Redox-Based Control of DNA Delivery Using Ferrocene-Containing Cationic Lipids

Cationic lipids have been investigated widely as agents for the delivery of DNA because they interact spontaneously with DNA to form lipid/DNA assemblies (called ‘lipoplexes’) with sizes, charges, and other properties that promote the internalization and processing of DNA by cells. In collaboration with colleagues at UW, we have developed and demonstrated new principles for active and addressable control over the structures and functional properties of lipoplexes (and the subsequent transfection of cells) using a model ferrocene-containing cationic lipid (BFDMA) that can be cycled reversibly between oxidized and reduced states by the chemical or electrochemical oxidation/reduction of ferrocene groups present in the tails of the lipid. We have demonstrated that changes in the oxidation state of BFDMA result in large differences in both (i) the physical properties of lipoplexes (e.g., lamellar v. amorphous nanostructures, differences in surface charge, etc.) and (ii) levels of in vitro gene expression when these lipoplexes are administered to cells. For example, lipoplexes formed using reduced BFDMA generally promote high levels of gene expression, whereas lipoplexes formed using oxidized BFDMA generally yield very low (background) levels of cell transfection.

Our results provide the basis of approaches that can be used to transform inactive lipoplexes to an active form ‘on-demand’ by contact with chemical reducing agents or by the application of externally applied electrochemical potentials. Ongoing work in our laboratory is focused on leveraging this basis for active control to develop new approaches to exert spatial and temporal control over the delivery to cells in vitro. Our recent discovery of mixed-lipid lipoplexes that are stable and active in culture environments containing high levels of serum (formed by combining redox-active BFDMA with other conventional lipid structures) provides new opportunities to investigate the potential of this redox-based approach to provide active control over the delivery of DNA to cells and tissues in vivo.

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