A 30 kDa polyethylene glycol-enfuvirtide complex enhances the exposure of enfuvirtide in lymphatic viral reservoirs in rats

Lisa M. Kaminskas, Charlotte C. Williams, Nathania J. Leong, Linda J. Chan, Neville J. Butcher, Orlagh M. Feeney, Christopher J.H. Porter, David Tyssen, Gilda Tachedjian, David B. Ascher

Research output: Contribution to journalArticleResearchpeer-review

Abstract

HIV therapy with anti-retroviral drugs is limited by the poor exposure of viral reservoirs, such as lymphoid tissue, to these small molecule drugs. We therefore investigated the effect of PEGylation on the anti-retroviral activity and subcutaneous lymphatic pharmacokinetics of the peptide-based fusion inhibitor enfuvirtide in thoracic lymph duct cannulated rats. Both the peptide and the PEG were quantified in plasma and lymph via ELISA. Conjugation to a single 5 kDa linear PEG decreased anti-HIV activity three-fold compared to enfuvirtide. Whilst plasma and lymphatic exposure to peptide mass was moderately increased, the loss of anti-viral activity led to an overall decrease in exposure to enfuvirtide activity. A 20 kDa 4-arm branched PEG conjugated with an average of two enfuvirtide peptides decreased peptide activity by six-fold. Plasma and lymph exposure to enfuvirtide, however, increased significantly such that anti-viral activity was increased two- and six-fold respectively. The results suggest that a multi-enfuvirtide-PEG complex may optimally enhance the anti-retroviral activity of the peptide in plasma and lymph.

Original languageEnglish
Pages (from-to)218-226
Number of pages9
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume137
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • Anti-viral
  • Enfuvirtide
  • Lymphatic
  • PEGylation
  • Pharmacokinetics

Cite this

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title = "A 30 kDa polyethylene glycol-enfuvirtide complex enhances the exposure of enfuvirtide in lymphatic viral reservoirs in rats",
abstract = "HIV therapy with anti-retroviral drugs is limited by the poor exposure of viral reservoirs, such as lymphoid tissue, to these small molecule drugs. We therefore investigated the effect of PEGylation on the anti-retroviral activity and subcutaneous lymphatic pharmacokinetics of the peptide-based fusion inhibitor enfuvirtide in thoracic lymph duct cannulated rats. Both the peptide and the PEG were quantified in plasma and lymph via ELISA. Conjugation to a single 5 kDa linear PEG decreased anti-HIV activity three-fold compared to enfuvirtide. Whilst plasma and lymphatic exposure to peptide mass was moderately increased, the loss of anti-viral activity led to an overall decrease in exposure to enfuvirtide activity. A 20 kDa 4-arm branched PEG conjugated with an average of two enfuvirtide peptides decreased peptide activity by six-fold. Plasma and lymph exposure to enfuvirtide, however, increased significantly such that anti-viral activity was increased two- and six-fold respectively. The results suggest that a multi-enfuvirtide-PEG complex may optimally enhance the anti-retroviral activity of the peptide in plasma and lymph.",
keywords = "Anti-viral, Enfuvirtide, Lymphatic, PEGylation, Pharmacokinetics",
author = "Kaminskas, {Lisa M.} and Williams, {Charlotte C.} and Leong, {Nathania J.} and Chan, {Linda J.} and Butcher, {Neville J.} and Feeney, {Orlagh M.} and Porter, {Christopher J.H.} and David Tyssen and Gilda Tachedjian and Ascher, {David B.}",
year = "2019",
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language = "English",
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pages = "218--226",
journal = "European Journal of Pharmaceutics and Biopharmaceutics",
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A 30 kDa polyethylene glycol-enfuvirtide complex enhances the exposure of enfuvirtide in lymphatic viral reservoirs in rats. / Kaminskas, Lisa M.; Williams, Charlotte C.; Leong, Nathania J.; Chan, Linda J.; Butcher, Neville J.; Feeney, Orlagh M.; Porter, Christopher J.H.; Tyssen, David; Tachedjian, Gilda; Ascher, David B.

In: European Journal of Pharmaceutics and Biopharmaceutics, Vol. 137, 01.04.2019, p. 218-226.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A 30 kDa polyethylene glycol-enfuvirtide complex enhances the exposure of enfuvirtide in lymphatic viral reservoirs in rats

AU - Kaminskas, Lisa M.

AU - Williams, Charlotte C.

AU - Leong, Nathania J.

AU - Chan, Linda J.

AU - Butcher, Neville J.

AU - Feeney, Orlagh M.

AU - Porter, Christopher J.H.

AU - Tyssen, David

AU - Tachedjian, Gilda

AU - Ascher, David B.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - HIV therapy with anti-retroviral drugs is limited by the poor exposure of viral reservoirs, such as lymphoid tissue, to these small molecule drugs. We therefore investigated the effect of PEGylation on the anti-retroviral activity and subcutaneous lymphatic pharmacokinetics of the peptide-based fusion inhibitor enfuvirtide in thoracic lymph duct cannulated rats. Both the peptide and the PEG were quantified in plasma and lymph via ELISA. Conjugation to a single 5 kDa linear PEG decreased anti-HIV activity three-fold compared to enfuvirtide. Whilst plasma and lymphatic exposure to peptide mass was moderately increased, the loss of anti-viral activity led to an overall decrease in exposure to enfuvirtide activity. A 20 kDa 4-arm branched PEG conjugated with an average of two enfuvirtide peptides decreased peptide activity by six-fold. Plasma and lymph exposure to enfuvirtide, however, increased significantly such that anti-viral activity was increased two- and six-fold respectively. The results suggest that a multi-enfuvirtide-PEG complex may optimally enhance the anti-retroviral activity of the peptide in plasma and lymph.

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