Hyaluronic acid: A review on its biology, aspects of drug delivery, route of administrations and a special emphasis on its approved marketed products and recent clinical studies.

Hyaluronic acid in ocular drug delivery.

Research efforts on nanomaterial-based therapies for the treatment of autoimmune diseases and cancer have spiked and have made rapid progress over the past years. Nanomedicine has been shown to contribute significantly to overcome current therapeutic limitations, exhibiting advantages compared to conventional therapeutics, such as sustained drug release, delayed drug degradation and site-specific drug delivery. Multiple nanodrugs have reached the clinic, but translation is often hampered by either low targeting efficiency or undesired side effects. Nanomaterials, and especially inorganic nanoparticles, have gained criticism due to their potential toxic effects, including immunological alterations. However, many strategies have been attempted to improve the therapeutic efficacy of nanoparticles and exploit their unique properties for the treatment of inflammation and associated diseases. In this review, we elaborate on the immunomodulatory effects of nanomaterials, with a strong focus on the underlying mechanisms that lead to these specific immune responses. Nanomaterials to be discussed include inorganic nanoparticles such as gold, silica and silver, as well as organic nanomaterials such as polymer-, dendrimer-, liposomal- and protein-based nanoparticles. Furthermore, various approaches for tuning nanomaterials in order to enhance their efficacy and attenuate their immune stimulation or suppression, with respect to the therapeutic application, are described. Additionally, we illustrate how the acquired insights have been used to design immunotherapeutic strategies for a variety of diseases. The potential of nanomedicine-based therapeutic strategies in immunotherapy is further illustrated by an up to date overview of current clinical trials. Finally, recent efforts into enhancing immunogenic cell death through the use of nanoparticles are discussed.

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Biomedical nanomaterials for immunological applications: ongoing research and clinical trials

Given that biodegradable in situ gelling delivery systems may have potential applications in the design of ophthalmic pharmaceutical formulations, this study, for the first time, aims to develop gelatin-g-poly(N-isopropylacrylamide) (GN) carriers for topical epigallocatechin gallate (EGCG) administration in the treatment of dry eye disease (DED). By temperature triggered sol-gel phase transition of copolymers, EGCG-loaded GN was prepared at 32 °C and characterized by FTIR, NMR, and HPLC analyses. Results of WST-1 and live/dead assays showed that GN materials have good compatibility with corneal epithelial cells. Gradual biodegradation of delivery carriers allowed sustained release of EGCG without drug toxicity. Anti-inflammatory and antioxidant activity studies also indicated effective therapeutic drug levels at each time point within 3 days of release. In a rabbit dry eye model, corneal epithelial defects was ameliorated by treatment with single-dose administration of EGCG-containing GN. Furthermore, drug molecules released from carrier materials could prevent further tear evaporation and loss of mucin-secreting goblet cells in diseased animals. Our findings suggest that GN carrier is responsible for enhanced pharmacological efficacy of topically instilled EGCG, thereby demonstrating the benefits of using biodegradable in situ gelling delivery system to overcome the drawbacks of limited dry eye relief associated with eye drop dosage form.

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Epigallocatechin Gallate-Loaded Gelatin-g-Poly(N-Isopropylacrylamide) as a New Ophthalmic Pharmaceutical Formulation for Topical Use in the Treatment of Dry Eye Syndrome

Dry eye disease (DED) has become common on a global scale in recent years. There is a wide prevalence of DED in different countries based on various ethnicities and environment. DED is a multifactorial ocular disorder. In addition to advanced age and gender, such factors as living at high altitude, smoking, pterygium, prolonged use of consumer electronics or overingesting of caffeine or multivitamins are considered to be the major risk factors of DED. We report the DED epidemiology in Taiwan firstly in this article. According to the pathophysiological factors and changes inthe composition of the tear film in DED, it can be categorized into several subtypes, including lipid anomaly dry eye, aqueous tear deficiency, allergic and toxic dry eye among others. Each subtype has its own cause and disease management; therefore, it is important for ophthalmologists to identify the type through literature review and investigation. The management of DED, relies not only on traditional medications such as artificial tears, gels and ointments, but also newer treatment options such as acupuncture, SYL1001, and nanomedicine therapy. We also conducted a comprehensive literature review including common subtypes and treatment of DED. Clearly, more clinical trials are needed to assess the efficacy and safety of the various treatments and common subtypes of DED.

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Dry Eye Disease: A Review of Epidemiology in Taiwan, and its Clinical Treatment and Merits.

