Development of PLGA-Encapsulated Disulfiram as an orphan drug for MALIGNANT mesothelioma


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Sathishkumar Kurusamy1,Vinodh Kannappan2,Andrew Pollard3,Garima Tyagi1,Sathishkumar Kurusamy4,Peng Liu5,Yaohe Wang5,Christopher Ireson6,Weiguang Wang7
1University of Wolverhampton,2Disulfican Ltd.,University of Wolverhampton,3Disulfican Ltd., Wolverhampton,4University of wolverhampton,5Barts Cancer Institute,6Pharmidex Ltd, UK,7Disulfican Ltd, University of Wolverhampton

Abstract

Background

Despite the current multimodal treatment including Pemetrexed/Cisplatin chemotherapy the prognosis of Malignant Mesothelioma (MM) barely changed in the past 4 decades. MM patients develop resistance to chemotherapy, driven by a subpopulation of cancer stem cells (CSCs). There is a pressing need for new drugs that targets CSCs, but anticancer drug development is a time consuming (15 years) and expensive (£1.2 billion) procedure, leading to high costs of the anticancer drugs. Therefore, drug repurposing has become an attractive strategy for drug development in recent years.

We have demonstrated that Disulfiram (DS), a clinically used anti-alcoholism drug, targets a wide range of cancers, including MM. DS specifically eradicates CSCs with low/no toxicity to normal cells. However, the use of DS as an anticancer drug is limited by its rapid degradation in the blood stream (~ 4 min) and extensive metabolic conversion in the liver. We have shown that the half-life of DS in bloodstream can be substantially improved by encapsulating DS into PLGA (poly-lactic-co-glycolic acid) polymeric particles. Supported by Innovate UK, our newly established spin-out company Disulfican Ltd., developed cGMP quality PLGA-Disulfiram microparticles for human administration and aimed to achieve orphan drug designation for the quick translation of PLGA-DS for MM treatment.

Method

Results

The GMP-PLGA-DS-Microparticles had a size range of 600nm-1,200nm with 7.75% drug loading. The GMP-PLGA-DS microparticles effectively destroyed MM cells in vitro at nanomolar concentrations (300-600nm), reversed chemoresistance, eradicated CSC population in culture and blocked migration and invasion. PLGA-DS presented strong synergistic activity with pemetrexed and cisplatin, indicating the potential for effective combination treatment in clinics. PLGA-DS significantly extended the survival rate of MM xenograft models showing curative effect on MM with low/no toxicity to vital organs.

Conclusion

Achieving orphan designation with our pre-clinical data package will speed up the approval process for phase 1 MM clinical trials.