PROJECT SUMMARY
Herpes simplex virus (HSV) keratitis is the leading cause of corneal ulcers and infection-associated blindness in
the United States. The existing antiviral therapies for the topical management of ocular herpes infections include
nucleoside analogs such as ganciclovir and trifluridine which need to be administered 5-8 times a day to control
the infection. Hence, current topical therapies have patient adherence issues which impact therapeutic
outcomes. In addition to the limited topical bioavailability, the emergence of drug resistance to acyclic
nucleosides has necessitated the development of long-acting antiviral therapies for the topical treatment of ocular
herpes infections. Our preliminary data show that adefovir dipivoxil (ADV), an off-patent, FDA-approved hepatitis
B virus DNA polymerase inhibitor, is well tolerated by the human corneal epithelial cells and is significantly more
active against HSV-1 and HSV-2 when compared to acyclovir, other acyclic nucleoside phosphonates such as
tenofovir, cidofovir, and their prodrugs. Our preliminary data further showed that thrice daily topical administration
of 1% ADV solution has a robust antiviral effect in a murine ocular herpes model compared to once daily 1%
ADV solution and thrice daily 0.15% ADV solution. Thus, strategies are needed to reduce the dosing frequency
of ADV to further improve ocular herpes therapy and patient compliance. We previously demonstrated that
hydrophilic ionizable antibiotics such as moxifloxacin can be converted to hydrophobic moxifloxacin salt and its
subsequent formulation into a mucoinert nanosuspension augmented the topical delivery and reduced the
administration frequency. Here, we extend this approach to improve ocular delivery of hydrophilic ionizable
antiviral drug, ADV. We hypothesize that the development of hydrophobic salts of ADV and their transformation
into mucoinert nanosuspensions (NS) will improve ocular delivery and prolong the release of ADV with a
concomitant reduction in dosing frequency. Aim 1 will focus on the evaluation of ADV solution compared to
currently approved topical anti-herpetic drugs, ganciclovir, and trifluridine using ex-vivo ocular permeability
studies, ocular PK in rabbits, and in vivo efficacy in a mouse model of ocular herpes. Aim 2 will focus on the
development and characterization of NS of various ADV hydrophobic salts followed by evaluation of their in vitro
cytocompatibility, in vitro antiviral activity, ex vivo corneal permeability, ocular PK in rabbits and in vivo efficacy
in a rabbit model of ocular herpes. We have already generated NS of ADV pamoate, a hydrophobic salt of ADV.
Our preliminary data show that once-daily topical ADV pamoate NS was significantly more effective than once
daily 1% ADV solution but equally effective as thrice daily 1% ADV solution in a murine model of ocular herpes
infection. We will evaluate selected nanoformulations of ADV hydrophobic salt in the rabbit model of ocular
herpes infection. Finally, we will evaluate the long-term safety of ADV solution and ADV nanoformulation in
rabbits. The successful completion of this project will lead to the development of clinically viable, patient-friendly
long-acting topical nanomedicine for the effective management of ocular herpes infections.
