Wafa Al-Jamal
Queen's University Belfast
Wafa Al-Jamal completed her PhD in Drug Delivery in 2008 at UCL School of Pharmacy, London. She is currently a Reader in Nanomedicine and Drug Delivery at Queen’s University Belfast. She is also a Prostate Cancer Research Fellow. Wafa joined the University of East Anglia as a Lecturer in Drug Delivery, after working as a senior research fellow at University College London and King’s College London.Her research focuses on developing cancer nanomedicines for combinatory therapy and theranostic applications. Her multidisciplinary research has been funded by the Royal Society, Prostate Cancer UK and EPSRC.
Introduction: Hypoxia pro-drugs have emerged as novel alternative cancer therapies. Tirapazamine (TPZ) is the most advanced hypoxia-activated prodrug and has shown great specificity and potency in inhibiting tumour growth at moderate to severe hypoxic conditions. It is currently in phase III clinical trials to treat cervical cancer, but its clinical efficacy has been limited due to rapid metabolism and consequently, poor diffusion in the tumour mass. The coordination of pro-drugs to metal centres has shown potential modulation in the physicochemical properties of pro-drugs, while maintaining their hypoxia selectivity. In this study, we report the preparation of copper-tirapazamine Cu(TPZ)2 complexes and their potential use as a selective hypoxia therapy for prostate cancer (PC).
Methods: Cu(TPZ)2 were prepared and characterised using different techniques, such as FTIR and MALDI-TOF, HPLC, UV/Vis, spectrofluorometry and TEM. TPZ and Cu(TPZ)2 in vitro cytotoxicity was assessed in different prostate cancer cell monolayers, cultured under normaxia and 1% hypoxia. The cytotoxicity was evaluated using resazurin cell viability assay. The potency and selectivity of Cu(TPZ)2 and TPZ were compared by calculating the HCR (hypoxia cytotoxicity ratio).
Results: Cu(TPZ)2 complexes were successfully prepared with a high yield (>70%). FTIR and MALDI, confirmed the complexation. Further analytical data, showed that both TPZ and Cu(TPZ)2 were stable over a wide range of solvents, buffers, and pH values. Furthermore, these complexes showed interesting properties that could have applications in theranostics and image-guided drug delivery. Cu(TPZ)2 complexes maintained their hypoxia selectivity in vitro and demonstrated a statistically significant potency at 1% hypoxia, compared to normaxic conditions. More interestingly, a high HCR ratio (>50) was observed in some PC cells, suggesting an enhanced therapeutic activity of Cu(TPZ)2 compared to TPZ alone.
Conclusions: This is the first study reporting the preparation and the characterisation of Cu(TPZ)2 complexes, as well as their enhanced toxicity in prostate cancer cells. Our hypoxia-selective complexes could be used in combination with chemo- or radio-therapy to enhance their therapeutic efficacy in advanced prostate cancer patients.
Acknowledgements: This work was supported by Prostate Cancer UK (Grant CDF-12-002), the Engineering and Physical Sciences Research Council (EPSRC) (EP/M008657/1), and University of East Anglia.
Targeted drug delivery and nanocarriers , Nanomedicine for cancer diagnosis & therapy
