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Preclinical evaluation of the therapeutic potential of antimicrobial 265 nm UVC for infectious keratitis.

ABSTRACTIntroduction: Chronic inflammatory diseases, including retinal diseases that are a major cause of vision loss, are associated with activation of the nucleotide-binding domain and leucine-rich repeat containing (NLR) protein-3 (NLRP3) inflammasome pathway. In chronic disease, the inflammasome becomes self-perpetuating, indicating a common pathway in such diseases irrespective of underlying etiology, and implying a shared solution is feasible. Connexin43 hemichannels correlate directly with NLRP3 inflammasome complex assembly (shown here in models of retinal disease). Connexin43 hemichannel-mediated ATP release is proposed to be the principal activator signal for inflammasome complex assembly in primary signal-sensitized cells. Connexin hemichannel block on its own is sufficient to inhibit the inflammasome pathway.Areas covered: We introduce chronic retinal disease, discuss available preclinical models and examine findings from these models regarding the targeting of connexin43 hemichannels and its effects on the inflammasome.Expert opinion: In over 25 animal disease models, connexin hemichannel regulation has shown therapeutic benefit, and one oral connexin hemichannel blocker, tonabersat (Xiflam), is Phase II ready with safety evidence in over 1000 patients. Regulating the connexin hemichannel provides a means to move quickly into clinical trials designed to ameliorate the progression of devastating chronic diseases of the eye, but also elsewhere in the body.

Dry eye disease (DED) is one of the most prevalent ocular surface disorders that presents clinically. Recently, the semifluorinated alkane (SFA) perfluorohexyloctane (NovaTears®; EvoTears®) entered the market for the management of evaporative DED, while perfluorobutylpentane has been used as a vehicle to enhance ocular drug delivery. This study evaluated the mechanisms by which SFAs might improve therapeutic outcomes in DED.

The present study reports on the development of a hybrid system by integrating poly(lactic-co-glycolic)acid nanoparticles (PLGA NPs) into light-responsive in-situforming injectable implants (ISFIs) for minimally invasive and safe intravitreal peptide delivery. In the first part of the study, peptide-loaded PLGA based nanoparticles (NPs) were developed using the two-step nanoprecipitation technique. Peptide compatibility with PLGA and polyvinyl alcohol was confirmed via IR spectroscopy. Developed NPs had a size of 149.3–235.4 nm, a polydispersity index between 0.24 and 0.46, a zeta potential of −32.4 to −27.0 mV and an entrapment efficiency of 34.3–55.3%. In the second part of the study, successful synthesis of methacrylated alginate (MA) and its subsequent photocrosslinking upon photoirridiation was confirmed by 1H NMR. Photocrosslinked MA exhibited the required clarity and its gelling time, morphology, syringeability, hardness, rate of swelling and degradation were found suitable for prolonging its residence in the posterior segment. The sulforhodamine B assay on human retinal pigment epithelium cells and the zebrafish embryo toxicity test confirmed the biocompatibility of NPs and ISFIs. Finally, NPs were incorporated into the ISFIs for improved particle retention and to further sustain drug release, suggesting the proposed hybrid system as an innovative and efficient ocular drug delivery platform.

Recent studies have shown that Connexin43 mimetic peptide (Cx43 MP) can prevent secondary damage following several retinal ischemic and inflammatory disorders by blocking the pathological opening of gap junction hemichannels. However, the poor stability of peptides and the presence of various intraocular barriers limit efficient retinal delivery in the clinical setting. The present study aimed to prolong the bioactivity of Cx43 MP and achieve targeted delivery to the retina by loading the peptide into hyaluronic acid (HA) coated human serum albumin nanoparticles (HSA NPs). Two different loading methods, adsorption and incorporation, were used with the peptide released slowly over a period of up to four months. Compared to uncoated particles, HA coated HSA NPs exhibited enhanced in vitrocellular uptake and ex vivoretinal penetration via HA-CD44 receptor mediated interactions. Furthermore, cell viability and Cx43 MP functionality assays showed that NPs protected Cx43 MP from degradation, sustained its release, and thus prolonged its bioactivity without reducing cell viability at concentrations used for Cx43 hemichannel blocking. Therefore, HA coated HSA NPs could have great potential for sustained and targeted delivery of Cx43 MP to treat various retinal inflammatory conditions.

Background: Blepharitis is considered one of the most common ocular surface conditions in optometry and ophthalmology practice. While azithromycin and dexamethasone have been used successfully to treat blepharitis, they are generally formulated as eye drops requiring frequent administration. Ocular inserts based on biodegradable polymers may overcome some of the problems associated with conventional eye drops such as the fast nasolacrimal drainage. Methods: Inserts with different β-glucan and hydroxypropyl methycellulose (HPMC) compositions were prepared using the solvent-casting method and evaluated in terms of their appearance, thickness, weight, pH, mechanical strength, bioadhesive properties and drug-polymer interactions. The ability of the ocular inserts to provide controlled release of the drugs was assessed through an in vitro release study of dexamethasone and an antibacterial assay for azithromycin. Results: All parameters were found acceptable for ocular use, with the film laminate exhibiting the highest tensile strength and mucoadhesion. Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared Spectroscopy (FTIR) revealed that the drugs were molecularly dispersed within the polymer films with no obvious interactions. Dexamethasone release was fast with 100% released within 1 hr. Azithromycin also showed a high burst release achieving the minimum inhibitory concentration after only 5 min; however, antibacterial activity was maintained for 24 hrs. Conclusion: Ocular inserts were successfully prepared and delivered both drugs over prolonged periods compared to conventional eye drops. However, additional coating may be required to further control the drug release.

Extracellular vesicles (EVs) are a group of cell-derived membrane vesicles of varying sizes that can be secreted by most cells. Depending on the type of cell they are derived from, EVs may contain a variety of cargo including proteins, lipids, miRNA, and DNA. Functionally, EVs play important roles in physiological and pathological processes through intercellular communication. While there has already been significant literature on the involvement of EVs in neurological and cardiovascular disease as well as cancer, recent evidence suggests that EVs may also play a role in mediating inflammatory eye diseases. This paper summarizes current advancements in ocular EV research as well as new ways by which EVs may be utilized as novel biomarkers of or therapeutics for inflammatory eye diseases.

Ion-activated in situgelling systems are able to cross-link with the cations present in the tear fluid, forming a gel on the ocular surface and prolonging corneal contact time. Corneal scrape wounding offers an exceptional model to investigate the efficacy of these formulations for connexin43 (Cx43) antisense oligodeoxynucleotide (AsODN) delivery used to improve wound repair. Systems based on gellan gum and carrageenan have previously been found advantageous in terms of their physicochemical properties, in vitroand in vivorelease profiles and precorneal retention. The present study describes AsODN penetration into corneal tissue after wounding and determines the formulations’ delivery efficacy by evaluating wound size, tissue inflammation and connexin levels. No difference was shown between the penetration patterns of the formulations, with most of the AsODN accumulating in the epithelium close to the wound leading edge and the stroma underlying the wound. However, significant differences were seen in the delivery efficacy, with gellan gum and carrageenan based systems resulting in the lowest connexin levels and subsequently in the greatest reduction in wound size, the least stromal edema and hypercellularity. This demonstrates their potential use as delivery vehicles for AsODNs to the ocular surface.

Antimicrobial ultraviolet C (UVC) has proven efficacy in vitroagainst keratitis isolates and has potential to treat corneal infection if safety can be confirmed.