Plengsuriyakarn Tullayakorn, Panrit Luxsana, Na-Bangchang Kesara
Center of Excellence in Molecular Biology and Pharmacology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani 12120, Thailand.
Faculty of Allied Health Science, Pathum Thani University, Pathum Thani 12000, Thailand.
Polymers (Basel). 2025 Aug 6;17(15):2151. doi: 10.3390/polym17152151.
Cholangiocarcinoma (CCA) is highly prevalent in the Greater Mekong sub-region, especially northeastern Thailand, where infection with the liver fluke Opisthorchis viverrini is a major etiological factor. Limited therapeutic options and the absence of reliable early diagnosis tools impede effective disease control. (Thunb.) DC.-long used in Thai and East Asian medicine, contains atractylodin (ATD), a potent bioactive compound with anticancer potential. Here, we developed ATD-loaded poly(lactic co-glycolic acid) nanoparticles (ATD PLGA NPs) and evaluated their antitumor efficacy against CCA. The formulated nanoparticles had a mean diameter of 229.8 nm, an encapsulation efficiency of 83%, and exhibited biphasic, sustained release, reaching a cumulative release of 92% within seven days. In vitro, ATD-PLGA NPs selectively reduced the viability of CL-6 and HuCCT-1 CCA cell lines, with selectivity indices (SI) of 3.53 and 2.61, respectively, outperforming free ATD and 5-fluorouracil (5-FU). They suppressed CL-6 cell migration and invasion by up to 90% within 12 h and induced apoptosis in 83% of cells through caspase-3/7 activation. Micronucleus assays showed lower mutagenic potential than the positive control. In vivo, ATD-PLGA NPs dose-dependently inhibited tumor growth and prolonged survival in CCA-xenografted nude mice; the high-dose regimen matched or exceeded the efficacy of 5-FU. Gene expression analysis revealed significant downregulation of pro-tumorigenic factors (VEGF, MMP-9, TGF-β, TNF-α, COX-2, PGE, and IL-6) and upregulation of the anti-inflammatory cytokine IL-10. Collectively, these results indicate that ATD-PLGA NPs are a promising nanotherapeutic platform for targeted CCA treatment, offering improved anticancer potency, selectivity, and safety compared to conventional therapies.
胆管癌（CCA）在大湄公河次区域，尤其是泰国东北部高度流行，在那里感染肝吸虫华支睾吸虫是主要的病因。有限的治疗选择和缺乏可靠的早期诊断工具阻碍了疾病的有效控制。（Thunb.）DC.——长期用于泰国和东亚医学，含有白术内酯（ATD），一种具有抗癌潜力的强效生物活性化合物。在这里，我们开发了负载ATD的聚乳酸-羟基乙酸共聚物纳米颗粒（ATD PLGA NPs），并评估了它们对CCA的抗肿瘤疗效。所制备的纳米颗粒平均直径为229.8 nm，包封率为83%，呈现双相持续释放，在7天内累积释放率达到92%。在体外，ATD-PLGA NPs选择性降低CL-6和HuCCT-1 CCA细胞系的活力，选择性指数（SI）分别为3.53和2.61，优于游离ATD和5-氟尿嘧啶（5-FU）。它们在12小时内将CL-6细胞的迁移和侵袭抑制高达90%，并通过激活caspase-3/7诱导83%的细胞凋亡。微核试验显示其致突变潜力低于阳性对照。在体内，ATD-PLGA NPs在CCA异种移植裸鼠中剂量依赖性地抑制肿瘤生长并延长生存期；高剂量方案与5-FU的疗效相当或超过5-FU。基因表达分析显示促肿瘤因子（VEGF、MMP-9、TGF-β、TNF-α、COX-2、PGE和IL-6）显著下调，抗炎细胞因子IL-10上调。总体而言，这些结果表明，ATD-PLGA NPs是一种有前景的纳米治疗平台，用于靶向治疗CCA，与传统疗法相比，具有更高的抗癌效力、选择性和安全性。
