基于肝素和壳聚糖的氧苯酚酸衍生物自组装聚集体用于乳腺癌治疗
Oleanolic acid derivative self-assembled aggregates based on heparin and chitosan for breast cancer therapy
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影响因子:8.5
分区:生物学2区 Top / 生化与分子生物学2区 应用化学2区 高分子科学2区
发表日期:2024 Oct
作者:
Kun Chen, Xin Zhu, Ruiqin Sun, Lingzhou Zhao, Junwei Zhao, Xiangxiang Wu, Can Wang, Huahui Zeng
DOI:
10.1016/j.ijbiomac.2024.134431
摘要
氧苯酚酸是一种天然产物中的活性成分，具有抗乳腺癌活性。然而，其水溶性差和生物利用度低限制了其临床应用。为改善氧苯酚酸的抗癌活性，我们合成了一种新型氧苯酚酸季铵盐（QDT），通过静电相互作用引入肝素中，并包覆壳聚糖，制备出QDT/肝素/壳聚糖纳米聚集体（QDT/HEP/CS NAs）。QDT/HEP/CS NAs表现出负电荷（-35.01 ± 4.38 mV）、适宜的平均粒径（150.45 ± 0.68 nm）且呈条带状，药物载荷率高（36%）。包覆的壳聚糖在生理条件下对QDT具有良好的防泄漏性能。更重要的是，在肿瘤细胞中的持续释放过程中，QDT能显著降低线粒体膜电位并诱导乳腺癌细胞凋亡。对4T1肿瘤负荷小鼠的体内抗肿瘤研究证实，QDT/HEP/CS NAs通过上调胱天蛋白酶-3、胱天蛋白酶-9和细胞色素C，显著增强抗癌效果，其高积累在肿瘤中归因于增强的渗透和滞留效应。此外，QDT/HEP/CS NAs在体外和体内显著提高了QDT的生物安全性和生物相容性。总之，开发具有高抗肿瘤活性、良好体内分布和生物相容性的QDT/HEP/CS NAs，为改善中药成分的抗癌效果提供了一种安全、简便且有前景的策略。
Abstract
Oleanolic acid is an active ingredient from natural products with anti-breast cancer activity. However, the poor solubility in water and low bioavailability have limited its effectiveness in clinic. To improve the anticancer activity of oleanolic acid, we synthesized a novel oleanolic quaternary ammonium (QDT), which, driven by electrostatic interactions, was introduced into heparin and coated with chitosan to obtain a QDT/heparin/chitosan nanoaggregate (QDT/HEP/CS NAs). QDT/HEP/CS NAs showed the negative zeta potential (-35.01 ± 4.38 mV), suitable mean particle size (150.45 ± 0.68 nm) with strip shape, and high drug loading (36 %). The coated chitosan had strong anti-leakage characteristics toward QDT under physiological conditions. More importantly, upon sustained release in tumor cells, QDT could significantly decrease the mitochondrial membrane potential and induce apoptosis of breast cancer cells. Further in vivo antitumor study on 4 T1 tumor-bearing mice confirmed the enhanced anticancer efficacy of QDT/HEP/CS NAs via upregulation of caspase-3, caspase-9 and cytochrome C, which was attributed to the high accumulation in tumor via the enhanced permeability and retention effect. Moreover, QDT/HEP/CS NAs significantly enhanced the biosafety and biocompatibility of QDT in vitro and in vivo. Collectively, the development of QDT/HEP/CS NAs with high antitumor activity, favorable biodistribution and good biocompatibility provided a safe, facile and promising strategy to improve the anti-cancer effect of traditional Chinese medicine ingredients.