Development of PLGA-Encapsulated Disulfiram as an orphan drug for MALIGNANT mesothelioma
Session type: Poster / e-Poster / Silent Theatre session
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.
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.
Achieving orphan designation with our pre-clinical data package will speed up the approval process for phase 1 MM clinical trials.