Self-assembled cationic micelles are an attractive platform for binding biologically-relevant polyanions such as heparin. This has potential applications in coagulation control, where a synthetic heparin rescue agent could be a useful replacement for protamine, which is in current clinical use. However, micelles can have low stability in human serum and unacceptable toxicity profiles. This paper reports the optimi- sation of self-assembled multivalent (SAMul) arrays of amphiphilic ligands to bind heparin in competitive conditions. Specifically, modification of the hydrophobic unit kinetically stabilises the self-assembled nanostructures, preventing loss of binding ability in the presence of human serum – cholesterol hydro- phobic units significantly outperform systems with a simple aliphatic chain. It is demonstrated that serum albumin disrupts the binding thermodynamics of the latter system. Molecular simulation shows aliphatic lipids can more easily be removed from the self-assembled nanostructures than the cholesterol ana- logues. This agrees with the experimental observation that the cholesterol-based systems undergo slower disassembly and subsequent degradation via ester hydrolysis. Furthermore, by stabilising the SAMul nano- structures, toxicity towards human cells is decreased and biocompatibility enhanced, with markedly improved survival of human hepatoblastoma cells in an MTT assay.

Self-assembled multivalent (SAMul) ligand systems with enhanced stability in the presence of human serum

Marson D.;Laurini E.;Pricl S.
;
2019-01-01

Abstract

Self-assembled cationic micelles are an attractive platform for binding biologically-relevant polyanions such as heparin. This has potential applications in coagulation control, where a synthetic heparin rescue agent could be a useful replacement for protamine, which is in current clinical use. However, micelles can have low stability in human serum and unacceptable toxicity profiles. This paper reports the optimi- sation of self-assembled multivalent (SAMul) arrays of amphiphilic ligands to bind heparin in competitive conditions. Specifically, modification of the hydrophobic unit kinetically stabilises the self-assembled nanostructures, preventing loss of binding ability in the presence of human serum – cholesterol hydro- phobic units significantly outperform systems with a simple aliphatic chain. It is demonstrated that serum albumin disrupts the binding thermodynamics of the latter system. Molecular simulation shows aliphatic lipids can more easily be removed from the self-assembled nanostructures than the cholesterol ana- logues. This agrees with the experimental observation that the cholesterol-based systems undergo slower disassembly and subsequent degradation via ester hydrolysis. Furthermore, by stabilising the SAMul nano- structures, toxicity towards human cells is decreased and biocompatibility enhanced, with markedly improved survival of human hepatoblastoma cells in an MTT assay.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2953816
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