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.
2019
Pubblicato
https://pubs.rsc.org/en/content/articlelanding/2019/BM/C9BM00745H
File in questo prodotto:
File Dimensione Formato  
Biomaterials Science_preref.pdf

Open Access dal 03/07/2020

Tipologia: Bozza finale post-referaggio (post-print)
Licenza: Copyright Editore
Dimensione 1.67 MB
Formato Adobe PDF
1.67 MB Adobe PDF Visualizza/Apri
c9bm00745h1.pdf

Accesso chiuso

Descrizione: Electronic Supplementary Material (ESI) for Biomaterials Science
Tipologia: Altro materiale allegato
Licenza: Copyright Editore
Dimensione 1.25 MB
Formato Adobe PDF
1.25 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
tena-solsona2019(1).pdf

Accesso chiuso

Tipologia: Documento in Versione Editoriale
Licenza: Copyright Editore
Dimensione 1.9 MB
Formato Adobe PDF
1.9 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2953816
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 5
social impact