Enzyme-triggered L-α/D-peptide Hydrogels as a Long-acting Injectable Platform for Systemic Delivery of HIV/AIDS Drugs.
Sophie M CoulterSreekanth PentlavalliLalitkumar K VoraYuming AnEmily R CrossKe PengKate McAulayRalf SchweinsRyan F DonnellyHelen O McCarthyGarry LavertyPublished in: Advanced healthcare materials (2023)
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, H 2 O). Subcutaneous administration of Napffk(AZT)Y[p]G-OH in Sprague Dawley rats demonstrated zidovudine blood plasma concentrations within the IC 50 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.
Keyphrases
- hiv aids
- hyaluronic acid
- drug release
- drug delivery
- tissue engineering
- antiretroviral therapy
- human immunodeficiency virus
- photodynamic therapy
- high throughput
- genome wide
- hiv infected
- wound healing
- drug induced
- electronic health record
- emergency department
- case report
- dna methylation
- machine learning
- extracellular matrix
- type diabetes
- climate change
- big data
- glycemic control
- south africa
- human health