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Anthoula Arta, Fredrik Melander, Thomas Lars Andresen, Andrew Urquhart; Development of dual corticosteroid loaded functionalized liposomes for enhanced drug delivery to the retinal endothelium. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5686.
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© ARVO (1962-2015); The Authors (2016-present)
Nanomedicines have been shown to hold promise for the treatment of posterior segment eye diseases. The goal of this work is to develop a novel, dual corticosteroid loaded, functionalized liposome that shows, based on in-vitro studies, enhanced uptake by Human Retinal Endothelial Cells (HRECs) and enhanced anti-inflammatory efficacy, when HRECs are under high glucose conditions, compared to non-targeting formulations.
We developed a liposome formulation loaded with corticosteroids both in the core, Prednisolone Hemisuccinate (PreH), and on the membrane, Prednisolone Palmitate (PreP). For enhancing the targeting of the HRECs, endothelial cell protein C receptor (EPCR) specific antibodies were functionalized on the surface of the carriers. Prednisolone Hemisuccinate was remote loaded, while 5% molar concentration of PreP was premixed with the lipids, and the encapsulated drugs were quantified by reverse phase HPLC. The in vitro uptake of the EPCR-targeting nanocarrier from HRECs was assessed by flow cytometry and confocal laser scanning microscopy (CLSM), in comparison to non-targeting liposomal formulations. The therapeutic potential of our novel liposomal system was determined by assessing their ability to inhibit the secretion of inflammatory mediators, IL-8 and IL-6, by HRECs that have been cultured under high glucose conditions (25mM) for 72 hours.
The EPCR targeting liposomal nanocarrier that we developed displayed at least 4-fold higher uptake compared to the non-targeting ones. This enhanced uptake was also translated into superior biological activity as the EPCR targeting, dual loaded liposomes, significantly reduced the secretion of IL-6 by 40% and IL-8 by 50% (p < 0.0001), compared to untreated cells (control), at levels similar to the non-stimulated/healthy cells which were cultured in normal glucose conditions. Additionally, they exhibited superior anti-inflammatory activity compared to the single loaded liposomes (PreH) (p < 0.001) and the free PreH (p < 0.01).
Targeting EPCR leads to higher levels of nanoparticle uptake by HRECs and enhanced efficacy. Moreover, even low concentrations of membrane loaded corticosteroids can significantly enhance the therapeutic efficacy of the liposomes.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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