Acyclovir prodrug combined with biodegradable nanoparticles improves antiviral activity against herpes simplex virus, suggesting better treatment options.
Abstract 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 and characterized by FTIR, NMR, and mass spectrometry. Its increased hydrophobicity improved encapsulation in PLGA relative to ACY. 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; SEM showed uniform particles. 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 minimal plaque reduction because the in vitro media lacked esterase to convert ACPD to ACY; with esterase, cleavage was confirmed by RP-HPLC. Corneal tissues contain esterase, in vivo activation may improve ACPD efficacy and bioavailability and overall therapeutic performance.
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Hakkimane et al. (2025) studied this question.
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