Enzyme-responsive in situ forming peptide hydrogels for long-acting delivery of HIV/AIDS drugs

A successful single, long-acting, highly user-adherent product that targets HIV/AIDS is a high priority for the World Health Organization due to the positive societal, health and economic impact this technology would provide. Key to addressing this challenge is overcoming patient medication adherence issues and complicated drug dosage regimens associated with existing therapies, including a commitment to daily intake of tablets. There is a need for a convenient and effective long-acting formulation to deliver drugs over a sustained period. The aim of our work is to develop an injectable in situ forming hydrogel implant for the delivery of a model HIV/AIDS antiretroviral drug, zidovudine (AZT), over 28 days using peptides that form hydrogels in response to phosphatase enzymes present in the subcutaneous/intramuscular space. The formulation is composed of a self-assembling ultrashort D or L- peptide hydrogelator composed of phosphorylated (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-OH (NapFFKY[p]-OH) to which AZT is conjugated covalently via an ester linkage and formulated as an antiretroviral-peptide injectable solution. Rheological analysis showed peptides demonstrated enzyme instructed self-assembly, forming hydrogels within minutes. In vivo blood plasma analysis revealed sustained drug delivery was achieved, within therapeutic levels, over a 35-day period.