A new liposomal formulation for antisense oligodeoxynucleotides with small size, high incorporation efficiency and good stability

Antisense oligodeoxynucleotides (asODN) are therapeutic agents that are designed to inhibit the expression of disease-related genes. However, their therapeutic use may be hindered due to their rapid clearance from blood and their inefficiency at crossing cell membranes. Cationic liposome complexes have been used to enhance the intracellular delivery of asODN in vitro; however, this type of carrier has unfavorable pharmacokinetics for most in vivo applications. Significant therapeutic activity of cationic liposomal asODN following systemic administration has not been demonstrated. In an effort to develop improved liposomal carriers for asODN for in vivo applications, we have evaluated the physical characteristics of two formulations which represent alternatives to cationic liposome-asODN complexes: asODN passively entrapped within neutral liposomes (PELA) and asODN formulated in a novel coated cationic liposomal formulation (CCL). Our results confirm that PELA can be extruded to small diameters that are suitable for intravenous administration. PELA are stable in human plasma; however, the incorporation efficiency is relatively low (similar to 20%). The CCL formulation can also be extruded to small diameters (< 200 nm), with significantly higher (80-100%) incorporation efficiency and are stable in 50% human plasma at 37 degrees C. A liposomal carrier for asODN with these characteristics may provide a significant therapeutic advantage over free asODN for some therapeutic applications. (C) 2000 Elsevier Science B.V. All rights reserved.