Download translation of an antialcoholism medicine into an

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.