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.
Highlights
It is predicted that the proportion of patients with diabetes mellitus (DM) will increase to 4.4%in 2030, and the management and prevention of DM are global public health problems [1,2].DM patients develop a prothrombotic state involving impaired coagulation, platelet dysfunction, and endothelial dysfunction [3,4] and the onset of diabetic complications, such as microvascular complications, nephropathy, and neuropathy
We previously showed that the instillation of suspensions containing DIS nanoparticles can supply more DDC to the aqueous humor and lens than a conventional formulation (DIS-sol) [28,29]
In this study, we designed an in situ gel incorporating DIS nanoparticles (Dis-NPs/ISG)
Summary
It is predicted that the proportion of patients with diabetes mellitus (DM) will increase to 4.4%. DM patients develop a prothrombotic state involving impaired coagulation, platelet dysfunction, and endothelial dysfunction [3,4] and the onset of diabetic complications, such as microvascular complications, nephropathy, and neuropathy. DR is one of the main microvascular complications in DM patients and is characterized by cell death in retinal capillaries, glial and neuronal dysfunction, vessel occlusion, vascular leakage, and visual impairment, resulting in blindness [5]. The pathogenic mechanisms of DR were investigated using animal models of DM, and Ins2Akita mice, a mouse model of type 1 diabetes, and rats with streptozocin-induced diabetes (STZ rats) have been. Cells 2020, 9, 2171 used as animal models to investigate DR [6,7]. It was reported that the morphologic changes in the retinal capillaries and retinal ultrastructures of 14-month-old
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