Surface-Engineered Breviscapine Nanocrystals for Enhanced Oral Absorption and Cardioprotection in Isoprenaline-Induced Myocardial Infarction

Fang Li,1,* Pengfei Yue,1,* Yuling Liu,2,* Liru Chen,3 Wenhui Hu,1 Haibin Zou,1 Quanda Yu,1 Wenli Shi,1 Yingchong Chen11Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang, 330004, People’s Republic of China; 2Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China; 3Department of Clinical Nutrition, Beijing Hospital, National Center for Gerontology, National Clinical Research Center for Gerontology, The Key Laboratory of Geriatrics of NHC, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingchong Chen, Email yc_chen1020@163.comPurpose: 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).Methods: 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.Results: 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 Cmax and AUC0-∞ 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.Conclusion: R8-F127-VES-modified nanocrystals provide a promising strategy for overcoming oral delivery barriers and enhancing the cardioprotective effects of orally administered BRE.Keywords: mucus penetration, BCS Class IV drug, oral absorption, P-glycoprotein inhibition, cardioprotection