“ TPGS-Functionalized Nanocarriers with Improved Flavonoid Oral Bioavailability and Therapeutic Action: Pharmacokinetic and Mechanistic Insights in Diabetes-Induced Retinopathy ”

Abstract

Diabetes mellitus is a metabolic disorder with escalating prevalence. It’s a chief cause of microvascular complications, notably diabetic retinopathy (DR), which can predispose to permanent vision loss. Inflammation and oxidative stress are pivotal contributors to the progression of DR. Luteolin (LUT), a naturally occurring flavonoid, possesses strong anti-inflammatory and antioxidant properties, offering therapeutic potential against DR. However, its clinical use is impeded by its restricted intestinal permeability and poor water solubility. In this study, twelve lipid–polymer hybrid nanoparticles (LPNPs) were developed using a 1³2² complete factorial design to explore the impact of three formulation variables: poly(ε-caprolactone) (PCL): d-alpha-Tocopheryl polyethylene glycol 1,000 succinate (TPGS) ratio (A), preparation technique (B) and phospholipid (PL) content (C). The optimized formulation (LP8), composed of 50 mg of phospholipid, PC: TPGS (2:1) and prepared via the emulsion solvent evaporation method, demonstrated a high zeta potential (−34.9 ± 5.2  mV), a small particle size (215.3 ± 10.3  nm), and a high entrapment efficiency (93.1 ± 2.4 %). Compared to LUT suspension, LP8 demonstrated prolonged in vitro drug release and markedly enhanced ex vivo intestinal permeability. In streptozotocin (STZ)-induced diabetes, LP8 resulted in significant reduction in hyperglycemia, retinal inflammation, oxidative stress and angiogenesis while preserving retinal structure. Moreover, LP8 significantly downregulated the expression of MDA, IL-1β, NLRP3, ASC, and VEGF while upregulated GSH and Nrf2 levels in the retina. Additionally, pharmacokinetic study confirmed a substantial improvement in oral bioavailability of LUT-loaded LP8 compared to LUT-suspension. These findings proposed that the optimized LUT-loaded LPNPs represent a potential oral nanoplatform for the effective management of DR.