Macromolecules for the Delivery of Cancer Chemotherapeutics
- Author(s): van der Poll, Derek Gregory
- Advisor(s): Frechet, Jean M. J.
- et al.
Chemotherapy is the practice of treating cancer with antineoplastic drugs. In general, these drugs are highly toxic, and in many patients the side effects from therapy become so severe that treatment is stopped before full tumor remission has occurred. Further, chemotherapeutics usually have poor water solubility and very short circulation lifetimes, which makes it difficult to get a significant fraction of the injected dose to the tumor site. The use of polymers as delivery vehicles for drugs is a strategy for improving the efficacy and reducing the side effects of toxic cancer drugs. The design of an ideal polymeric system for drug delivery is a very active area of research and PEGylated dendrimers are among the most promising. Here we report the design, synthesis and biological evaluation of a biodegradable and versatile PEGylated dendrimer. We also report the preliminary results of a project involving hyaluronic acid functionalized liposomes.
Chapter 1 is a brief overview of the background and history of polymers in drug delivery. The relevance of dendrimers is described in the context of other polymer delivery systems that have begun the transition into clinical development.
Chapter 2 describes the synthesis and characterization of a PEGylated dendrimer that is biodegradable, robust, and has a nine step synthesis to drug loaded material. The polymer was functionalized with the drug, doxorubicin, and evaluated in mice. The in vivo chemotherapy experiment in Balb/c mice inoculated with murine C26 colon carcinoma resulted in nine out of ten long fully cured mice.
Chapter 3 describes the application of PEGylated dendrimers with platinum therapeutics. In order to increase the number of drug attachment sites on the dendrimer, the dendrimer core is used as a macroinitiator to carry out a ring-opening radial growth polymerization of the N-carboxy anhydride of glutamic acid. The terminal amines are then PEGylated and platinum chelators are attached to the glutamic acid side chains. Preliminary biological evaluation revealed that the polymer released platinum too quickly and therefore did not significantly improve the efficacy of the drug. This information was what inspired the research in chapter 4.
Chapter 4 presents the synthesis and characterization of a small library of polymer bound platinum chelators. The chelators were loaded with diaminocyclohexane platinate (DACHPt). Differences in the ring size and ligand strength are examined in relation to drug release rate and cytotoxity. The most promising chelators were taken forward and evaluated in the C26 colon carcinoma model alongside the clinical drug, cisplatin, as a positive control.
Chapter 5 outlines an attempt to develop a new class of platinum (II) drugs that are specially tailored for polymeric drug delivery. A small library of heterocyclic diamine ligands functionalized with a ketone moiety was synthesized. The ligands were loaded with platinum (II) and the complexes were screened for their in vitro toxicity. The complexes with high potency were attached to polymers via a hydrazone bond and evaluated in vivo.
Chapter 6 outlines a new synthetic approach toward hyaluronic acid (HA) functionalized liposomes. HA, a naturally occurring polysaccharide is specific ligand for the CD44 receptor which is overexpressed on a number of cancer cell types. Using oxime chemistry, lipid molecules were attached to various lengths of HA oligomers at their reducing ends. The glycolipids were then incorporated into fluorescently labeled liposomes. The cells preferentially internalized the HA-targeted liposomes and did not internalize non-targeted control liposomes.