Introduction Dry-eye syndrome (DES) is a general eye disease. Eye drops are the common ophthalmological medication. However, the ocular barrier makes it difficult to attain high drug bioavailability. Nanomedicine is a promising alternative treatment for ocular diseases and may increase drug content in the affected eye. Methods To explore this potential, we constructed nanoparticles (NPs) containing an anti-inflammatory agent for DES treatment. The NPs were made of gelatin-epigallocatechin gallate (EGCG) with surface decoration by hyaluronic acid (HA) and designated "GEH". The particle size, surface charge, and morphology were evaluated. The in vitro biocompatibility and anti-inflammation effect of nanoparticles were assayed via culturing with human corneal epithelium cells (HCECs) and in vivo therapeutic effect was examined in a DES rabbit's model. Results The synthesized GEH NPs had a diameter of approximately 250 nm and were positively charged. A coculture experiment revealed that 20 µg/mL GEH was not cytotoxic to HCECs and that an EGCG concentration of 0.2 µg/mL downregulated the gene expression of IL1B and IL6 in inflamed HCECs. Large amounts of GEH NPs accumulated in the cytoplasm of HCECs and the ocular surfaces of rats and rabbits, indicating the advantage of GEH NPs for ocular delivery of medication. Twice-daily topical treatment with GEH NPs was performed in a rabbit model of DES. The ocular surface of GEH-treated rabbits displayed normal corneal architecture with no notable changes in inflammatory cytokine levels in the cornea lysate. The treatment improved associated clinical signs, such as tear secretion, and fluorescein staining recovered. Conclusion We successfully produced GEH NPs with high affinity for HCECs and animal eyes. The treatment can be delivered as eye drops, which retain the drug on the ocular surface for a longer time. Ocular inflammation was effectively inhibited in DES rabbits. Therefore, GEH NPs are potentially valuable as a new therapeutic agent delivered in eye drops for treating DES.

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Gelatin-epigallocatechin gallate nanoparticles with hyaluronic acid decoration as eye drops can treat rabbit dry-eye syndrome effectively via inflammatory relief.

Dry eye syndrome (DES) is a common ophthalmological disease that decreases tear secretion and causes dryness, photophobia, pain, severe corneal rupture, and even blindness. Ocular and lacrimal gland inflammation is one of the pathological mechanisms underlying DES. Therefore, effective suppression of inflammation is a crucial strategy for the treatment of DES. Lutein, commonly found in healthy foods, has anti-inflammatory effects in corneal or retina-related cells and may be a potential therapy for DES. The addition of lutein to artificial tears (AT) as an eye-drop formulation for DES treatment in a mouse model was studied in the present work. Polyvinyl alcohol (PVA) was used as a thickener to increase the viscosity of eye drops to prolong drug retention on the ocular surface. A WST-8 assay in human corneal epithelial cells (HCE-2) showed that a concentration of <5 μM lutein (L5) and <1% PVA (P1) maintained the cell viability at 80%. A real-time PCR showed that the inflamed human corneal epithelial cells (HCECs) cocultured with L5P1 had downregulated expression of inflammatory genes such as IL-1β, IL-6, and TNF-α. In a benzalkonium chloride- (BAC) induced DES mouse model, AT/L5P1 could repair damaged corneas, elevate tear secretion, increase the number of goblet cells, and inhibit the production of inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, in the cornea. In conclusion, we demonstrate that lutein/PVA as eye drops could prolong the drug ocular retention time and effectively to decrease inflammation in DES mice. Therefore, lutein, obtained from eye drops, has a potential therapeutic role for DES.

Development of Lutein-Containing Eye Drops for the Treatment of Dry Eye Syndrome.

A lutein-containing ophthalmic composition, wherein the ophthalmic composition is mainly consisting of a natural anti-inflammatory substance, a substance with increasing liquid viscosity, and an artificial tear The substance with increasing liquid viscosity could apply the ophthalmic composition to elongate the retention time on the ocular surface, thereby increasing the retention time of anti-inflammatory substance on the ocular surface for treating dry eye syndrome and inhibiting ocular surface inflammation

Zhi-Yu Chen

Papers

Gelatin-epigallocatechin gallate nanoparticles with hyaluronic acid decoration as eye drops can treat rabbit dry-eye syndrome effectively via inflammatory relief.

Development of Lutein-Containing Eye Drops for the Treatment of Dry Eye Syndrome.

Lutein-containing ophthalmic composition