菲色丁（FIS）是一种多功能生物活性类黄酮，最近被用作抗癌药物对抗包括乳腺癌在内的各种癌症。然而，其差的水溶性限制了其临床应用。在当前的工作中，首次使用大豆磷脂酰胆碱与胆固醇一起复杂化菲色丁，形成了一种新型生物相容性植物体系，称为“胆色草”。为了提高菲色丁对乳腺癌的抗肿瘤活性，制备了带有阳离子胆色草（mPHY）的硬脂酰胺，并进一步用透明质酸（HPHY）进行修饰，使其通过表面暴露的磷脂酰丝氨酸和CD-44受体定向至癌细胞。体外表征研究揭示了两种修饰的囊泡（mPHY和HPHY）的有希望的理化性质，包括优良的菲色丁络合效率（˷100%），改善的正辛醇/水溶解度以及持续的24小时内药物释放。对MDA-MB-231细胞系的体外细胞线研究显示，与自由药物和传统药物-磷脂负载体系相比，修饰的囊泡的IC50抑制率分别提高了10倍和3.5倍。临床前研究表明，两种修饰的胆色草（mPHY和HPHY）的细胞毒性相当，并且显著超过了自由药物的细胞毒性。转化生长因子-β1及其非经典相关信号通路ERK1/2、NF-κB和MMP-9参与了阻止肿瘤发生。因此，为菲色丁量身定制新型植物体纳米系统可能会打开其对抗癌症的临床应用机会。©2023年。作者。

Fisetin (FIS) is a multifunctional bioactive flavanol that has been recently exploited as anticancer drug against various cancers including breast cancer. However, its poor aqueous solubility has constrained its clinical application. In the current work, fisetin is complexed for the first time with soy phosphatidylcholine in the presence of cholesterol to form a novel biocompatible phytosomal system entitled "cholephytosomes." To improve fisetin antitumor activity against breast cancer, stearylamine bearing cationic cholephytosomes (mPHY) were prepared and furtherly modified with hyaluronic acid (HPHY) to allow their orientation to cancer cells through their surface exposed phosphatidylserine and CD-44 receptors, respectively. In vitro characterization studies revealed promising physicochemical properties of both modified vesicles (mPHY and HPHY) including excellent FIS complexation efficiency (˷100%), improved octanol/water solubility along with a sustained drug release over 24 h. In vitro cell line studies against MDA-MB-231 cell line showed about 10- and 3.5-fold inhibition in IC50 of modified vesicles compared with free drug and conventional drug-phospholipid complex, respectively. Preclinical studies revealed that both modified cholephytosomes (mPHY and HPHY) had comparable cytotoxicity that is significantly surpassing free drug cytotoxicity. TGF-β1and its non-canonical related signaling pathway; ERK1/2, NF-κB, and MMP-9 were involved in halting tumorigenesis. Thus, tailoring novel phytosomal nanosystems for FIS could open opportunity for its clinical utility against cancer.© 2023. The Author(s).