PO.ET02.08 · 实验与分子治疗
用于乳腺癌精准联合化疗的模块化脂质基口服药物递送系统
A modular lipid-based oral drug delivery system for precision combination chemotherapy in breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌是美国女性癌症相关死亡的第三大原因。治疗选择通常包括化疗，其涉及使用高效但有毒的药物，这些药物可引起严重的不良反应，进一步恶化患者病情，在某些情况下导致致命结局。此外，化疗药物的口服递送受到生物利用度差的限制，这源于胃肠道恶劣的酸性和酶环境、低口服吸收以及广泛的肝首过代谢，这些因素导致了与常规化疗相关的显著毒性并降低了治疗效率。本研究旨在开发和评估一种甘露糖胺修饰的冷冻干燥自乳化药物递送系统（SEDDS），能够共同递送化疗药物以增强口服吸收并改善乳腺癌治疗的靶向递送。
方法：使用不同比例的Labrasol、Capryol 90、Labrafac PG和Gellucire 44/14优化并制备了四种SEDDS制剂。将含有多柔比星（doxorubicin）和鸭脚木碱（ellipticine）的初级油包水乳液在被动混合下分散到含甘露糖胺的外部水相中，形成水包油包水双乳液。随后将制剂冷冻干燥以得到固体、可分散的SEDDS。对制剂的粒径、多分散指数、稳定性和形态（SEM）进行了表征。还评估了热行为（DSC、XRD）、药物释放曲线（体外溶出）、渗透性（MDCK细胞系）和细胞摄取（MDA-MB-231和MDA-MB-468细胞系）。
结果：优化的表面活性剂-油比例（1:9和2:8的水相:油相比例）产生了适用于SEDDS开发的稳定初级乳液和双乳液。显微镜确认了三相w/o/w结构，内部水滴被包裹在脂质相内并被外部水相包围。SEDDS表现出190-587 nm的粒径和0.005-0.336的PDI值。冷冻干燥SEDDS的热分析表明形成了具有缓释动力学的无定形混合物。荧光成像显示了双药物负载制剂的高效细胞摄取。
结论：成功开发了一种甘露糖胺修饰的SEDDS，实现了多柔比星和鸭脚木碱的双重负载，具有良好的稳定性、缓释性和高效细胞摄取。这项工作展示了这一脂质基、模块化口服递送平台在实现具有改善的生物利用度和降低毒性的单药及联合化疗方面的潜力。通过将创新的制剂科学与靶向药物递送相结合，这项工作为设计安全有效的癌症治疗方案的更广泛努力做出了贡献。
查看英文原文 English abstract
Breast cancer is the third leading cause of cancer-related deaths among women in the United States. Treatment options often include chemotherapy, which involves the use of highly potent but toxic medications that can cause severe adverse reactions, further worsening the patient's condition and, in some cases, leading to fatal outcomes. Additionally, oral delivery of chemotherapeutic agents is limited by poor bioavailability, arising from the harsh acidic and enzymatic environment of the gastrointestinal tract, low oral absorption, and extensive hepatic first pass metabolism, which contribute to the significant toxicity and reduce therapeutic efficiency associated with conventional chemotherapies. This study aimed to develop and evaluate a mannosamine modified, freeze-dried self-emulsifying drug delivery system (SEDDS) capable of co-delivering chemotherapeutic agents to enhance oral absorption and improve targeted delivery for breast cancer treatment
Methods: Four SEDDS formulations were optimized and prepared using varying ratios of Labrasol, Capryol 90, Labrafac PG, and Gellucire 44/14. Primary water-in-oil emulsions containing doxorubicin and ellipticine were dispersed into an external aqueous phase containing mannosamine to form water-in-oil-in-water double emulsions under passive mixing. Formulations were subsequently freeze dried to yield solid, dispersible SEDDS. The formulations were characterized for particle size, polydispersity index, stability, and morphology (SEM). Thermal behavior (DSC, XRD), drug release profile (In vitro Dissolution), permeation (MDCK cell line), and cellular uptake (MDA MB-231 and MDA MB-468 cell lines) were also assessed.
Results: Optimized surfactant-to-oil ratios (1:9 and 2:8 aqueous: oil phase ratios) produced stable primary and double emulsions suitable for SEDDS development. Microscopy confirmed triphasic w/o/w structures with internal aqueous droplets encapsulated within a lipid phase and surrounded by an external aqueous phase. SEDDS demonstrated particle sizes between 190-587 nm and PDI values of 0.005-0.336. Thermal analyses of freeze dried SEDDS indicated the formation of amorphous mixtures with sustained release kinetics. Fluorescence imaging showed efficient cellular uptake of the dual drug loaded formulations.
Conclusion: A mannosamine modified SEDDS was successfully developed, enabling dual loading of doxorubicin and ellipticine with favorable stability, sustained release, and efficient cellular uptake. This work demonstrates the potential of this lipid-based, modular oral delivery platform to enable mono and combination chemotherapy with improved bioavailability and reduced toxicity. By integrating innovative formulation science with targeted drug delivery, this work contributes to broader efforts at designing safe and effective treatments for cancer.
利益披露 Disclosure
S. Soni, None..
T. Andey, None.