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A novel class of bioreponsive nanomedicines for localised reinstatement of bioactivity and specific targeting [Abstract]

Azzopardi, Ernest A. ORCID:, Ferguson, Elaine Lesley ORCID: and Thomas, David William ORCID: 2014. A novel class of bioreponsive nanomedicines for localised reinstatement of bioactivity and specific targeting [Abstract]. The Lancet 383 , S9. 10.1016/S0140-6736(14)60272-5

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Background Gram-negative infection is a global health concern. We present a custom-engineered, novel, patented, dextrin-colistin conjugate that can mask the toxicity of colistin; this conjugate allows controlled, enzymatically mediated dextrin degradation (unmasking) and reinstatement of colistin activity at the infected site. In the presence of amylase, the lead candidate EA-4 (1·0 mol% succinoylation, 11·2 % w/w colistin, molecular weight ∼10 300 g/mol) maximally unmasked and was equally effective to the clinical colistin formulation against strains of multidrug resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae (minimum inhibitory concentration ≤4 g/L), but suppression of bacterial viability was six times longer. Here we report ex-vivo and in-vivo activity, pharmacokinetics and pharmacodynamics, and toxicity. Methods We used a newly validated two-compartment static dialysis bag model under infinite sink conditions to unmask EA-4 directly in six samples of infected burn wound fluid. We assessed wound versus plasma amylase partitioning with a Phadebas amylase test. We established pharmacokinetics (with high-performance liquid chromatography and ELISA) and toxicity (clinical variables) in an intravenous, escalating-dose Sprague Dawley rat model (35 rats). Findings Significant partitioning of amylase to the infected burn fluid occurred, despite normal plasma amylase (∼6·8:1, p<0·05), and controlled EA-4 unmasking was observed (48 h peak 68%, p<0·05). EA-4 showed no in-vivo toxicity even at maximum protocol dose (0·5 mg/L). However, severe clinical toxicity limited colistin dosing to 0·1 mg/L. Substantial improvement in pharmacokinetic variables compared with colistin were recorded—namely, plasma half-life (1·6 vs 0·9 h), clearance (2·8 vs 13·4 mL/min per kg), and last measurable concentration (>24 vs 4 h). Interpretation These findings support proof of principle for the first bioresponsive macromolecular antibiotic class, which is equally potent to the current clinical alternative, but presents substantially improved toxicity and pharmacokinetic characteristics. Moreover, the ability for localised targeted, enzyme-mediated reinstatement of activity has implications for future design of controlled drug release polymer therapeutic systems. Imminent scale-up studies and testing in man are the next steps.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RM Therapeutics. Pharmacology
Additional Information: Spring Meeting for Clinician Scientists in Training February 2014
Publisher: Elsevier
ISSN: 0140-6736
Funders: European Union (European Social Fund), STEPS scheme (Government of Malta, EU), Welsh Government
Last Modified: 12 Dec 2022 09:00

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