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Stability enhancing N-Terminal PEGylation of oxytocin exploiting different polymer architectures and conjugation approaches
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Collins, Jennifer, Kempe, Kristian, Wilson, Paul, Blindauer, Claudia A., McIntosh, Michelle P., Davis, Thomas P., Whittaker, Michael R. and Haddleton, David M. (2016) Stability enhancing N-Terminal PEGylation of oxytocin exploiting different polymer architectures and conjugation approaches. Biomacromolecules, 17 (8). pp. 2755-2766. doi:10.1021/acs.biomac.6b00919 ISSN 1525-7797.
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Official URL: http://dx.doi.org/10.1021/acs.biomac.6b00919
Abstract
Oxytocin, a cyclic nine amino acid neurohypophyseal hormone therapeutic, is effectively used in the control of postpartum hemorrhaging (PPH) and is on the WHO List of Essential Medicines. However, oxytocin has limited shelf life stability in aqueous solutions, particularly at temperatures in excess of 25 °C and injectable aqueous oxytocin formulations require refrigeration (<8 °C). This is particularly problematic in the hot climates often found in many developing countries where daytime temperatures can exceed 40 °C and where reliable cold-chain storage is not always achievable. The purpose of this study was to develop N-terminal amine targeted PEGylation strategies utilizing both linear PEG and polyPEG “comb” polymers as an effective method for stabilizing solution formulations of this peptide for prolonged storage in the absence of efficient cold-chain storage. The conjugation chemistries investigated herein include irreversible amine targeted conjugation methods utilizing NHS ester and aldehyde reductive amination chemistry. Additionally, one reversible conjugation method using a Schiff base approach was explored to allow for the release of the native peptide, thus, ensuring that biological activity remains unaffected. The reversibility of this approach was investigated for the different polymer architectures, alongside a nonpolymer oxytocin analogue to monitor how pH can tune native peptide release. Elevated temperature degradation studies of the polymer conjugates were evaluated to assess the stability of the PEGylated analogues in comparison to the native peptide in aqueous formulations to mimic storage conditions in developing nations and regions where storage under appropriate conditions is challenging.
| Item Type: | Journal Article | ||||||||||||||||||||||||
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| Subjects: | Q Science > QP Physiology R Medicine > RG Gynecology and obstetrics |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Oxytocin -- Research, Uterine hemorrhage -- Prevention, Uterus -- Contraction, Mothers -- Mortality -- Developing countries, Women -- Health and hygiene -- Developing countries, World Health Organization | ||||||||||||||||||||||||
| Journal or Publication Title: | Biomacromolecules | ||||||||||||||||||||||||
| Publisher: | American Chemical Society | ||||||||||||||||||||||||
| ISSN: | 1525-7797 | ||||||||||||||||||||||||
| Official Date: | 2016 | ||||||||||||||||||||||||
| Dates: |
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| Volume: | 17 | ||||||||||||||||||||||||
| Number: | 8 | ||||||||||||||||||||||||
| Page Range: | pp. 2755-2766 | ||||||||||||||||||||||||
| DOI: | 10.1021/acs.biomac.6b00919 | ||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||
| Date of first compliant deposit: | 24 February 2017 | ||||||||||||||||||||||||
| Date of first compliant Open Access: | 27 February 2017 | ||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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