Aggregation of PEGylated liposomes driven by hydrophobic forces

Tamás Bozó, T. Mészáros, J. Mihály, A. Bóta, M. Kellermayer, J. Szebeni, Benedek Kálmán

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Polyethylene glycol (PEG) is widely used to sterically stabilize liposomes and improve the pharmacokinetic profile of drugs, peptides and nanoparticles. Here we report that ammonium sulfate (AS) can evoke the aggregation of PEGylated vesicles in a concentration-dependent manner. Liposomes with 5 mol% PEG were colloidally stable at AS concentrations up to 0.7 mM, above which they precipitated and formed micron-size aggregates with irregular shape. While aggregation was reversible up to 0.9 M of AS, above 1 M fusion occurred, which irreversibly distorted the size distribution. Zeta potential of liposomes markedly increased from −71 ± 2.5 mV to 2 ± 0.5 mV upon raising the AS concentration from 0 to 0.1 M, but no considerable increase was seen during further AS addition, showing that the aggregation is independent of surface charge. There was no aggregation in the absence of the PEG chains, and increasing PEG molar% shifted the aggregation threshold to lower AS concentrations. Changes in the FTIR spectral features of PEGylated vesicles suggest that AS dehydrates PEG chains. Other kosmotropic salts also led to aggregation, while chaotropic salts did not, which indicates a general kosmotropic phenomenon. The driving force behind aggregation is likely to be the hydrophobic effect due to salting out the polymer similarly to what happens during protein purification or Hydrophobic Interaction Chromatography. Since liposome aggregation and fusion may result in difficulties during formulation and adverse reaction upon application, the phenomena detailed in this paper may have both technological and therapeutical consequences.

Original languageEnglish
Pages (from-to)467-474
Number of pages8
JournalColloids and Surfaces B: Biointerfaces
Volume147
DOIs
Publication statusPublished - Nov 1 2016

Fingerprint

ammonium sulfates
Liposomes
Ammonium Sulfate
Agglomeration
glycols
polyethylenes
Polyethylene glycols
Salts
fusion
Fusion reactions
salts
Fourier Transform Infrared Spectroscopy
chromatography
Pharmacokinetics
Hydrophobic and Hydrophilic Interactions
purification
Nanoparticles
Zeta potential
Surface charge
peptides

Keywords

  • Aggregation
  • Ammonium sulfate
  • Fusion
  • Hydrophobic effect
  • Kosmotropic salt
  • Liposome
  • PEG

ASJC Scopus subject areas

  • Biotechnology
  • Medicine(all)
  • Surfaces and Interfaces
  • Physical and Theoretical Chemistry
  • Colloid and Surface Chemistry

Cite this

Aggregation of PEGylated liposomes driven by hydrophobic forces. / Bozó, Tamás; Mészáros, T.; Mihály, J.; Bóta, A.; Kellermayer, M.; Szebeni, J.; Kálmán, Benedek.

In: Colloids and Surfaces B: Biointerfaces, Vol. 147, 01.11.2016, p. 467-474.

Research output: Contribution to journalArticle

@article{91a408531b5e4524a8c835fe43160410,
title = "Aggregation of PEGylated liposomes driven by hydrophobic forces",
abstract = "Polyethylene glycol (PEG) is widely used to sterically stabilize liposomes and improve the pharmacokinetic profile of drugs, peptides and nanoparticles. Here we report that ammonium sulfate (AS) can evoke the aggregation of PEGylated vesicles in a concentration-dependent manner. Liposomes with 5 mol{\%} PEG were colloidally stable at AS concentrations up to 0.7 mM, above which they precipitated and formed micron-size aggregates with irregular shape. While aggregation was reversible up to 0.9 M of AS, above 1 M fusion occurred, which irreversibly distorted the size distribution. Zeta potential of liposomes markedly increased from −71 ± 2.5 mV to 2 ± 0.5 mV upon raising the AS concentration from 0 to 0.1 M, but no considerable increase was seen during further AS addition, showing that the aggregation is independent of surface charge. There was no aggregation in the absence of the PEG chains, and increasing PEG molar{\%} shifted the aggregation threshold to lower AS concentrations. Changes in the FTIR spectral features of PEGylated vesicles suggest that AS dehydrates PEG chains. Other kosmotropic salts also led to aggregation, while chaotropic salts did not, which indicates a general kosmotropic phenomenon. The driving force behind aggregation is likely to be the hydrophobic effect due to salting out the polymer similarly to what happens during protein purification or Hydrophobic Interaction Chromatography. Since liposome aggregation and fusion may result in difficulties during formulation and adverse reaction upon application, the phenomena detailed in this paper may have both technological and therapeutical consequences.",
keywords = "Aggregation, Ammonium sulfate, Fusion, Hydrophobic effect, Kosmotropic salt, Liposome, PEG",
author = "Tam{\'a}s Boz{\'o} and T. M{\'e}sz{\'a}ros and J. Mih{\'a}ly and A. B{\'o}ta and M. Kellermayer and J. Szebeni and Benedek K{\'a}lm{\'a}n",
year = "2016",
month = "11",
day = "1",
doi = "10.1016/j.colsurfb.2016.06.056",
language = "English",
volume = "147",
pages = "467--474",
journal = "Colloids and Surfaces B: Biointerfaces",
issn = "0927-7765",
publisher = "Elsevier",

