Systemic Anti-Inflammatory Therapy Aided by Curcumin-Laden Double-Headed Nanoparticles Combined with Injectable Long-Acting Insulin in a Rodent Model of Diabetes Eye Disease

Abstract

Therapeutic interventions that counter emerging targets in diabetes eye diseases are lacking. We hypothesize that a combination therapy targeting inflammation and hyperglycemia can prevent diabetic eye diseases. Here, we report a multipronged approach to prevent diabetic cataracts and retinopathy by combining orally bioavailable curcumin-laden double-headed (two molecules of gambogic acid conjugated to terminal carboxyl groups of poly(D,L-lactide-co-glycolide)) nanoparticles and injectable basal insulin. The combination treatment led to a significant delay in the progression of diabetic cataracts and retinopathy, improving liver function and peripheral glucose homeostasis. We found a concurrent reduction in lens aggregate protein, AGEs, and increased mitochondrial ATP production. Importantly, inhibition of Piezo1 protected against hyperglycemia-induced retinal vascular damage suggesting possible involvement of Piezo1 in the regulation of retinal phototransduction. Histologic evaluation of murine small intestines revealed that chronic administration of curcumin-laden double-headed nanoparticles was well tolerated, circumventing the fear of nanoparticle toxicity. These findings establish the potential of anti-inflammatory and antihyperglycemic combination therapy for the prevention of diabetic cataracts and retinopathy.

Polyester Nanoparticles with Controlled Topography for Peroral Drug Delivery Using Insulin as a Model Protein

“…In this study, glucagon levels were significantly lower in the diabetes groups compared to the healthy control group, indicating that glucagon secretion decreased in STZ-induced rats. In previous studies conducted by our lab, a similar trend was observed, wherein glucagon positive cells were significantly lower than the control groups . Following the treatment, glucagon levels increased significantly in the P2Ns-4C-GA and P2Ns groups, and levels were comparable to that of the control group, followed by glucagon levels in the P2Ns-2C-GA and LA INS groups.…”

“…Plasma ALP levels were significantly lower in the P2Ns-4C-GA and INS groups (Figure f), whereas there was no significant difference between the treated and diabetic groups for AST (Figure e). ALT is a more specific liver enzyme than AST and ALP (both of which are expressed in other organs). , Gamma Glutamyl Transferase (GGT) was also analyzed, as high plasma GGT levels indicate liver damage seen in NAFLD and liver adiposity. , In this study, plasma GGT concentrations in the terminal plasma were significantly lower in groups P2Ns-2C-GA and P2Ns-4C-GA than in the diabetic group (Figure g). Data from liver panels indicate that treatment with INS-laden nanoparticles significantly improves liver function, particularly in ligand-coated nanoparticle groups.…”

“…This arrangement introduces numerous pendant carboxylic acid groups along the polymeric backbone . We further demonstrated conjugating a small molecule ligand on P2s; gambogic acid (GA) binds noncompetitively to transferrin receptors. − The linker used in these studies was a short ethylenediamine (2C), effectively conjugating the GA to P2s (Figure ). Ethylenediamine has been utilized as a linker in diverse applications, particularly on the surface of nanoparticles. , …”

“…Dynamic light scattering (DLS) revealed nanoparticle sizes in the range of approximately 260–290 nm, with zeta potentials > ±20 mV, indicative of stable emulsions and therefore less likely to aggregate (Table ). Furthermore, we have previously shown that GA-decorated nanoparticles in this size range are appropriate for oral absorption. − , …”

Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

“…However, continuous breakthroughs are still required for their poor pharmacokinetics, low bioavailability, strong side effects, and inaccurate distribution. [29,30] A clinical study involving individuals afflicted with Friedreich's ataxia, a type of brain disease, demonstrated that only high-dose resveratrol (5g/day) alleviated symptoms. However, it showed no impact on mitochondrial function and led to the onset of gastrointestinal adverse reactions.…”