Odeh Fadwa, Nsairat Hamdi, Alshaer Walhan, Alsotari Shrouq, Buqaien Rula, Ismail Said, Awidi Abdalla, Al Bawab Abeer
Department of Chemistry, The University of Jordan Amman 11942 Jordan
Cell Therapy Center, The University of Jordan Amman 11942 Jordan
RSC Adv. 2019 Nov 13;9(64):37148-37161. doi: 10.1039/c9ra07560g.
Curcumin (CRM) is a natural polyphenol with antioxidative, anti-inflammatory, and anticancer therapeutic properties. However, CRM therapeutic potential is limited by low water solubility and bioavailability. Intraliposomal remote loading describes the retention of drugs in liposome cores in response to transmembrane pH gradient. The current study describes for the first time the remote loading of CRM into liposomes using secondary (E-βCD) and tertiary (D-βCD) amino-modified β-cyclodextrins (βCDs) as carriers and solubilizers. βCDs were chemically modified to prepare the ionizable weak base functional group followed by forming a guest-host complex of CRM in the modified βCDs hydrophobic cavities a solvent evaporation encapsulation technique. These complexes were then actively loaded into preformed liposomes, composed of DPPC/cholesterol (65/35 molar ratio) pH gradient. The formation of CRM-βCDs inclusion complexes was characterized using UV-Vis spectroscopy, thermal analysis, and NMR spectroscopy. The complex stoichiometric ratio was determined to be 1 : 1 of CRM-βCDs based on Job's plot which was also confirmed by the modified Benesi-Hildebrand equation with increasing probability of forming the 1 : 2 ratio of CRM-βCDs. The apparent formation constants ( ) of 51.6, 100.9 and 55.4 mM were determined for CRM-βCD, CRM-E-βCD, and CRM-D-βCD complexes, respectively. Liposome size, charge and polydispersity index indicate the presence of a homogeneous population before and after active loading. The encapsulation efficiencies of CRM-βCD complexes into pH gradient preformed liposomes were 16.5, 51.1, and 41.7 for CRM-βCD, CRM-E-βCD, and CRM-D-βCD, respectively, showing more than 5 fold increase compared to normal liposomes. The current study provides a novel remote loading approach utilizing chemically modified cyclodextrins to incorporate hydrophobic drugs into liposomes.
姜黄素（CRM）是一种具有抗氧化、抗炎和抗癌治疗特性的天然多酚。然而，CRM的治疗潜力受到低水溶性和生物利用度的限制。脂质体内远程加载描述了药物响应跨膜pH梯度而保留在脂质体核心中。本研究首次描述了使用仲（E-βCD）和叔（D-βCD）氨基修饰的β-环糊精（βCDs）作为载体和增溶剂将CRM远程加载到脂质体中。对βCDs进行化学修饰以制备可电离的弱碱官能团，然后在修饰的βCDs疏水腔内形成CRM的客体-主体复合物，采用溶剂蒸发包封技术。然后将这些复合物主动加载到由DPPC/胆固醇（摩尔比65/35）组成的预制脂质体中，并利用pH梯度。使用紫外-可见光谱、热分析和核磁共振光谱对CRM-βCDs包合物的形成进行了表征。基于乔布图确定CRM-βCDs的络合化学计量比为1∶1，修正的贝内西-希尔德布兰德方程也证实了这一点，同时形成1∶2比例的CRM-βCDs的可能性增加。分别测定了CRM-βCD、CRM-E-βCD和CRM-D-βCD复合物的表观形成常数（）为51.6、100.9和55.4 mM。脂质体大小、电荷和多分散指数表明主动加载前后存在均匀群体。CRM-βCD复合物在pH梯度预制脂质体中的包封效率分别为CRM-βCD的16.5%、CRM-E-βCD的51.1%和CRM-D-βCD的41.7%，与正常脂质体相比增加了5倍以上。本研究提供了一种利用化学修饰环糊精将疏水药物掺入脂质体的新型远程加载方法。
