Synthesis and biological evaluation of polymer-autotaxin inhibitor conjugates for the treatment of ovarian cancer

Abstract

Autotaxin is an extracellular phospholipase D that catalyses the hydrolysis of lysophosphatidyl choline (LPC) to bioactive lipid lysophosphatidic acid (LPA). LPA has been implicated in many pathological processes relevant to cancer, including cell migration and invasion, proliferation, and survival. Patients with ovarian cancer often present with an accumulation of ascites fluid in the intraperitoneal cavity which contains LPA at concentrations up to 80 micromolar. Autotaxin is also found at increased levels in the ascites fluid of patients with ovarian cancer and is over-expressed in ovarian cancer tumours that are resistant to chemotherapy. Maintaining a high local concentration of an autotaxin inhibitor within the peritoneal cavity is likely to be important to ensure sufficient and prolonged inhibition of autotaxin. The residence time of small molecular weight drugs in the peritoneal cavity may not be adequate because they are quickly absorbed through the peritoneal capillaries into systemic circulation. Polymers are becoming an increasingly useful tool in the delivery of drugs and have the potential to improve the properties of small molecules, including intraperitoneal residence time. In this thesis, the synthesis of polymer-autotaxin inhibitor conjugates is described, followed by the biological evaluation of the conjugates.

Firstly, the synthesis of a dendrimer-S32826 conjugate and its biological evaluation is reported. S32826 is a LPA analogue with a high potency against autotaxin. This dendrimer-autotaxin inhibitor conjugate was found to inhibit autotaxin activity using two different substrates and two different sources of autotaxin, and to decrease the migration of an ovarian cancer cell line modified to overexpress autotaxin. Furthermore, the conjugate potentiated activation of caspase 3/7 induced by carboplatin. However, conjugation of the drug to the dendrimer significantly reduced its potency.

Subsequently the synthesis of an icodextrin-autotaxin inhibitor conjugate and its biological evaluation was undertaken. Structure-based drug design was used to identify an appropriate locus to cross link icodextrin to an autotaxin inhibitor described by Albers et al. with a thiazolidinedione core. The icodextrin-autotaxin inhibitor conjugate was also found to inhibit autotaxin activity using two different substrates and two different sources of autotaxin. Furthermore, the conjugate was found to reduce migration of an ovarian cell line modified to over express autotaxin. Conjugation to icodextrin led to an increase in solubility and a decrease in permeability compared to the free drug. Finally, the icodextrin-autotaxin inhibitor conjugate was administered to the peritoneal cavity of mice. After 24 hours, 30% of the drug was still detected in the peritoneal cavity. These observations suggest that the drug conjugate may be useful in the treatment of ovarian cancer.