Studies of natural product derivatives: targeted polymer drug conjugates
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Polymer drug conjugates are an emerging class of therapeutic agent that offer advantages in the treatment of cancer through long circulation times and passive targeting. A further benefit of using a polymeric framework is that it readily allows attachment of targeting motifs to enhance the drug specificity, as well as allowing variation of the drug component. In this work a series of targeted polymer drug conjugates were prepared that incorporated different drugs via peptide linkers designed to be stable in circulation but degradable at the target site. In order to ensure stability in circulation, it was necessary to ensure the drugs were conjugated to the biodegradable linkers via amides, which required the introduction of amine functionalities to the natural-product drugs. The required hemisyntheses were successfully carried out, although yields were sometimes disappointing. An effort to allow an assessment of the pharmacokinetic effects of using a polymeric scaffold was made through the attempted synthesis of low molecular weight analogues of the polymer drug conjugates, with success in some cases. A recently developed polymeric precursor was used in the preparation of the polymer drug conjugates but was found to undergo an unexpected side-reaction, which may prevent the long term development of this particular precursor. The desired conjugates were nonetheless successfully produced on a scale suitable for initial biological testing. Both the high and low molecular weight constructs synthesised showed reduced cytotoxicities to P388 murine leukemia cells and are currently awaiting in vitro testing to truly evaluate their utility.