Sebastiano Masuzzo

Background: Sirtuin-1 (SIRT1), a histone deacetylase enzyme expressed in ocular tissues with intracellular localization, plays a critical protective role against various degenerative ocular diseases. The link between reduced SIRT1 levels and diabetic retinopathy (DR) has prompted the exploration of natural therapeutic compounds that act as SIRT1 agonists. Curcumin (CUR), which has been shown to upregulate SIRT1 expression, is one such promising compound. However, effective delivery of CUR to the deeper ocular tissues, particularly the retina, remains a challenge due to its poor solubility and limited ocular penetration following topical administration. Within this context, the development of self-nanoemulsifying drug delivery systems (SNEDDS) for CUR topical ocular delivery represents a novel approach. Methods: In accordance with our prior research, optimized SNEDDS loaded with CUR were developed and characterized post-reconstitution with simulated tear fluid (STF) at a 1:10 ratio, showing suitable physicochemical and technological parameters for ocular delivery. Results: An entrapment efficiency (EE%) of approximately 99% and an absence of drug precipitation were noticed upon resuspension with STF. CUR-SNEDDS resulted in a better stability and release profile than free CUR under simulated ocular conditions. In vitro analysis of mucoadhesive properties revealed that CUR-SNEDDS, modified with a cationic lipid, demonstrated enhanced interactions with mucin, indicating the potential for improved ocular retention. Cytotoxicity tests demonstrated that CUR-SNEDDS did not affect the viability of human corneal epithelial (HCE) cells up to concentrations of 3 μM and displayed superior antioxidant activity compared to free CUR in an oxidative stress model using retinal pigment epithelial (ARPE-19) cells exposed to hydroquinone (HQ). Cell uptake studies confirmed an enhanced accumulation of CUR within the retinal cells following exposure to CUR-SNEDDS compared to neat CUR. CUR-SNEDDS, at lower concentrations, were found to effectively induce SIRT1 expression. Conclusions: The cytocompatibility, antioxidant properties, and enhanced cellular uptake suggest that these developed systems hold promise as formulations for the delivery of CUR to the retina.

Sirtuin-1 (SIRT1), a histone deacetylase enzyme expressed in ocular tissues with intracellular localization, plays a protective role against multiple ocular diseases such as retinal degeneration, cataracts, and optic neuritis. The correlation between diabetic retinopathy (DR) and decreased levels of SIRT1 has stimulated investigation into natural therapeutic compounds that function as agonists. Curcumin (CUR), which upregulates SIRT1 protein expression, has been identified as a molecule with agonist properties. However, the challenge lies in delivering CUR effectively to the deeper layers of the eye, as retinal, due to its poor solubility and inadequate ocular penetration after topical administration. Within this context, the development of self-nanoemulsifying drug delivery systems (SNEDDS) for CUR topical ocular delivery can represent a novel approach. In accordance with our prior research, optimized SNEDDS loaded with CUR were characterized post-reconstitution with simulated tear fluid (STF) at a 1:10 ratio.Optimal parameters were achieved, ensuring mean globule size<50 nm, PDI <0.2, emulsification time 95%), viscosity, pH, and osmolarity close to physiological values. An entrapment efficiency (EE%) of approximately 99% and absence of drug precipitation were noted upon resuspension with STF. CUR loaded in these systems exhibited better stability than free CUR up to 1 week exposed to different conditions and demonstrated burst release following sustained release under simulated ocular conditions. Mucoadhesion studies were performed in STF for both CUR-SNEDDS and CUR-SNEDDS positively charged with dimethyldidodecylammonium bromide (DDAB). SNEDDS exhibited no adverse effects on the viability of human corneal epithelial (HCE) cells up to 3 μM and demonstrated superior antioxidant activity compared to neat CUR on retinal cells (ARPE-19) exposed to hydroquinone. Cell uptake studies confirmed enhanced accumulation of CUR within retinal cells (around 20% of CUR internalized) following exposure to CUR-SNEDDS compared to neat CUR (0-0.5% of CUR internalized). CUR-SNEDDS, at lower concentrations, were found to effectively induce SIRT1 expression. The cytocompatibility, antioxidant properties, and enhanced cellular uptake suggest that these developed systems hold promise as formulations for the delivery of CUR to the retina.