Novel conjugates of autotaxin inhibitors for the treatment of ovarian cancer

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Hemming, R.A., 2018. Novel conjugates of autotaxin inhibitors for the treatment of ovarian cancer. PhD, Nottingham Trent University.

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Abstract

Over 7000 women are diagnosed with ovarian cancer each year in the UK. This disease is characterized by a particularly poor survival rate (40% at stage III, after 5 years), leading it to become known as a "silent killer". This poor survival rate is due, in part, to the biological mechanisms by which cancer cells become resistant to drugs used in chemotherapy. The enzyme autotaxin has been strongly implicated in this process. Whilst many autotaxin inhibitors are extremely potent in vitro, when tested in vivo they have been found to perform poorly. This is partly because the drugs can be rapidly absorbed from their site of action, through the wall of the peritoneal cavity, before undergoing hepatic metabolism.

Herein we present a novel strategy that is designed to increase the residence time of an autotaxin inhibitor within the peritoneal cavity, using a novel polymer-drug conjugate approach for drug delivery. This was achieved through the attachment of a known autotaxin inhibitor to a high molecular weight polymer (Icodextrin or Inulin), known to be retained within the peritoneal cavity for extended periods of time. To our knowledge, Icodextrin has never been used as a vehicle for drug delivery outside of our research group. This thesis demonstrates the application of this novel drug conjugate approach, across a range of autotaxin inhibitors and polymers. The effect of polymer-drug loading on activity was also investigated, which to our knowledge has never been studied before with the supports used in this study. To facilitate this, a novel conjugation method was developed for the attachment of drug molecules to the polymer, which yielded 11 drug conjugates in total, which were then evaluated for their biological activity. The drug conjugates were found to be highly potent in separate assay types, with IC50 values as low as 300 ± 40 ng / mL-1 for Inulin-drug conjugates and 698 ± 294 ng / mL-1 for Icodextrin conjugates. This study also revealed the effect of drug loading on biological activity, which gave an unexpected result which could influence the design of polymer-drug conjugates in the future. The peritoneal retention of an Inulin autotaxin inhibitor conjugate was studied in mice for the first time. The effect of intra polymer cross-linking on biological activity has also been evaluated.

Overall, the work described within this thesis could be used to provide an effective new therapeutic approach for the treatment of ovarian cancer; additionally the polymer therapeutic approach described in this work has the potential to be used in application to treat a variety of diseases.

Item Type:	Thesis
Creators:	Hemming, R.A.
Date:	September 2018
Rights:	This work is the intellectual property of the author. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the owner(s) of the Intellectual Property Rights.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	03 Dec 2018 11:25
Last Modified:	03 Dec 2018 11:25
URI:	https://irep.ntu.ac.uk/id/eprint/35204