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" TPGS-Functionalized Nanocarriers with improved flavonoid oral bioavailability and therapeutic Action: Pharmacokinetic and Mechanistic Insights in Diabetes-Induced Retinopathy ".

Maha Abdelmonem,A. Al-Mokaddem,Mohamed Y. Zakaria

Published 2025 in European journal of pharmaceutics and biopharmaceutics

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.

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