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Targeted Delivery of Novel Platinum (IV) Anti-Cancer Prodrugs
Physical targeting of drugs
More than one in three people in the UK will develop cancer. Platinum compounds such as cisplatin, oxaliplatin and carboplatin are highly effective front-line cancer treatments. They are often most successful when used in combination with other agents. However, they attack healthy cells as well as cancer cells, resulting in side-effects such as severe nausea and permanent kidney damage. There is an urgent need to treat cancer successfully and affordably, while reducing side-effects.
Targeting drug delivery using an external stimulus - like light or ultrasound - allows precise control over both the location and timing of drug release. It can also be used to tackle resistance to treatment, by releasing a number of different agents in the same location, and allows better control over their relative concentrations than simple administration. Furthermore, it improves the potential for theranostics – the combination of imaging and therapy within the same molecule, so that the progress of treatment can be monitored in real time. Delivery of drugs specifically to where they are needed means a smaller dose needs to be given to the patient, and less undelivered drug will need to be broken down and removed from the body, reducing potential side-effects. Ultimately we aim for this research to have a positive impact on both the quality and length of life of cancer patients.
Using ultrasound to deliver Pt(IV) anti-cancer prodrugs
Our current research builds on our previous work (see references) developing light-activated Pt(IV) prodrugs (prodrugs are inactive precursors to drugs – they need to be activated in some way in order to exert their biological effect). Ultrasound is particularly promising because it can be highly focused and can penetrate deeply into tissue. Medical ultrasound devices are clinically widespread and relatively affordable, making using ultrasound to target drug action an exciting possibility. In collaboration with Dr. Robert Carlisle, Prof. Eleanor Stride and Prof. Constantin Coussios at the Institute for Biomedical Engineering in Oxford we are encapsulating new Pt(IV) prodrugs which can be delivered to cancer cells using ultrasound. Once taken up into cancer cells, the platinum drug will be converted to an active form by reducing agents in the cells, and will kill the cells by interfering with metabolism and binding to DNA. Cell tests will investigate how good the drugs are at killing cells. The packaging of the drugs will be optimised so that in the absence of ultrasound activation the packaged drug is not released, but when ultrasound is used it is readily released. Platinum can be easily detected in small amounts by standard chemical techniques like spectroscopy, allowing the distribution of platinum compounds to be readily assessed.
Developing new platinum-lanthanide theranostic agents
In collaboration with Prof. Stephen Faulkner in the Department of Chemistry we are developing new platinum-lanthanide complexes which can be used for both imaging and treatment.
Developing multi-modal Pt(IV) prodrugs for diffuse intrinsic glioma with H3K27M mutations
Brain tumours are the most common cause of death of children and young people under 40. Paediatric high grade gliomas (HGG) are highly aggressive, with a poor clinical prognosis, and diffuse midline glioma with H3K27M mutations (formerly known as DIPG) although rare - is the leading cause of death from brain cancer in children. We are developing novel Pt(IV) prodrugs for treatment these gliomas in collaboration with Dr. Alex Bullock and Dr. Paul Brennan (Structural Genomics Consortium, Oxford) and Jeff O’Meara (M4KPharma network). We are involved with the Children’s Brain Tumour Drug Delivery Consortium (CBTDDC) and since delivery across the blood brain barrier is a significant challenge, we are investigating a range of delivery methods including microbubble-mediated ultrasound (collaboration with Prof. E Stride, Institute of Biomedical Engineering, Oxford) and convection enhanced delivery (collaboration with Steven Gill MD, Bristol Medical School, UK).
1. G. Karunanithy, R. J. Wheeler, L. R. Tear, N. J. Farrer, S. Faulkner, An in-cell diffusion method to characterize the size, abundance and permeability of cells, J. Magn. Reson. 2018, doi.org/10.1016/j.jmr.2018.12.001
2. N. J. Farrer,* G. Sharma, R. Sayers, E. Shaili, P. J. Sadler, "Platinum (IV) azido complexes undergo copper-free click reactions with alkynes", Dalton Trans, 2018, 47, 10553 - 10560.
3. Yao Zhao, N. J. Farrer, H. Li, J. S. Butler, R. J. McQuitty, A. Habtemariam, F. Wang, P. J. Sadler, "De novo generation of singlet oxygen and ammine ligands by photoactivation of a platinum anticancer complex", Angew. Chem. Int. Ed., 2013, 52, 13633 – 13637.
4. Y. Zhao, J. A. Woods, N. J. Farrer, K. S. Robinson, J. Pracharova, J. Kasparkova, O. Novakova, H. Li, L. Salassa, A. M. Pizarro, G. J. Clarkson, L. Song, V. Brabec, P. J. Sadler, " Diazido Mixed-Amine Platinum(IV) Anticancer Complexes Activatable byVisible-Light Form Novel DNA Adducts" Chem Eur. J., 2013, 19, 9578 – 9591.
5. C. R. Barone, C. Coletti, R. J. McQuitty, N. J. Farrer, G. Lorusso, L. Maresca, A. Marrone, G. Natile, C. Paciﬁo, S. Parsons, N. Re, P. J. Sadler, F. J. White, "Photo-isomerisation of alkenyl complexes of platinum(II): structural, spectroscopic, kinetic and computational Investigations", Dalton Trans., 2013, 42, 6840 – 6851. 6. J. S. Butler, J. A. Woods, N. J. Farrer, M. E. Newton, P. J. Sadler "Tryptophan Switch for a photoactivated platinum anticancer complex " J. Am. Chem. Soc., 2012, 134, 16508– 16511.
7. Y. Zhao, G. M. Roberts, S. E. Greenough, N. J. Farrer, M. J. Paterson, W. H. Powell, V. G. Stavros, P. J. Sadler, “ Two-photon-activated ligand exchange in platinum(II) complexes"Angew. Chem. Int. Ed., 2012, 51, 11263 – 11266.
