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 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-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 (K _f) of 51.6, 100.9 and 55.4 mM^-2 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.

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