ABSTRACT
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-ßCD) and tertiary (D-ßCD) amino-modified ß-cyclodextrins (ßCDs) as carriers and solubilizers. ßCDs were chemically modified to prepare the ionizable weak base functional group followed by forming a guest-host complex of CRM in the modified ßCDs hydrophobic cavities via a solvent evaporation encapsulation technique. These complexes were then actively loaded into preformed liposomes, composed of DPPC/cholesterol (65/35 molar ratio) via pH gradient. The formation of CRM-ßCDs 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-ßCDs 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-ßCDs. The apparent formation constants (K f) of 51.6, 100.9 and 55.4 mM-2 were determined for CRM-ßCD, CRM-E-ßCD, and CRM-D-ßCD 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-ßCD complexes into pH gradient preformed liposomes were 16.5, 51.1, and 41.7 for CRM-ßCD, CRM-E-ßCD, and CRM-D-ßCD, 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.