8. A. F. Westendorf, J. A. Woods,K. Korpis,R. Grünert, N. J. Farrer, L. Salassa,P. J. Sadler, P. J. Bednarski "trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)]: a light activated platinum complex that kills human cancer cells by an apoptosis-independent mechanism", Mol. Cancer Ther. 2012, 11, 1894 – 1904.
9. H-C. Tai, Y. Zhao, N. J. Farrer, A. E. Anastasi, G. Clarkson, P. J. Sadler, R. J. Deeth "A Computational Approach to Tuning the Photochemistry of Platinum(IV) Anticancer Agents", Chem Eur. J., 2012, 18, 10630 – 10642.
10. H-C. Tai, R. Brodbeck, J. Kasparkova, N. J. Farrer, V. Brabec, P. J. Sadler, R. J. Deeth, "Combined Theoretical and Computational Study of Interstrand DNA Guanine–Guanine Cross-Linking by trans-[Pt(pyridine)2] Derived from the Photoactivated Prodrug trans,trans,trans-[Pt(N3)2(OH)2(pyridine)2]", Inorg. Chem., 2012, 51, 6830 – 6841.
11. S. Unterkofler, R. J. McQuitty, T. G. Euser, N. J. Farrer, P. J. Sadler, P. St.J. Russell, "Microfluidic integration of photonic crystal fibers for online photochemical reaction analysis", Opt. Lett., 2012, 37, 1952 – 1954.
12. J. Pracharova, L. Zerzankova, J. Stepankova, O. Novakova, N. J. Farrer, Peter J. Sadler, V. Brabec, J. Kasparkova, Interactions of DNA with a New Platinum(IV) Azide Dipyridine Complex Activated by UVA and Visible Light: Relationship to Toxicity in Tumor Cells, Chem. Res. Toxicol., 2012, 25, 1099 – 1111.
13. N. J. Farrer, K. L. Vikse, R. McDonald, J. S. McIndoe, "Proton sponge phosphanes: reversibly chargeable ligands for ESI-MS analysis", Eur. J. Inorg. Chem., 2012, 733–740.
14. N. J. Farrer*, P. Gierth, P. J. Sadler, "Probing Platinum Azides with 15N and 14N NMR Spectroscopy" Chem. Eur J., 2011, 17, 12059 – 12066.
15. N. J. Farrer, J. A. Woods, L. Salassa, Y. Zhao, K. S. Robinson, G. Clarkson, F. S. Mackay, P. J. Sadler "A Potent Trans Diimine Platinum Anticancer Complex Photoactivated by Visible Light". Angew. Chem. Int. Ed., 2010, 49, 8905 – 8908. Assigned VIP status (top 5%).
16. N. J. Farrer, N. Monk, J. Heron, J. Lough, P.J. Sadler, "(RSC)2 : Chemistry, Performance, and Pedagogy – an interactive approach to periodic trends", Chem. Ed. Res. Pract., 2010, 11, 308 –313.
17. J. S. Y. Chen, T. G. Euser, N. J. Farrer, P. J. Sadler, M. Scharrer, P. St.J. Russell, "Photochemistry in Photonic Crystal Fiber Nanoreactors" Chem. Eur. J., 2010, 16, 5607 – 5612.
18. N. J. Farrer, J. A. Woods, V. P. Munk, F. S. Mackay, P. J. Sadler, "Photocytotoxic trans-Diam(m)ine PlatinumI(IV) Diazido Complexes More Potent than Their cis Isomers", Chem. Res. Toxicol., 2010, 23, 413 – 421.
19. N. J. Farrer, R. McDonald, T. Piga, J. S. McIndoe, "Bisphosphine monoxides with o-phenylene backbones in Pt, Pd and Fe complexes" Polyhedron, 2010, 29, 254–261.
20. F. S. Mackay, N. J. Farrer, L. Salassa, H-C.Tai, R. J. Deeth, S. A. Moggach, P. A. Wood, S. Parsons, P. J. Sadler, "Synthesis, characterisation and photochemistry of PtIV pyridyl azido acetato complexes" Dalton Trans., 2009, 2315 – 2325.
21. N. J. Farrer, L. Salassa, P. J. Sadler, "Photoactivated chemotherapy (PACT): the potential of excited-state d-block metals in medicine." Dalton Trans. 2009, 10690 – 10701.
22. T. G. Euser, J. S. Y. Chen, M. Scharrer, N. J. Farrer, P. J. Sadler, P. St. J. Russell, "Quantitative broadband chemical sensing in air-suspended solid-core fibers" J. Applied. Phys., 2008, 103, 103108/1 – 103108/7.
23. N. J. Farrer, P. J. Sadler, "Photochemotherapy: Targeted Activation of Metal Anticancer Complexes" Aust. J. Chem., 2008, 61, 669 – 674.
24. N. J. Farrer, R. McDonald, J. S. McIndoe, "Proton Sponge Phosphines: Electrospray-active Ligands", Dalton Trans., 2006, 4570 – 4579. Highlighted in “Chemical Science”, 2006, 11.
- N. J. Farrer, P. J. Sadler, "Medicinal Inorganic Chemistry: State of the Art, New Trends and a Vision for the Future" Bioinorganic Medicinal Chemistry, Alessio (Ed.), Wiley, 2010, 1 – 47.
- N. J. Farrer, J. S. McIndoe, "Choice of Ionization for Analysis of Various Substances: Organometallics", Encyclopedia of Mass Spectrometry, Elsevier: Amsterdam. Eds. M. L. Gross and R. M. Caprioli, 2007, Vol.6 (Ionization Methods), 903 – 915.