Enzyme-Triggered l-alpha/d-Peptide Hydrogels as a Long-Acting Injectable Platform for Systemic Delivery of HIV/AIDS Drugs

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Article

关键词: D-AMINO ACIDS;    HIV PREEXPOSURE PROPHYLAXIS;    MOLECULAR-WEIGHT HYDROGELS;    SUPRAMOLECULAR HYDROGELS;    IN-VITRO;    SELF;    RELEASE;    ANTIBACTERIAL;    DIPEPTIDE;    SCAFFOLDS;   

DOI  :  10.1002/adhm.202203198

来源: SCIE

【 摘 要 】

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-alpha peptide hydrogelator, namely phosphorylated (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-OH (NapFFKY-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 (approximate to 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 degrees C, pH 7.4, H2O). Subcutaneous administration of Napffk(AZT)YG-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.

【 授权许可】

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