Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug.

Autor: Sanderson L; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London, United Kingdom., da Silva M; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London, United Kingdom., Sekhar GN; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London, United Kingdom., Brown RC; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London, United Kingdom., Burrell-Saward H; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Fidanboylu M; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London, United Kingdom., Liu B; King's College London, Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, London, United Kingdom., Dailey LA; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London, United Kingdom., Dreiss CA; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London, United Kingdom., Lorenz C; King's College London, Theory & Simulation of Condensed Matter Group, Department of Physics, Strand, London, United Kingdom., Christie M; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London, United Kingdom., Persaud SJ; King's College London, Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, London, United Kingdom., Yardley V; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Croft SL; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Valero M; Physical Chemistry Department, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain., Thomas SA; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2021 Apr 15; Vol. 15 (4), pp. e0009276. Date of Electronic Publication: 2021 Apr 15 (Print Publication: 2021).
DOI: 10.1371/journal.pntd.0009276
Abstrakt: Background: Human African trypanosomiasis (HAT or sleeping sickness) is caused by the parasite Trypanosoma brucei sspp. The disease has two stages, a haemolymphatic stage after the bite of an infected tsetse fly, followed by a central nervous system stage where the parasite penetrates the brain, causing death if untreated. Treatment is stage-specific, due to the blood-brain barrier, with less toxic drugs such as pentamidine used to treat stage 1. The objective of our research programme was to develop an intravenous formulation of pentamidine which increases CNS exposure by some 10-100 fold, leading to efficacy against a model of stage 2 HAT. This target candidate profile is in line with drugs for neglected diseases inititative recommendations.
Methodology: To do this, we evaluated the physicochemical and structural characteristics of formulations of pentamidine with Pluronic micelles (triblock-copolymers of polyethylene-oxide and polypropylene oxide), selected candidates for efficacy and toxicity evaluation in vitro, quantified pentamidine CNS delivery of a sub-set of formulations in vitro and in vivo, and progressed one pentamidine-Pluronic formulation for further evaluation using an in vivo single dose brain penetration study.
Principal Findings: Screening pentamidine against 40 CNS targets did not reveal any major neurotoxicity concerns, however, pentamidine had a high affinity for the imidazoline2 receptor. The reduction in insulin secretion in MIN6 β-cells by pentamidine may be secondary to pentamidine-mediated activation of β-cell imidazoline receptors and impairment of cell viability. Pluronic F68 (0.01%w/v)-pentamidine formulation had a similar inhibitory effect on insulin secretion as pentamidine alone and an additive trypanocidal effect in vitro. However, all Pluronics tested (P85, P105 and F68) did not significantly enhance brain exposure of pentamidine.
Significance: These results are relevant to further developing block-copolymers as nanocarriers, improving BBB drug penetration and understanding the side effects of pentamidine.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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