Advancement on Sustained Antiviral Ocular Drug Delivery for Herpes Simplex Virus Keratitis: Recent Update on Potential Investigation

Abstract

The eyes are the window to the world and the key to communication, but they are vulnerable to multitudes of ailments. More serious than is thought, corneal infection by herpes simplex viruses (HSVs) is a prevalent yet silent cause of blindness in both the paediatric and adult population, especially if immunodeficient. Globally, there are 1.5 million new cases and forty thousand visual impairment cases reported yearly. The Herpetic Eye Disease Study recommends topical antiviral as the front-line therapy for HSV keratitis. Ironically, topical eye solutions undergo rapid nasolacrimal clearance, which necessitates oral drugs but there is a catch of systemic toxicity. The hurdle of antiviral penetration to reach an effective concentration is further complicated by drugs' poor permeability and complex layers of ocular barriers. In this current review, novel delivery approaches for ocular herpetic infection, including nanocarriers, prodrugs, and peptides are widely investigated, with special focus on advantages, challenges, and recent updates on in situ gelling systems of ocular HSV infections. In general congruence, the novel drug delivery systems play a vital role in prolonging the ocular drug residence time to achieve controlled release of therapeutic agents at the application site, thus allowing superior ocular bioavailability yet fewer systemic side effects. Moreover, in situ gel functions synergistically with nanocarriers, prodrugs, and peptides. The findings support that novel drug delivery systems have potential in ophthalmic drug delivery of antiviral agents, and improve patient convenience when prolonged and chronic topical ocular deliveries are intended.

Keywords: herpes simplex virus keratitis; in situ ophthalmic gel; mucoadhesive; novel approaches; ocular drug delivery; safety.

Figure 1

Herpes simplex virus 1 (HSV-1) is classified into the Alphaherpesvirinae family, a sub-family of Herpesviridae. It is an enveloped DNA virus consisting of a linear double-strand genome protected inside an icosahedral capsid. The inner tegument is made up of a layer of mRNA and proteins, whereas the outer lipid bilayer envelope contains glycoproteins. These glycoproteins are responsible for the invasion of the virus into the host cell.

Figure 2

Stages of HSV-1 replication in corneal epithelial cells. Abbreviation: HPSE, heparanase, an enzyme which cleaves heparan sulfate proteoglycans to prevent virions from being trapped by the proteoglycans, thus promoting virion egress.

Figure 3

Ocular irritation study conducted by Alkholief et al., revealing (A) normal condition of rabbit eye; (B) mild redness and inflammation in the conjunctival area by the first hour post-administration; (C) increased redness and inflammation by the third hour; (D) reduced redness and inflammation by the sixth hour; (E) complete reduction of redness and inflammation by the twelfth hour, adapted with permission from [66], Elsevier, 2019.

Figure 4

A mouse model of corneal keratitis was given 100 μL of 0.5mM of G1 (peptides with alternating charges), G2 (peptides with repetitive charges), and designated peptide (control) as a prophylactic eye drop followed by the inoculation of HSV-1. Immunohistochemistry was carried out using anti-HSV-1 glycoprotein D (gD) polyclonal antibody on day 4 and day 7 post-infection to detect the HSV-1 gD expression in the cornea. (a) chronic inflammation was observed together with significant brown staining in the pretreated cornea with control on day 4, which was indicating the expression of HSV-1 gD; (b) on day 4, HSV-1 gD staining was not detected in the cornea pretreated with G1 peptide; (c) on day 4, HSV-1 gD staining was not detected in the cornea pretreated with G2 peptide; (d) the staining was disappeared in the cornea pretreated with control on day 7 but the damage of the corneal epithelium was observed; (e) on day 7, HSV-1 gD staining was not detected in the cornea pretreated with G1 peptide and the corneal epithelium remained intact; (f) on day 7, HSV-1 gD staining was not detected in the cornea pretreated with G2 peptide and the corneal epithelium remained intact. The results indicated G1 and G2 significantly blocked the entry of HSV-1, adapted with permission from [85], American society for biochemistry and molecular biology, 2011.

Figure 5

The sections from pig corneas received indicated treatments, where the epithelial cells are shown in blue, while the virus is shown in green. The phosphate-buffered saline (PBS) + HSV-1-treated cells showed the presence of virus while G2-C + HSV-1-treated cells did not. It could be deduced that the peptide, G2-C, released from the contact lens was effective in inhibiting HSV-1 infection, adapted from [87], ARVO Journals, 2016.