Engineered Lecithin-Polymer Hybrid Micelles for Enhanced Gallic Acid Delivery: Response Surface Optimization and Preclinical Evaluation

Abstract

Oxidative stress is regarded as a major pathogenic key factor in chronic idiopathic pulmonary fibrosis (IPF), a disease with high mortality and an unclear cause. Gallic acid (GA) is a natural polyphenolic compound that shows significant antioxidant potential. However, its therapeutic effectiveness is limited due to low oral bioavailability, rapid metabolism, and poor aqueous solubility. To overcome such barriers, lecithin–polymer hybrid micelles (LPHM) were engineered as a nanocarrier platform for GA delivery. This study investigated the formulation and optimization of GA-loaded LPHM for pulmonary fibrosis therapy. LPHM were optimized using a D-optimal experimental design, assessing the drug amount (X1) and polymer type (X2: Pluronic® P123 or D-α-tocopheryl polyethylene glycol succinate, TPGS) on entrapment efficiency (Y1), particle size (Y2), and zeta potential (Y3). The optimized formula, comprising TPGS with 17 mg GA, showed an entrapment efficiency of 96.78 ± 1.45%, a particle size of 120.22 ± 1.45 nm, and a zeta potential of − 32.12 ± 0.97 mV. In-vitro release demonstrated a biphasic sustained-release profile. In-vivo pharmacokinetics showed a 7.35-fold increase in oral bioavailability of the optimized formula as compared to free GA. In a bleomycin-induced IPF model, the optimized formula significantly mitigated fibrotic progression, as evidenced by reductions in transforming growth factor-β, matrix metalloproteinase-7, hydroxyproline, and collagen-1. Overall, GA-loaded LPHM represent a promising oral drug delivery strategy for IPF, with broader potential in managing chronic diseases that demand sustained release and enhanced systemic exposure.