Surface-Engineered Breviscapine Nanocrystals for Enhanced Oral Absorption and Cardioprotection in...

Breviscapine (BRE) possesses excellent cardioprotective efficacy against myocardial infarction (MI). However, its oral application is severely hindered by BCS Class IV properties, including poor solubility and permeability, accompanied by P-glycoprotein (P-gp)-mediated drug efflux and gastrointestinal absorption barriers. Arginine-rich CPPs such as R8 can promote cellular uptake, whereas cationic surface characteristics may restrict particle mobility in gastrointestinal mucus. Conversely, hydrophilic and electro-neutral surfaces favor mucus penetration but may reduce epithelial uptake. This imposes challenges for balancing these two absorption barriers. To solve these problems, we developed surface-engineered nanocrystals with sequential barrier-crossing capability (R8-F127-VES@BRE-NCs).

We engineered multifunctional nanocrystals (R8-F127-VES@BRE-NCs) featuring a sequential barrier-crossing design: nanocrystal technology increases saturation solubility, Pluronic F127 imparts mucus-penetrating capability, R8 peptide facilitates epithelial internalization, and Vitamin E Succinate (VES) may contribute to efflux modulation.

Comprehensive characterization and in vitro studies suggested that this integrated design helped address the trade-off between mucus diffusion and epithelial uptake. Pharmacokinetic studies revealed a marked enhancement in oral BRE absorption, with C_max and AUC_0-∞ increased to 185.76 ng/mL and 1418.34 ng·mL^-1·h (4.27- and 7.37-fold over BRE-raw). Following establishment of the isoprenaline-induced myocardial injury model, 14-day oral treatment with R8-F127-VES@BRE-NCs showed enhanced cardioprotective effects, as evidenced by reduced infarct size and improved oxidative stress-related biochemical indicators.

R8-F127-VES-modified nanocrystals provide a promising strategy for overcoming oral delivery barriers and enhancing the cardioprotective effects of orally administered BRE.