Han Yang, Fan Junyong, Xia Wei, Dong Xiao, Ye Ying
Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China; Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai, 201203, People's Republic of China.
Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China; Department of Nuclear Medicine, Pudong New Area Gongli Hospital, 219 Miaopu Road, Pudong, Shanghai, 200135, People's Republic of China.
Biochem Biophys Res Commun. 2025 Aug 8;774:152049. doi: 10.1016/j.bbrc.2025.152049. Epub 2025 May 19.
Primary liver cancer remains a major contributor to global cancer-related mortality. Echinacoside, a bioactive phenylethanoid glycoside isolated from traditional Chinese medicinal herbs, has shown potent anti-tumor effects. In this study, poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating echinacoside (E@PLGA and E@PLGA-FA) were synthesized via the double emulsification method. Their physicochemical properties, drug release kinetics, and anti-cancer efficacy were systematically evaluated through in vitro and in vivo models. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analyses revealed that the particle sizes of E@PLGA and E@PLGA-FA were approximately 91 nm and 100 nm, respectively, with zeta potentials of -22.50 mV and -31.89 mV. The polydispersity index (PDI) of E@PLGA and E@PLGA-FA was determined to be 0.16 ± 0.01 and 0.19 ± 0.01, respectively. The encapsulation efficiency and drug-loading capacity of echinacoside in E@PLGA-FA were 28.78 % and 12.05 %, respectively, slightly lower than those in E@PLGA nanoparticles (40.34 % and 16.12 %), likely due to folic acid modification altering PLGA solubility during formulation. In vitro release profiles demonstrated pH-dependent drug release: 22 % at physiological pH (7.4) versus 67 % under acidic conditions (pH 5.5) over 12 h, indicating tumor microenvironment-responsive behavior. Furthermore, E@PLGA-FA significantly inhibited the proliferation of HepG2 cells, induced apoptosis, caused cell cycle arrest at the G0/G1 phase, and suppressed cell mobility. Meanwhile, the protein levels of MMP2, MMP9 and Bax were increased after exposure to E@PLGA and E@PLGA-FA, whereas the protein levels of COL-Ⅰ, COL-Ⅱ, Bcl-2, Cyclin D1, and PCNA were decreased. In vivo, E@PLGA-FA effectively inhibited tumor growth, induced tumor cell apoptosis, and exhibited tumor-specific accumulation confirmed by fluorescence imaging. In addition, The E@PLGA-FA nanoparticle intervention did not induce pathological damage or inflammatory responses in murine liver and kidney tissues, suggesting a favorable safety profile for this compound. In conclusion, we engineered a novel tumor-targeted PLGA-based nanoparticle system for echinacoside delivery, which synergizes pH-responsive drug release, multi-mechanistic anti-cancer effects, and biosafety, offering a promising therapeutic platform for hepatocellular carcinoma.
原发性肝癌仍然是全球癌症相关死亡的主要原因。紫锥菊苷是一种从传统中草药中分离出的具有生物活性的苯乙醇苷，已显示出强大的抗肿瘤作用。在本研究中，通过双乳化法合成了包裹紫锥菊苷的聚乳酸-乙醇酸共聚物（PLGA）纳米粒（E@PLGA和E@PLGA-FA）。通过体外和体内模型系统地评估了它们的物理化学性质、药物释放动力学和抗癌效果。透射电子显微镜（TEM）和动态光散射（DLS）分析表明，E@PLGA和E@PLGA-FA的粒径分别约为91nm和100nm，zeta电位分别为-22.50mV和-31.89mV。E@PLGA和E@PLGA-FA的多分散指数（PDI）分别确定为0.16±0.01和0.19±0.01。紫锥菊苷在E@PLGA-FA中的包封率和载药量分别为28.78%和12.05%，略低于E@PLGA纳米粒（40.34%和16.12%），这可能是由于叶酸修饰在制剂过程中改变了PLGA的溶解度。体外释放曲线表明药物释放具有pH依赖性：在生理pH（7.4）下12小时释放22%，而在酸性条件（pH 5.5）下释放67%，表明具有肿瘤微环境响应行为。此外，E@PLGA-FA显著抑制HepG2细胞的增殖，诱导细胞凋亡，使细胞周期停滞在G0/G1期，并抑制细胞迁移。同时，暴露于E@PLGA和E@PLGA-FA后，MMP2、MMP9和Bax的蛋白水平升高，而COL-Ⅰ、COL-Ⅱ、Bcl-2、Cyclin D1和PCNA的蛋白水平降低。在体内，E@PLGA-FA有效抑制肿瘤生长，诱导肿瘤细胞凋亡，并通过荧光成像证实具有肿瘤特异性蓄积。此外，E@PLGA-FA纳米粒干预未在小鼠肝脏和肾脏组织中诱导病理损伤或炎症反应，表明该化合物具有良好的安全性。总之，我们构建了一种新型的基于PLGA的肿瘤靶向纳米粒系统用于紫锥菊苷的递送，该系统协同了pH响应性药物释放、多机制抗癌作用和生物安全性，为肝细胞癌提供了一个有前景的治疗平台。
