Award details

Intravenous lipid emulsions: engineering and biological characterisation of new generation emulsions

Reference	BB/I016643/1
Principal Investigator / Supervisor	Professor Snjezana Stolnik-Trenkic
Co-Investigators / Co-Supervisors	Dr Mathew Cherian, Professor Amir Ghaemmaghami, Dr Christopher Homan, Dr Jean-Luc Trouilly, Professor Bettina Wolf
Institution	University of Nottingham
Department	Sch of Pharmacy
Funding type	Skills
Value (£)	91,932
Status	Completed
Type	Training Grants
Start date	01/10/2011
End date	30/09/2015
Duration	48 months

Abstract

unavailable

Summary

Aim: This project aims to provide fundamental understanding to underpin the design and early development of new generation lipid emulsions for intravenous application in clinic, which are based on components of interest to the industrial sponsor. It will provide new and fundamental understanding of emulsion formulations from new components and connect this with the biological properties of the formulations relevant for clinical application. Background: Intravenous emulsions are oil-in-water emulsions of triglycerides and are clinically applied as vehicles for administration of drugs or as the parenteral nutrition in patients, and particularly, premature neonates. In the last decade, and based on increased understanding of lipid emulsion metabolism, the typical compositions of intravenous emulsions have been changed to reduce adverse effects (eg 20% vs 10% composition as the latter has higher level of free lipids causing oversaturation of the lipoprotein lipase). The current notion in the field is to replace typically used triglycerides and to explore new components to reduce adverse effects (eg reduce inflammatory eicosanoids or avoid linoleic acid overload) and/or to provide a positive therapeutic effect (eg omega-3 acids effects on retinal and cognitive development of foetus and infants). However, a number of recent publications use classical formulation protocols with an ad hoc addition of new components, without evidence of study at the fundamental level what effects these new additions have on the emulsion formulation and properties. Moreover, studies on the effect of these new additions on the lipolysis, cellular uptake and pathways, and immunology will be required to assess the potential clinical usefulness of the new formulations. The aim of the proposed project will be achieved in three phases. Phase 1. Formulation and physicochemical characterisation: Experimental design and laboratory analyses will be applied to assess the effect that mixing of several different lipids (including compounds of interest to Baxter) has on (i) interfacial behaviour, (ii) lipid phase viscosity and its impact on the efficiency of the comminution process, (iii) charge and size distribution of the emulsion droplets (iv) emulsion stability, viscosity and emulsion 'break-down'. The physicochemical characterisation will include: particle size, zeta potential, morphology, rheology, interfacial tension and interfacial rheology. Phase 2. In vitro biological characterisation: A number of factors, including lipids composition, have been identified to impact the clearance and metabolism of lipid emulsions. Phase 2 hence focuses on in vitro studies of lipolysis and cellular metabolism of lipid emulsions from 'Phase 1'. The level of free lipids will be measured. Cellular association and internalization will be studied following incorporation of 3H-cholesteryl oleoyl ether, and/or a fluorescent probe. Labelled emulsions will be applied to the cells in culture (J774 macrophage, HUVEC endothelial and primary hepatocytes) under different conditions (eg exogenous apoE). Cell deposition and utilization of lipids will be assessed. Phase 3. Analyses of potential immuno-modulatory effects: The potential adverse immune-modulatory properties of new intravenous emulsions present a safety concern, particularly as these are often used in immune-compromised patients. Immune-modulatory effects for emulsions from 'Phase 1' will be assessed through their impact on monocytes, T cells, dendritic cells (DC) and neutrophils, as follows. Peripheral blood monocytes will be stimulated with emulsion samples and intracellular cytokine staining and multi-colour FACS analysis will be used to measure the level of cytokine production. DCs functional properties (endocytosis and T cell activation) after treatment with emulsion samples will be assessed. The impact of emulsions on neutrophils' respiratory burst, phagocytic ability and cytokine profile will be studied.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Training Grant - Industrial Case

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