Cationic lipids bearing succinic-based, acyclic and macrocyclic hydrophobic domains: Synthetic studies and in vitro gene transfer
| Autor: | Emile Jubeli, Nada Abdul Khalique, William P. D. Goldring, David G. Nicholson, Amanda B. Maginty, Helge B. Larsen, Michael D. Pungente, Liji Raju |
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| Rok vydání: | 2016 |
| Předmět: |
Macrocyclic Compounds
Stereochemistry Trimethylamine CHO Cells Gene delivery 010402 general chemistry Transfection 01 natural sciences chemistry.chemical_compound Plasmid Cricetulus Cations Cricetinae Drug Discovery Animals Dimethylamine Pharmacology Gel electrophoresis 010405 organic chemistry Chemistry Organic Chemistry Cationic polymerization Gene Transfer Techniques Succinates General Medicine DNA Lipids In vitro 0104 chemical sciences Biophysics lipids (amino acids peptides and proteins) Hydrocarbons Acyclic Hydrophobic and Hydrophilic Interactions Plasmids |
| Zdroj: | European journal of medicinal chemistry. 125 |
| ISSN: | 1768-3254 |
| Popis: | In this communication we describe the construction of four succinic-based cationic lipids, their formulation with plasmid DNA (pDNA), and an evaluation of their in vitro gene delivery into Chinese hamster ovarian (CHO-K1) cells. The cationic lipids employed in this work possess either a dimethylamine or trimethylamine headgroup, and a macrocyclic or an acyclic hydrophobic domain composed of, or derived from two 16-atom, succinic-based acyl chains. The synthesized lipids and a co-lipid of neutral charge, either cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), were formulated in an overall 3:2 cationic-to-neutral lipid molar ratio, then complexed with plasmid DNA (pDNA). The relative transfection performance was evaluated via a comparison between matched versus mismatched formulations defined by the rigidity relationship between the lipids employed. Gel electrophoresis was used to characterize the binding of the lipid formulations with plasmid DNA and the relative degree of plasmid degradation using a DNase I degradation assay. Small angle X-ray diffraction (SAXD) was employed to characterize the packing morphology of the lipid-DNA complexes. In general, the succinic unit embedded within the hydrophobic domain of the cationic lipids was found to improve lipid hydration. The transfection assays revealed a general trend in which mismatched formulations that employed a rigid lipid combined with a non-rigid (or flexible) lipid, outperformed the matched formulations. The results from this work suggest that the design of the cationic lipid structure and the composition of the lipoplex formulation play key roles in governing the transfection performance of nonviral gene delivery agents. |
| Databáze: | OpenAIRE |
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