Aspects of nonviral gene therapy: Correlation of molecular parameters with lipoplex structure and transfection efficacy in pyridinium-based cationic lipids

作者：Parvizi Paria; Jubeli Emile; Raju Liji; Khalique Nada Abdul; Almeer Ahmed; Allam Hebatalla; Al Manaa Maryem; Larsen Helge; Nicholson David; Pungente Michael D^*; Fyles Thomas M

来源：International Journal of Pharmaceutics, 2014, 461(1-2): 145-156.

DOI：10.1016/j.ijpharm.2013.11.045

• Cationic lipids
• Pyridinium-based lipids
• Shape parameter
• SAXS
• Lipoplex formulation
• DNA transfer
• Gene therapy

This study seeks correlations between the molecular structures of cationic and neutral lipids, the lipid phase behavior of the mixed-lipid lipoplexes they form with plasmid DNA, and the transfection efficacy of the lipoplexes. Synthetic cationic pyridinium lipids were co-formulated (1:1) with the cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC), and these lipids were co-formulated (3:2) with the neutral lipids 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) or cholesterol. All lipoplex formulations exhibited plasmid DNA binding and a level of protection from DNase I degradation. Composition-dependent transfection (beta-galactosidase and GFP) and cytotoxicity was observed in Chinese hamster ovarian-Kl cells. The most active formulations containing the pyridinium lipids were less cytotoxic but of comparable activity to a Lipofectamine 2QQQTM control. Molecular structure parameters and partition coefficients were calculated for all lipids using fragment additive methods. The derived shape parameter values correctly correlated with observed hexagonal lipid phase behavior of lipoplexes as derived from small-angle X-ray scattering experiments. A transfection index applicable to hexagonal phase lipoplexes derived from calculated parameters of the lipid mixture (partition coefficient, shape parameter, lipoplex packing) produced a direct correlation with transfection efficiency. 2013 Elsevier B.V.

• 出版日期2014-1-30