Coulter, S. M. et al. (2023) Enzyme‐triggered L‐α/D‐peptide hydrogels as a long‐acting injectable platform for systemic delivery of HIV/AIDS drugs. Advanced Healthcare Materials, 12(18), 2203198. (doi: 10.1002/adhm.202203198) (PMID:36880399)
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Abstract
Eradicating HIV/AIDS by 2030 is a central goal of the World Health Organization. Patient adherence to complicated dosage regimens remains a key barrier. There is a need for convenient long-acting formulations that deliver drugs over sustained periods. This paper presents an alternative platform, an injectable in situ forming hydrogel implant to deliver a model antiretroviral drug (zidovudine [AZT]) over 28 days. The formulation is a self-assembling ultrashort d or l-α peptide hydrogelator, namely phosphorylated (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-OH (NapFFKY[p]-OH), covalently conjugated to zidovudine via an ester linkage. Rheological analysis demonstrates phosphatase enzyme instructed self-assembly, with hydrogels forming within minutes. Small angle neutron scattering data suggest hydrogels form narrow radius (≈2 nm), large length fibers closely fitting the flexible cylinder elliptical model. d-Peptides are particularly promising for long-acting delivery, displaying protease resistance for 28 days. Drug release, via hydrolysis of the ester linkage, progress under physiological conditions (37 °C, pH 7.4, H2O). Subcutaneous administration of Napffk(AZT)Y[p]G-OH in Sprague Dawley rats demonstrate zidovudine blood plasma concentrations within the half maximal inhibitory concentration (IC50) range (30–130 ng mL−1) for 35 days. This work is a proof-of-concept for the development of a long-acting combined injectable in situ forming peptide hydrogel implant. These products are imperative given their potential impact on society.
Item Type: | Articles |
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Additional Information: | S.M.C. and S.P. contributed equally to this work. This work was supported by the EPSRC (grant number EP/S031561/1); the Wellcome Trust (grant number 07618/Z/17/Z); the MRC (grant number MC_PC_18060), and Invest NI (grant number 2111/130282815) awards to G.L. The experiment at the Institut Laue-Langevin was allocated beam time under experiment number 9-13-972 (https://doi.org/10.5291/ILL-DATA.9-13-972). This work benefited from the use of the SasView application, originally developed under NSF award DMR-0520547. SasView contains code developed with funding from the European Union's Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement no. 654000. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | McAulay, Dr Kate |
Authors: | Coulter, S. M., Pentlavalli, S., Vora, L. K., An, Y., Cross, E. R., Peng, K., McAulay, K., Schweins, R., Donnelly, R. F., McCarthy, H. O., and Laverty, G. |
College/School: | College of Science and Engineering > School of Chemistry |
Journal Name: | Advanced Healthcare Materials |
Publisher: | Wiley |
ISSN: | 2192-2640 |
ISSN (Online): | 2192-2659 |
Published Online: | 07 March 2023 |
Copyright Holders: | Copyright © 2023 The Authors |
First Published: | First published in Advanced Healthcare Materials 12(18):2203198 |
Publisher Policy: | Reproduced under a Creative Commons license |
Data DOI: | 10.17034/67d0cd6f-5bed-4148-b986-f43975b0392c |
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