Rattanaseth Pornpattra, Katewongsa Kanlaya, Intuyod Kitti, Pinlaor Somchai, Thanan Raynoo, Sakonsinsiri Chadamas
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
ACS Appl Bio Mater. 2025 Jun 18. doi: 10.1021/acsabm.5c00628.
Cholangiocarcinoma (CCA), a malignancy of the bile duct epithelium, represents a significant public health issue in the Greater Mekong Subregion, including Thailand. Its aggressive characteristics and late-stage diagnosis lead to poor prognosis and elevated mortality rates. Chemotherapy faces limitations, including the requirement for high and frequent dosages, low cellular uptake, and side effects. To address these challenges, poly(d,l-lactide--glycolide) (PLGA) nanoparticles (NPs) encapsulating doxorubicin (DOX), a chemotherapeutic drug, were developed via a modified nanoprecipitation technique. PLGA was chosen for its biocompatibility and controlled release properties, while the intrinsic fluorescence of DOX allowed cellular uptake monitoring. Among various formulations, Formulation A4 yielded uniform, smooth and spherical NPs with an average diameter of 341 nm, a surface charge of -23 mV, and a suitable encapsulation efficiency. DOX-PLGA NPs were characterized in terms of hydrodynamic diameter (D), morphology, heterogeneity of particle sizes, surface charge and surface functional groups, and encapsulation efficiency (EE). Blank NPs, prepared under identical conditions without DOX, were nonhemolytic and biocompatible. The release profile of the DOX-PLGA NPs showed a biphasic pattern, characterized by both a burst and sustained release, fitting the Korsmeyer-Peppas model. DOX was released more rapidly in an acidic environment compared to physiological pH. DOX-PLGA NPs exhibited greater cytotoxicity relative to free DOX in both KKU-213A and KKU-055 CCA cells, along with increased cellular uptake. In gemcitabine-resistant KKU-213B cells, DOX-PLGA NPs exhibited significantly enhanced cytotoxic effects. The prepared DOX-PLGA NPs demonstrated favorable physicochemical properties, enhanced drug delivery, and improved anticancer activity, highlighting their potential as an efficient DDS for CCA treatment.
胆管癌（CCA）是一种胆管上皮恶性肿瘤，在包括泰国在内的大湄公河次区域是一个重大的公共卫生问题。其侵袭性特征和晚期诊断导致预后不良和死亡率上升。化疗面临诸多限制，包括需要高剂量且频繁给药、细胞摄取率低以及副作用。为应对这些挑战，通过改良的纳米沉淀技术制备了包裹化疗药物阿霉素（DOX）的聚（d，l - 丙交酯 - 乙交酯）（PLGA）纳米颗粒（NPs）。选择PLGA是因其具有生物相容性和控释特性，而DOX的固有荧光可用于监测细胞摄取情况。在各种制剂中，制剂A4产生了均匀、光滑且呈球形的纳米颗粒，平均直径为341 nm，表面电荷为 - 23 mV，且具有合适的包封率。对DOX - PLGA NPs进行了流体动力学直径（D）、形态、粒径异质性、表面电荷和表面官能团以及包封率（EE）等方面的表征。在相同条件下制备的不含DOX的空白纳米颗粒无溶血作用且具有生物相容性。DOX - PLGA NPs的释放曲线呈现双相模式，其特征为突释和缓释，符合Korsmeyer - Peppas模型。与生理pH值相比，DOX在酸性环境中释放得更快。在KKU - 213A和KKU - 055 CCA细胞中，DOX - PLGA NPs相对于游离DOX表现出更大的细胞毒性，同时细胞摄取增加。在吉西他滨耐药的KKU - 213B细胞中，DOX - PLGA NPs表现出显著增强的细胞毒性作用。所制备的DOX - PLGA NPs表现出良好的物理化学性质、增强的药物递送能力和改善的抗癌活性，突出了它们作为一种用于CCA治疗的高效药物递送系统的潜力。
