Objective In order to improve the targeting release of gambogic acid, a folic acid-modified gambogic acid nanocrystals-phospholipid composite drug delivery system (GA-NCs@PL-FA) was designed and prepared, and its prescription process was optimized. The physicochemical properties, in vitro anti-hepatocarcinoma activity and in vivo tissue distribution characteristics of GA-NCs@PL-FA were investigated. Methods Gambogic acid nanocrystals (GA-NCs) were prepared by CO₂-assisted precipitation method, and then GA-NCs@PL-FA was constructed by thin film hydration method. The prescription process was optimized by single factor investigation and central composite design-response surface methodology (CCD-RSM). The microscopic morphology was observed by transmission electron microscopy (TEM), and the particle size, ζ potential, encapsulation efficiency, drug loading and stability were determined. The in vitro release behavior in pH 7.4, 6.5 phosphate buffer (PBS, containing 0.5% Tween 80) was investigated by dialysis bag method. The effects of different administration groups on the viability and migration ability of HepG2 cells were evaluated by cell counting kit-8 (CCK-8) method and cell scratch test. The content of gambogic acid in each tissue of tumor-bearing nude mice was determined by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and its tissue distribution and tumor tissue enrichment ability were analyzed. Results The GA-NCs@PL-FA was spherical, the particle size was (183.07 ±0.55) nm, the ζ potential was (−17.70 ±0.17) mV, the encapsulation efficiency and drug loading were (84.64 ±0.57)% and (4.33 ±0.07)%, respectively. The properties were stable after 7 d at 4, 25 ℃. In both release media, it showed obvious sustained release effect. In vitro experiments showed that compared with gambogic acid, GA-NCs and folic acid-free gambogic acid nanocrystals-phospholipid composite drug delivery system (GA-NCs@PL), GA-NCs@PL-FA had a stronger inhibitory effect on the proliferation and migration of HepG2 cells, and the half inhibitory concentration (IC₅₀) was reduced to 0.50 μg/mL. The tissue distribution test confirmed that GA-NCs@PL-FA could prolong the retention time of gambogic acid in vivo and promote its enrichment in tumor tissues, with good targeting. Conclusion The formulation and preparation process of GA-NCs@PL-FA were optimized. The system had uniform particle size, good drug loading performance, good sustained release effect and in vitro anti-hepatoma activity, and showed strong tumor tissue enrichment ability. It can provide reference for the development and clinical application of gambogic acid targeted preparations.

gambogic acid  /  folic acid  /  nanocrystals  /  preparation technology  /  in vitro release  /  tissue distribution