Shanghai Key Laboratory of Functional Materials Chemistry, State Key Laboratory of Bioreactor Engineering and Institute of Applied Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, PR China.
Institut Galien Paris-Sud, CNRS UMR 8612, Univ. Paris-Sud, Université Paris-Saclay, LabEx LERMIT, F-92296, Châtenay-Malabry cedex, France.
Colloids Surf B Biointerfaces. 2019 Jan 1;173:217-225. doi: 10.1016/j.colsurfb.2018.09.023. Epub 2018 Sep 11.
In this work, we used the small angle X-ray scattering (SAXS) method for controlled preparation of in situ forming sustained-release carriers for the antitumor drug bufalin (BUF), which has very poor solubility and a considerable cardiotoxicity in a non-encapsulated state. To that aim, we exploited the pseudo-ternary phase diagram of an oil(O)/surfactant(S)/water(W) system containing medium chain capric/caprylic triglycerides (MCT) and a co-surfactant blend of Macrogol (15)-hydroxystearate (Solutol HS 15) and sorbitan monooleate (Span 80). Two compositions with different oil contents (sample B and C) were selected from the microemulsion region of the phase diagram in order to study the effect of the aqueous environment on their structural behavior. A phase transition from a microemulsion (ME) to a liquid crystalline phase (LC) was established by SAXS upon progressive dilution. The drug bufalin (BUF) was encapsulated in the microemulsions with low viscosity, whereas the release of the drug occurred from the in situ generated lamellar liquid crystalline structures. The formulations were characterized by SAXS, dynamic light scattering (DLS), cryogenic transmission electron microscopy (Cryo-TEM), rheology, drug loading and encapsulation efficiency, and in vitro release profiles. A correlation was suggested between the structures of the in situ phase-transition formed LCME formulations, the differences in their viscosities and drug release profiles. The performed cytotoxicity, cell apoptosis and pharmacokinetic experiments showed an enhanced bioavailability of BUF after encapsulation. These results suggest potential clinical applications for the obtained safe in situ phase-transition sustained-release formulations of BUF.
在这项工作中，我们使用小角 X 射线散射（SAXS）方法来控制抗癌药物蟾毒灵（BUF）的原位形成缓释载体的制备，BUF 在未封装状态下溶解度很差，而且具有相当大的心脏毒性。为此，我们利用含有中链甘油三酸酯（MCT）的油（O）/表面活性剂（S）/水（W）体系的伪三元相图和聚乙二醇（15）-羟基硬脂酸酯（Solutol HS 15）和山梨坦单油酸酯（Span 80）的共表面活性剂混合物来开发。从相图的微乳液区域选择了两种具有不同油含量的组合物（样品 B 和 C），以研究水相环境对其结构行为的影响。通过 SAXS 逐渐稀释，从微乳液（ME）到液晶相（LC）的相转变得以建立。蟾毒灵（BUF）被包裹在低粘度的微乳液中，而药物则从原位生成的层状液晶结构中释放出来。通过 SAXS、动态光散射（DLS）、低温透射电子显微镜（Cryo-TEM）、流变学、药物负载和包封效率以及体外释放曲线对制剂进行了表征。建议在原位相转变形成的 LCME 制剂的结构、它们的粘度差异和药物释放曲线之间建立相关性。进行的细胞毒性、细胞凋亡和药代动力学实验表明，BUF 封装后生物利用度提高。这些结果表明，所获得的 BUF 安全原位相转变缓释制剂具有潜在的临床应用前景。
