Complement activation by PEGylated liposomes containing prednisolone

Jolanda M. Van Den Hoven, Reka Nemes, Josbert M. Metselaar, Bastiaan Nuijen, Jos H. Beijnen, Gert Storm, J. Szebeni

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Infusion of PEGylated liposomes can give rise to hypersensitivity reactions (HSRs) in a relatively large number of patients. Previously it has been shown that these reactions can be caused by activation of the complement (C) system by a negative charge on the anchor molecule of PEG at the liposomal surface. In this study it is tested whether the activation of the C system by PEG-liposomes could be significantly reduced to values comparable to nonreactive liposomal formulations, by changing the PEGylation-profile on the liposomal surface. Therefore, the formation of C activation markers SC5b-9, C3a, C4d and Bb in normal human serum by both prednisolone loaded and empty liposomes with a variation of PEG chain length, PEG surface concentration, PEG anchor molecule and liposomal size was determined using in vitro assays. The tested liposomes caused no or only mild (30%) activation of C except for one formulation wherein the PEG2000 was anchored to cholesterol (CHOL-PEG2000). The latter liposomes caused paralleling rises in SC5b-9 and Bb levels, suggesting excess activation of the alternative pathway. While the relative safety of weak C activator liposomes remains to be confirmed in vivo, the unique, non-charge and non-antibody-mediated direct conversion of C3 by CHOL-PEG2000 liposomes (although argues against the clinical development of these vesicles) opens new opportunities to understand liposomal C activation at the molecular level.

Original languageEnglish
Pages (from-to)265-271
Number of pages7
JournalEuropean Journal of Pharmaceutical Sciences
Volume49
Issue number2
DOIs
Publication statusPublished - May 13 2013

Fingerprint

Complement Activation
Prednisolone
Liposomes
Hypersensitivity
Cholesterol
Safety
Serum

Keywords

  • Complement activation
  • Hypersensitivity reactions
  • Infusion reactions
  • PEGylated liposomes

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Van Den Hoven, J. M., Nemes, R., Metselaar, J. M., Nuijen, B., Beijnen, J. H., Storm, G., & Szebeni, J. (2013). Complement activation by PEGylated liposomes containing prednisolone. European Journal of Pharmaceutical Sciences, 49(2), 265-271. https://doi.org/10.1016/j.ejps.2013.03.007

Complement activation by PEGylated liposomes containing prednisolone. / Van Den Hoven, Jolanda M.; Nemes, Reka; Metselaar, Josbert M.; Nuijen, Bastiaan; Beijnen, Jos H.; Storm, Gert; Szebeni, J.

In: European Journal of Pharmaceutical Sciences, Vol. 49, No. 2, 13.05.2013, p. 265-271.

Research output: Contribution to journalArticle

Van Den Hoven, JM, Nemes, R, Metselaar, JM, Nuijen, B, Beijnen, JH, Storm, G & Szebeni, J 2013, 'Complement activation by PEGylated liposomes containing prednisolone', European Journal of Pharmaceutical Sciences, vol. 49, no. 2, pp. 265-271. https://doi.org/10.1016/j.ejps.2013.03.007
Van Den Hoven JM, Nemes R, Metselaar JM, Nuijen B, Beijnen JH, Storm G et al. Complement activation by PEGylated liposomes containing prednisolone. European Journal of Pharmaceutical Sciences. 2013 May 13;49(2):265-271. https://doi.org/10.1016/j.ejps.2013.03.007
Van Den Hoven, Jolanda M. ; Nemes, Reka ; Metselaar, Josbert M. ; Nuijen, Bastiaan ; Beijnen, Jos H. ; Storm, Gert ; Szebeni, J. / Complement activation by PEGylated liposomes containing prednisolone. In: European Journal of Pharmaceutical Sciences. 2013 ; Vol. 49, No. 2. pp. 265-271.
@article{c34a1292db2c4c3082b104db9cc16302,
title = "Complement activation by PEGylated liposomes containing prednisolone",
abstract = "Infusion of PEGylated liposomes can give rise to hypersensitivity reactions (HSRs) in a relatively large number of patients. Previously it has been shown that these reactions can be caused by activation of the complement (C) system by a negative charge on the anchor molecule of PEG at the liposomal surface. In this study it is tested whether the activation of the C system by PEG-liposomes could be significantly reduced to values comparable to nonreactive liposomal formulations, by changing the PEGylation-profile on the liposomal surface. Therefore, the formation of C activation markers SC5b-9, C3a, C4d and Bb in normal human serum by both prednisolone loaded and empty liposomes with a variation of PEG chain length, PEG surface concentration, PEG anchor molecule and liposomal size was determined using in vitro assays. The tested liposomes caused no or only mild (30{\%}) activation of C except for one formulation wherein the PEG2000 was anchored to cholesterol (CHOL-PEG2000). The latter liposomes caused paralleling rises in SC5b-9 and Bb levels, suggesting excess activation of the alternative pathway. While the relative safety of weak C activator liposomes remains to be confirmed in vivo, the unique, non-charge and non-antibody-mediated direct conversion of C3 by CHOL-PEG2000 liposomes (although argues against the clinical development of these vesicles) opens new opportunities to understand liposomal C activation at the molecular level.",
keywords = "Complement activation, Hypersensitivity reactions, Infusion reactions, PEGylated liposomes",
author = "{Van Den Hoven}, {Jolanda M.} and Reka Nemes and Metselaar, {Josbert M.} and Bastiaan Nuijen and Beijnen, {Jos H.} and Gert Storm and J. Szebeni",
year = "2013",
month = "5",
day = "13",
doi = "10.1016/j.ejps.2013.03.007",
language = "English",
volume = "49",
pages = "265--271",
journal = "European Journal of Pharmaceutical Sciences",
issn = "0928-0987",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - Complement activation by PEGylated liposomes containing prednisolone

