Preparation and Evaluation of Folic Acid-Modified Gambogic Acid Nanocrystals-Phospholipid Composite Drug Delivery System
Gambogic acid (GA) exhibits potent anticancer activity but suffers from poor aqueous solubility, rapid systemic clearance, and lack of tumor selectivity. This study designed a folic acid-modified gambogic acid nanocrystals-phospholipid composite drug delivery system (GA-NCs@PL-FA) to enhance targeted delivery. GA-NCs were prepared via CO2-assisted precipitation, followed by thin-film hydration to construct GA-NCs@PL-FA. Central composite design-response surface methodology optimized the formulation. The optimized system displayed spherical morphology with a particle size of 183.07 ± 0.55 nm, zeta potential of −17.70 ± 0.17 mV, encapsulation efficiency of 84.64 ± 0.57%, and drug loading of 4.33 ± 0.07%. Stability tests showed no significant changes after 7 days at 4°C and 25°C. In vitro release in pH 7.4 and 6.5 PBS (0.5% Tween 80) demonstrated sustained release. CCK-8 and scratch assays on HepG2 cells revealed that GA-NCs@PL-FA exhibited stronger inhibition of proliferation and migration compared to free GA, GA-NCs, and GA-NCs@PL, with an IC50 of 0.50 μg/mL. UPLC-MS/MS tissue distribution in tumor-bearing nude mice confirmed prolonged systemic retention and enhanced tumor accumulation. The findings indicate that GA-NCs@PL-FA integrates sustained release, active targeting, and improved antitumor efficacy, offering a viable strategy for the targeted delivery of poorly soluble gambogic acid.