dendrimers, is presented and discussed. In the first chapter, the general principles of drug and imaging agent delivery via dendrimers and other macromolecules are discussed, as well as the differences found among the various systems commonly employed for this purpose. With a focus on dendrimers, this chapter will go on to address the importance of fidelity to ideal molecular structure, synthetic tailorability, and optimal pharmacokinetic profile in these systems, and how such aspects are installed or maintained with minimal synthetic investment.;In chapter 2, the gradual development of our current dendrimer platform is discussed, as well as several surprising reaction sequences encountered along the way. Starting from promising but synthetically demanding polyester dendrimers, the development of several polyamide structures is discussed, along with their respective advantages and disadvantages, before progressing on to current hybrid structures that offer a highly favorable compromise between the two systems. Tailorability available within these systems to address several common needs and problems is also discussed.;In chapter 3, an investigation into the feasibility of creating a drug carrier of an elongated shape and its potential benefits in pharmacokinetics is discussed. The platform for such a carrier begins with the living anionic ring opening polymerization of a lysine derived N-carboxyanhydride (NCA) monomer, after which dendronization and elaboration by copper catalyzed "click" chemistry are used to transform this polymer into a biocompatible drug carrier with a predefined aspect ratio. The biodistribution of this elongated carrier and its comparison to other architectures with regards to in vivo behavior is also discussed.;In chapter 4, the attachment of an analog of a highly potent potential chemotherapeutic agent, tubulysin, is discussed. This chapter outlines the process for evaluation of potential agents for their use with polymeric drug delivery, and how the native drug can be tailored for the purpose. The synthesis of the new drug analog and its polymer conjugate is then discussed, followed by its preliminary in vitro analysis, and finally its in vivo performance in tumored mice. In chapter 5, the delivery of magnetic resonance imaging (MRI) active contrast agents with dendrimers is discussed. This will involve a brief introduction to the field of gadolinium based imaging, what agents are currently in use and how they work, and how these agents can potentially be improved by polymeric delivery systems. The change in performance for several small molecule gadolinium chelators upon binding to an esteramide dendrimer will be presented to support this discussion. Finally, the potential for similar chelates containing different lanthanides to be used in alternate or multimodal imaging polymeric systems will be presented. In chapter 6, the theme of using polymeric carriers for diagnostics will be continued with discussion of a dendrimer capable of imaging with PET, but the complexity and potential performance of the system will be increased with the addition of a targeting group specific to atherosclerosis markers. The additional synthetic considerations introduced into this system will be discussed, followed by how they may be addressed.