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

Marta Tena-Solsona; Domenico Marson; Ana Campo Rodrigo; Stephen Bromfield; Beatriu Escuder; Juan F. Miravet; Nadezda Apostolova; Erik Laurini; Sabrina Pricl; David Kelham Smith

doi:10.1039/c9bm00745h

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

Marta Tena-Solsona, Domenico Marson, Ana Campo Rodrigo, Stephen Bromfield, Beatriu Escuder, Juan F. Miravet, Nadezda Apostolova, Erik Laurini, Sabrina Pricl, David Kelham Smith

Chemistry

Research output: Contribution to journal › Article › peer-review

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 optimisation 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 hydrophobic 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 analogues. 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 nanostructures, toxicity towards human cells is decreased and biocompatibility enhanced, with markedly improved survival of human hepatoblastoma cells in an MTT assay.

Original language	English
Pages (from-to)	3812-3820
Number of pages	9
Journal	Biomaterials Science
Volume	7
Early online date	2 Jul 2019
DOIs	https://doi.org/10.1039/c9bm00745h
Publication status	Published - Aug 2019

Bibliographical note

© The Royal Society of Chemistry 2019. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

Access to Document

10.1039/c9bm00745h

Marta Biomaterials Science REVISED
© The Royal Society of Chemistry 2019. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.
Accepted author manuscript, 8.38 MB
Marta Biomaterials Supporting Information
© The Royal Society of Chemistry 2019. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.
Accepted author manuscript, 6.09 MB

Cite this

@article{893233f664914b0cbba9dde7bc24ac73,

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

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 optimisation 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 hydrophobic 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 analogues. 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 nanostructures, toxicity towards human cells is decreased and biocompatibility enhanced, with markedly improved survival of human hepatoblastoma cells in an MTT assay.",

author = "Marta Tena-Solsona and Domenico Marson and {Campo Rodrigo}, Ana and Stephen Bromfield and Beatriu Escuder and Miravet, {Juan F.} and Nadezda Apostolova and Erik Laurini and Sabrina Pricl and Smith, {David Kelham}",

note = "{\textcopyright} The Royal Society of Chemistry 2019. This is an author-produced version of the published paper. Uploaded in accordance with the publisher{\textquoteright}s self-archiving policy. Further copying may not be permitted; contact the publisher for details.",

year = "2019",

month = aug,

doi = "10.1039/c9bm00745h",

language = "English",

volume = "7",

pages = "3812--3820",

journal = "Biomaterials Science",

issn = "2047-4830",

publisher = "The Royal Society of Chemistry",

}

TY - JOUR

T1 - Self-assembled multivalent (SAMul) ligand systems with enhanced stability in the presence of human serum

AU - Tena-Solsona, Marta

AU - Marson, Domenico

AU - Campo Rodrigo, Ana

AU - Bromfield, Stephen

AU - Escuder, Beatriu

AU - Miravet, Juan F.

AU - Apostolova, Nadezda

AU - Laurini, Erik

AU - Pricl, Sabrina

AU - Smith, David Kelham

N1 - © The Royal Society of Chemistry 2019. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2019/8

Y1 - 2019/8

N2 - 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 optimisation 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 hydrophobic 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 analogues. 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 nanostructures, toxicity towards human cells is decreased and biocompatibility enhanced, with markedly improved survival of human hepatoblastoma cells in an MTT assay.

AB - 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 optimisation 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 hydrophobic 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 analogues. 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 nanostructures, toxicity towards human cells is decreased and biocompatibility enhanced, with markedly improved survival of human hepatoblastoma cells in an MTT assay.

U2 - 10.1039/c9bm00745h

DO - 10.1039/c9bm00745h

M3 - Article

SN - 2047-4830

VL - 7

SP - 3812

EP - 3820

JO - Biomaterials Science

JF - Biomaterials Science

ER -