AU - Van Den Hoven, Jolanda M.

AU - Nemes, Reka

AU - Metselaar, Josbert M.

AU - Nuijen, Bastiaan

AU - Beijnen, Jos H.

AU - Storm, Gert

AU - Szebeni, J.

PY - 2013/5/13

Y1 - 2013/5/13

N2 - Infusion of PEGylated liposomes can give rise to hypersensitivity reactions (HSRs) in a relatively large number of patients. Previously it has been shown that these reactions can be caused by activation of the complement (C) system by a negative charge on the anchor molecule of PEG at the liposomal surface. In this study it is tested whether the activation of the C system by PEG-liposomes could be significantly reduced to values comparable to nonreactive liposomal formulations, by changing the PEGylation-profile on the liposomal surface. Therefore, the formation of C activation markers SC5b-9, C3a, C4d and Bb in normal human serum by both prednisolone loaded and empty liposomes with a variation of PEG chain length, PEG surface concentration, PEG anchor molecule and liposomal size was determined using in vitro assays. The tested liposomes caused no or only mild (30%) activation of C except for one formulation wherein the PEG2000 was anchored to cholesterol (CHOL-PEG2000). The latter liposomes caused paralleling rises in SC5b-9 and Bb levels, suggesting excess activation of the alternative pathway. While the relative safety of weak C activator liposomes remains to be confirmed in vivo, the unique, non-charge and non-antibody-mediated direct conversion of C3 by CHOL-PEG2000 liposomes (although argues against the clinical development of these vesicles) opens new opportunities to understand liposomal C activation at the molecular level.

AB - Infusion of PEGylated liposomes can give rise to hypersensitivity reactions (HSRs) in a relatively large number of patients. Previously it has been shown that these reactions can be caused by activation of the complement (C) system by a negative charge on the anchor molecule of PEG at the liposomal surface. In this study it is tested whether the activation of the C system by PEG-liposomes could be significantly reduced to values comparable to nonreactive liposomal formulations, by changing the PEGylation-profile on the liposomal surface. Therefore, the formation of C activation markers SC5b-9, C3a, C4d and Bb in normal human serum by both prednisolone loaded and empty liposomes with a variation of PEG chain length, PEG surface concentration, PEG anchor molecule and liposomal size was determined using in vitro assays. The tested liposomes caused no or only mild (30%) activation of C except for one formulation wherein the PEG2000 was anchored to cholesterol (CHOL-PEG2000). The latter liposomes caused paralleling rises in SC5b-9 and Bb levels, suggesting excess activation of the alternative pathway. While the relative safety of weak C activator liposomes remains to be confirmed in vivo, the unique, non-charge and non-antibody-mediated direct conversion of C3 by CHOL-PEG2000 liposomes (although argues against the clinical development of these vesicles) opens new opportunities to understand liposomal C activation at the molecular level.

KW - Complement activation

KW - Hypersensitivity reactions

KW - Infusion reactions

KW - PEGylated liposomes

UR - http://www.scopus.com/inward/record.url?scp=84876171479&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876171479&partnerID=8YFLogxK

U2 - 10.1016/j.ejps.2013.03.007

DO - 10.1016/j.ejps.2013.03.007

M3 - Article

C2 - 23528740

AN - SCOPUS:84876171479

VL - 49

SP - 265

EP - 271

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

SN - 0928-0987

IS - 2

ER -