Title
Enzyme-Triggered L-α/D-Peptide Hydrogels as a Long-Acting Injectable Platform for Systemic Delivery of HIV/AIDS Drugs
Author
Coulter, Sophie M., Sreekanth Pentlavalli, Lalitkumar K. Vora, Yuming An, Emily R. Cross, Ke Peng, Kate McAulay, Ralf Schweins, Ryan F. Donnelly, Helen O. McCarthy, and Garry Laverty
Year
2023
Journal
Advanced Healthcare Materials
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) 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 demonstrated phosphatase enzyme instructed self-assembly, with hydrogels forming within minutes. Small angle neutron scattering data suggested hydrogels form narrow radius (?2 nm), large length fibers closely fitting the flexible cylinder elliptical model. D-peptides were particularly promising for long-acting delivery, displaying protease resistance for 28 days. Drug release, via hydrolysis of the ester linkage, progressed under physiological conditions (37 °C, pH 7.4, H2O). Subcutaneous administration of Napffk(AZT)Y[p]G-OH in Sprague Dawley rats demonstrated zidovudine blood plasma concentrations within the IC50 range (30 ? 130 ng/mL) 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. This article is protected by copyright. All rights reserved
Instrument
J-815
Keywords
Long-acting Injectable Platform,HIV,AIDS