In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats

Abstract

We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80–250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy.

Revealing the Angiopathy of Lacrimal Gland Lesion in Type 2 Diabetes

“…In the present study, we found several potential small molecular compounds to reverse the altered expression of the DEGs, which might improve lacrimal lesions and vasculature dysfunction in T2DM. It was reported that the therapy of an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) might contribute to restore retinal dysfunction in diabetic retinopathy (DR), a diabetic vascular lesion (Deguchi et al, 2020 ). Bumetanide also has been demonstrated to play an important role in antidiabetic activity with low in vitro cell toxicity through antiinflammatory effects (Navas et al, 2020 ) and can reduce diabetic vascular dysfunction by suppression of angiogenesis (Topper et al, 1997 ; Guzel et al, 2020 ).…”

Potential of Stimuli-Responsive In Situ Gel System for Sustained Ocular Drug Delivery: Recent Progress and Contemporary Research

“…The formulation was stable, as not aggregation or participation was reported in 1 month and gelled at 37 • C. Prolonged retinal residence time was observed after the instillation of gel. These studies have shown the effectiveness of in situ gels in the treatment of retinopathy [55].…”

“…Prolonged retinal residence time was observed after the instillation of gel. These studies have shown the effectiveness of in situ gels in the treatment of retinopathy [ 55 ].…”

Recent developments of temperature‐responsive polymers for ophthalmic applications

“…Nagai's group in Japan took a similar nanoparticle/hydrogel approach to treat DR 115 . Methylcellulose (MC) was added to disulfiram (DIS) nanoparticles to form an in situ ophthalmic gel formulation (DIS‐NPs/ISG).…”