Liposome-encapsulated EF24-HPβCD inclusion complex: a preformulation study and biodistribution in a rat model

Authors: Agashe, H.1; Lagisetty, P.1; Sahoo, K.1; Bourne, D.1; Grady, B.2; Awasthi, V.3

Source: Journal of Nanoparticle Research, Volume 13, Number 6, June 2011 , pp. 2609-2623(15)

Publisher: Springer

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3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24) is an anti-proliferative diphenyldifluoroketone analog of curcumin with more potent activity. The authors describe a liposome preparation of EF24 using a “drug-in-CD-in liposome” approach. An aqueous solution of EF24 and hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex (IC) was used to prepare EF24 liposomes. The liposome size was reduced by a combination of multiple freeze–thaw cycles. Co-encapsulation of glutathione inside the liposomes conferred them with the capability of labeling with imageable radionuclide Tc-99m. Phase solubility analysis of EF24-HPβCD mixture provided k 1:1 value of 9.9 M−1. The enhanced aqueous solubility of EF24 (from 1.64 to 13.8 mg/mL) due to the presence of HPβCD helped in the liposome preparation. About 19% of the EF24 IC was encapsulated inside the liposomes (320.5 ± 2.6 nm) by dehydration–rehydration technique. With extrusion technique, the size of 177 ± 6.5 nm was obtained without any effect on encapsulation efficiency. The EF24-liposomes were evaluated for anti-proliferative activity in lung adenocarcinoma H441 and prostate cancer PC-3 cells. The EF24-liposomes demonstrated anti-proliferative activity superior to that of plain EF24 at 10 μM dose. When injected in rats, the Tc-99m-labeled EF24-liposomes cleared from blood with an α-t 1/2 of 21.4 min and β-t 1/2 of 397 min. Tissue radioactivity counting upon necropsy showed that the majority of clearance was due to the uptake in liver and spleen. The results suggest that using “drug-in-CD-in liposome” approach is a feasible strategy to formulate an effective parenteral preparation of EF24. In vitro studies show that the liposomal EF24 remains anti-proliferative, while presenting an opportunity to image its biodistribution.

Keywords: Curcumin; EF24; Hydroxypropyl-β-cyclodextrin; Inclusion complex; Liposomes; Nanomedicine

Document Type: Research Article


Affiliations: 1: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, 1110 N. Stonewall Avenue, Oklahoma City, OK, 73117, USA 2: School of Chemical, Biological and Materials Engineering, 100 East Boyd, Norman, OK, 73019, USA 3: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, 1110 N. Stonewall Avenue, Oklahoma City, OK, 73117, USA, Email:

Publication date: June 1, 2011

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