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

Lisa Sanderson; Marcelo da Silva ORCID logo; Gayathri N Sekhar; Rachel C Brown ORCID logo; Hollie Burrell-Saward; Mehmet Fidanboylu ORCID logo; Bo Liu ORCID logo; Lea Ann Dailey ORCID logo; Cécile A Dreiss ORCID logo; Chris Lorenz ORCID logo; +6 more... Mark Christie; Shanta J Persaud ORCID logo; Vanessa Yardley; Simon L Croft ORCID logo; Margarita Valero ORCID logo; Sarah A Thomas ORCID logo; (2021) Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug. PLoS neglected tropical diseases, 15 (4). e0009276-. ISSN 1935-2727 DOI: 10.1371/journal.pntd.0009276
Copy

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.


picture_as_pdf
Drug reformulation for a neglected disease.pdf
subject
Published Version
Available under Creative Commons: 3.0

View Download

Atom BibTeX OpenURL ContextObject in Span Multiline CSV OpenURL ContextObject Dublin Core Dublin Core MPEG-21 DIDL EndNote HTML Citation JSON MARC (ASCII) MARC (ISO 2709) METS MODS RDF+N3 RDF+N-Triples RDF+XML RIOXX2 XML Reference Manager Refer Simple Metadata ASCII Citation EP3 XML
Export

Downloads