Kwak Kijung, Yu Bo, Mouli Samdeep K, Larson Andrew C, Kim Dong-Hyun
Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.
J Vasc Interv Radiol. 2020 Oct;31(10):1697-1705.e3. doi: 10.1016/j.jvir.2020.01.026. Epub 2020 Aug 6.
To develop bile acid-stabilized multimodal magnetic resonance (MR) imaging and computed tomography (CT)-visible doxorubicin eluting lipiodol emulsion for transarterial chemoembolization of hepatocellular carcinoma (HCC).
Ferumoxytol, a US Food and Drug Administration-approved iron oxide nanoparticle visible under MR imaging was electrostatically complexed with doxorubicin (DOX). An amphiphilic bile acid, sodium cholate (SC), was used to form a stable dispersion of ferumoxytol-DOX complex in lipiodol emulsion. Properties of the fabricated emulsion were characterized in various component ratios. Release kinetics of DOX were evaluated for the chemoembolization applications. Finally, in vivo multimodal MR imaging/CT imaging properties and potential therapeutic effects upon intra-arterial (IA) infusion bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion were evaluated in orthotopic McA-Rh7777 HCC rat models.
DOX complexed with ferumoxytol through electrostatic interaction. Amphiphilic SC bile acid at the interface between the aqueous ferumoxytol-DOX complexes and lipiodol enabled a sustained DOX release (17.2 ± 1.6% at 24 hours) at an optimized component ratio. In McA Rh7777 rat HCC model, IA-infused emulsion showed a significant contrast around tumor in both T2-weighted MR imaging and CT images (P = .044). Hematoxylin and eosin and Prussian blue staining confirmed the local deposition of IA-infused SC bile acid-stabilized emulsion in the tumor. The deposited emulsion induced significant increases in TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) stain-positive cancer cell apoptosis compared to those in a group treated with the nonstabilized emulsion.
SC bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion demonstrated sustained drug release and multimodal MR imaging/CT imaging capabilities. The new lipiodol-based formulation may enhance the therapeutic efficacy of chemoembolization in HCC.
研发用于肝细胞癌（HCC）经动脉化疗栓塞的胆汁酸稳定的多模态磁共振（MR）成像及计算机断层扫描（CT）可见的阿霉素洗脱碘油乳剂。
将美国食品药品监督管理局批准的在MR成像下可见的氧化铁纳米颗粒——多聚麦芽糖铁，与阿霉素（DOX）进行静电复合。使用两亲性胆汁酸胆酸钠（SC）在碘油乳剂中形成多聚麦芽糖铁-DOX复合物的稳定分散体。在不同的组分比例下对制备的乳剂的性质进行表征。评估DOX在化疗栓塞应用中的释放动力学。最后，在原位McA-Rh7777 HCC大鼠模型中评估经动脉（IA）注入胆汁酸稳定的多聚麦芽糖铁-DOX-碘油乳剂的体内多模态MR成像/CT成像特性及潜在治疗效果。
DOX通过静电相互作用与多聚麦芽糖铁复合。在水相多聚麦芽糖铁-DOX复合物与碘油之间的界面处的两亲性SC胆汁酸，在优化的组分比例下实现了DOX的持续释放（24小时时为17.2±1.6%）。在McA Rh7777大鼠HCC模型中，IA注入的乳剂在T2加权MR成像和CT图像中均显示肿瘤周围有明显的对比（P = 0.044）。苏木精-伊红染色和普鲁士蓝染色证实IA注入的SC胆汁酸稳定的乳剂在肿瘤中的局部沉积。与用未稳定化乳剂治疗的组相比，沉积的乳剂使TUNEL（末端脱氧核苷酸转移酶dUTP缺口末端标记）染色阳性的癌细胞凋亡显著增加。
SC胆汁酸稳定的多聚麦芽糖铁-DOX-碘油乳剂具有持续的药物释放及多模态MR成像/CT成像能力。这种基于碘油的新制剂可能会提高HCC化疗栓塞的治疗效果。
