Tang Jun, Yang Yimeng, He Zihan, Wang Chuting, Gao Ziwei, Meng Yan, Chen Xinyan, Wang Qi, Zheng Guohua, Hu Junjie, Chang Cong
School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China.
Hubei Shizhen Laboratory, Wuhan, Hubei, 430061, China.
Mater Today Bio. 2025 Feb 27;31:101581. doi: 10.1016/j.mtbio.2025.101581. eCollection 2025 Apr.
Intrahepatic cholangiocarcinoma (ICC) is a rare malignant tumor with limited treatment options. Celastrol (Cela) shows potential treatment for ICC, but its clinical use is hindered by poor water solubility and toxic side effects. To address these challenges and enhance its anti-tumor efficacy, we developed hyaluronic acid (HA)-coated triphenylphosphine complex-modified liposomes (HCTL) for accurate delivery of Cela to tumor cell mitochondria.HCTL enhances Cela's water solubility and demonstrates a high rate of encapsulation, stability, and sustained drug release behavior. Moreover, HCTL exhibits outstanding anti-ICC efficacy by efficiently inducing apoptosis in ICC cells via the mitochondrial pathway due to its precise targeting capabilities. In an in-situ ICC mouse model activated by hydrodynamic transfection of AKT and Yap, HCTL downregulates tumor-associated proliferative indices, attenuates the severity of liver injury and modulates the tumor microenvironment. Importantly, HCTL overcomes systemic toxicity associated with Cela. To sum up, HCTL is a potentially effective drug delivery system for ICC treatment.
肝内胆管癌（ICC）是一种罕见的恶性肿瘤，治疗选择有限。雷公藤红素（Cela）显示出对ICC的潜在治疗作用，但其临床应用因水溶性差和毒副作用而受到阻碍。为应对这些挑战并增强其抗肿瘤疗效，我们开发了透明质酸（HA）包被的三苯基膦络合物修饰脂质体（HCTL），用于将Cela准确递送至肿瘤细胞线粒体。HCTL提高了Cela的水溶性，并表现出高包封率、稳定性和持续释药行为。此外，由于其精确的靶向能力，HCTL通过线粒体途径有效诱导ICC细胞凋亡，展现出出色的抗ICC疗效。在通过水动力转染AKT和Yap激活的原位ICC小鼠模型中，HCTL下调肿瘤相关增殖指数，减轻肝损伤严重程度并调节肿瘤微环境。重要的是，HCTL克服了与Cela相关的全身毒性。综上所述，HCTL是一种用于ICC治疗的潜在有效药物递送系统。