}

TY - JOUR

T1 - Aggregation of PEGylated liposomes driven by hydrophobic forces

AU - Bozó, Tamás

AU - Mészáros, T.

AU - Mihály, J.

AU - Bóta, A.

AU - Kellermayer, M.

AU - Szebeni, J.

AU - Kálmán, Benedek

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Polyethylene glycol (PEG) is widely used to sterically stabilize liposomes and improve the pharmacokinetic profile of drugs, peptides and nanoparticles. Here we report that ammonium sulfate (AS) can evoke the aggregation of PEGylated vesicles in a concentration-dependent manner. Liposomes with 5 mol% PEG were colloidally stable at AS concentrations up to 0.7 mM, above which they precipitated and formed micron-size aggregates with irregular shape. While aggregation was reversible up to 0.9 M of AS, above 1 M fusion occurred, which irreversibly distorted the size distribution. Zeta potential of liposomes markedly increased from −71 ± 2.5 mV to 2 ± 0.5 mV upon raising the AS concentration from 0 to 0.1 M, but no considerable increase was seen during further AS addition, showing that the aggregation is independent of surface charge. There was no aggregation in the absence of the PEG chains, and increasing PEG molar% shifted the aggregation threshold to lower AS concentrations. Changes in the FTIR spectral features of PEGylated vesicles suggest that AS dehydrates PEG chains. Other kosmotropic salts also led to aggregation, while chaotropic salts did not, which indicates a general kosmotropic phenomenon. The driving force behind aggregation is likely to be the hydrophobic effect due to salting out the polymer similarly to what happens during protein purification or Hydrophobic Interaction Chromatography. Since liposome aggregation and fusion may result in difficulties during formulation and adverse reaction upon application, the phenomena detailed in this paper may have both technological and therapeutical consequences.

AB - Polyethylene glycol (PEG) is widely used to sterically stabilize liposomes and improve the pharmacokinetic profile of drugs, peptides and nanoparticles. Here we report that ammonium sulfate (AS) can evoke the aggregation of PEGylated vesicles in a concentration-dependent manner. Liposomes with 5 mol% PEG were colloidally stable at AS concentrations up to 0.7 mM, above which they precipitated and formed micron-size aggregates with irregular shape. While aggregation was reversible up to 0.9 M of AS, above 1 M fusion occurred, which irreversibly distorted the size distribution. Zeta potential of liposomes markedly increased from −71 ± 2.5 mV to 2 ± 0.5 mV upon raising the AS concentration from 0 to 0.1 M, but no considerable increase was seen during further AS addition, showing that the aggregation is independent of surface charge. There was no aggregation in the absence of the PEG chains, and increasing PEG molar% shifted the aggregation threshold to lower AS concentrations. Changes in the FTIR spectral features of PEGylated vesicles suggest that AS dehydrates PEG chains. Other kosmotropic salts also led to aggregation, while chaotropic salts did not, which indicates a general kosmotropic phenomenon. The driving force behind aggregation is likely to be the hydrophobic effect due to salting out the polymer similarly to what happens during protein purification or Hydrophobic Interaction Chromatography. Since liposome aggregation and fusion may result in difficulties during formulation and adverse reaction upon application, the phenomena detailed in this paper may have both technological and therapeutical consequences.

KW - Aggregation

KW - Ammonium sulfate

KW - Fusion

KW - Hydrophobic effect

KW - Kosmotropic salt

KW - Liposome

KW - PEG

UR - http://www.scopus.com/inward/record.url?scp=84984626814&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84984626814&partnerID=8YFLogxK

U2 - 10.1016/j.colsurfb.2016.06.056

DO - 10.1016/j.colsurfb.2016.06.056

M3 - Article

C2 - 27588427

AN - SCOPUS:84984626814

VL - 147

SP - 467

EP - 474

JO - Colloids and Surfaces B: Biointerfaces

JF - Colloids and Surfaces B: Biointerfaces

SN - 0927-7765

ER -