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Transcript
TRANSLATION OF AN ANTI-ALCOHOLISM DRUG INTO A NON-PROFIT ANTICANCER DRUG USING NANOTECHNOLOGY Vinodh Kannappan*, Zhipeng Wang*, John Darling and Weiguang Wang Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY Pressing need for new anticancer drugs Nanotechnology improves the efficacy of Disulfiram We recently developed and characterized novel formulations of DS such as • There are 2.5 million people living with Cancer in the UK. Liposomal DS (Lipo-DS), Poly (lactic-co-glycolic acid)-DS, DS-Gold nanoparticles and • The average price of anticancer drugs increased 15-fold over the last 10 years. polymeric micelle-DS (DS-NPs). Encapsulation into nanoparticles Free Disulfiram £5 billion Cost of Cancer to NHS UK £18 £1.2 billion billion million Cost of Cancer to UK Economy NHS spend on anticancer drugs NHSCancer drugs fund (CDF) Cost of Drug per patient per year £340 Sorafenib£39,000 Imatinib £21,000 Nilotinib £21,000 Dasatinib£31,000 Bosutinib£76,000 Synribo £100,000 Ponatinib £90,000 Lapatinib £24000 PLGA-Nanoparticles 50-100 nm Nano-lipid 40-200 nm Polymeric Micelles Gold Nanoparticles 20 nm 20 nm 100 90 80 70 60 50 40 30 20 10 0 Extended time in circulation (4 hours). Free DS Lipo-DS DS-NPs 0 10sec 30sec 2min 4min 10min 20min 30min 1h 2h 4h 8h 24h • Most anticancer drugs have severe side effects. Moreover, they often do not cure cancer. % DS detected in serum • The NHS spends around £1.2 billion every year on anticancer drugs. Versatile routes of administration. Controlled drug release. Cancer Stem Cells - Prime Targets in Cancer Prevents non-specific tissue damage. Good bio-distribution, reduced dose. • Cancers contain a small population of cancer stem cells (CSCs) that are highly resistant to anticancer drugs. CSCs result in tumour metastasis, recurrence and poor prognosis. Kills bulk tumour cells but CSCs Survives Primary Tumour Tumour recurrence Chemotherapy Hypoxic core induced Cancer Stem cells Primary Tumour with a CSC core Metastasis to other organs More migration ability Escape from Primary Tumour Site Drug repositioning and Disulfiram • Development of a new drug takes an average of 15 years and costs £1.15 billion. • Repurposing FDA approved drugs for new uses is an established shortcut between the lab DS-Nano particles eradicates cancer stem cells and stop their migration and invasion capacity in cell culture conditions. and clinics - An attractive strategy for anticancer drug development. Tumour cells injected in mice Drug development process - 10-17 years - Less than 10 % Success rate • Disulfiram (DS) is an anti-alcoholism drug that has been used for over 60 years. • DS forms a complex with Copper (Cu) that kills cancer cells through generation of reactive oxygen species. Disulfiram selectively kills cancer cells using copper Non-Specific Killing and Anticancer drug resistance Normal cell Cancer Stem Cancer cell cells Normal cell Cancer cell High ALDH Protein Cancer Stem cells Disulfiram specifically inhibit ALDH Disulfiram blocks drug efflux pump Drug efflux protein Low Copper Treatment with Disulfiram + Copper ALDH protein Detoxify drugs DS-Nano particles can suppress tumour growth in animal models and prevents cancer spreading to other organs. DS-Cu Complex Drug pumped out by efflux Cell survives Days after Treatment High Copper High Copper Anticancer drugs Non specific Cell death killing Tumour Volume (mm3) Drug repositioning - 3-12 years Generates Toxic Reactive Oxygen Species that kills cells Cell survives Cell death Cell death Compared with normal tissues, cancer tissues often possess higher levels of intracellular Cu which enables DS to selectively target cancer cells. A very low dose of nano- DS along with oral Copper supplement showed a remarkable tumour inhibiting effect in xenograft models of breast cancer, brain tumour, lung cancer and liver cancer, without any adverse side effects or toxicity to normal tissues. Conclusions Problems for using Disulfiram in cancer treatment • The potential clinical application of DS in cancer treatment is hampered by its very short • DS is an FDA approved drug which is available for less than a £1 for a 500mg tablet. • Nano-encapsulated DS in combination with Cu eradicates multiple cancers by half-life in the bloodstream (less than 2 min). • New formulations of DS with longer half-life in the bloodstream are required to establish targeting CSCs. • Nano-encapsulated DS may be translated quickly into clinical use. the true efficacy of DS in cancer. • Nano-drug-delivery is a cutting edge technology that enables us to protect and deliver • Development of DS based anticancer therapeutics will provide millions of patients with affordable anticancer drug. vulnerable drugs in the bloodstream. ACKNOWLEDGEMENTS: We would thank British Lung Foundation (RG14-8) and EU FP7 (PIIF-GA-2013-629478 NANODISCAN) for supporting this project. We also thank Dr. Mark Morris, University of Wolverhampton, for reviewing and providing valuable suggestions for this poster. * These authors have equally contributed to this work.