Biodegradable PLGA nanoparticles of acyclovir and an acyclovir prodrug for potential enhanced therapy against HSV-1...

Herpes simplex virus-1 (HSV-1) is a widespread, recurrent infection that causes herpes simplex keratitis (HSK), an ocular disease that can lead to vision impairment. Conventional acyclovir (ACY) therapy is limited by poor bioavailability, rapid clearance, and frequent dosing. We developed an esterified acyclovir prodrug (ACPD) formulated as biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to improve stability, enable sustained release, and enhance antiviral activity against HSV-1. ACPD was synthesized, ACY-NPs and ACPD-NPs were prepared by nanoprecipitation and single-emulsion solvent evaporation method respectively. Optimized NPs measured 200-300 nm with polydispersity indices of 0.23-0.47 and zeta potentials of - 27 to - 29 mV. ACPD-NPs provided sustained release for 28 days. Cytotoxicity in Vero cells yielded CC50 values of 960 µM (ACY-NPs) and 1000 µM (ACPD-NPs). In HSV-1-infected Vero cells, ACY-NPs exhibited greater antiviral efficacy than free ACY, whereas ACPD and ACPD-NPs showed limited plaque reduction because the tested in vitro media lacked esterase to convert ACPD to ACY. When tested with esterase, cleavage was confirmed by RP-HPLC. Evaluation of ACPD-NPs therapeutic efficacy should be further validated in ocular tissues and in an in vivo ocular model, where esterase enzymes are present. Since corneal tissues contain esterase, its activation may improve ACPD efficacy in in vivo models, which in turn increases bioavailability and overall therapeutic efficacy of ACPD-NPs.