(584ap) Aliphatic Lipid Substitution On Aminoglycoside-Based Polymers: Plasmid Delivery and Transgene Expression | AIChE

(584ap) Aliphatic Lipid Substitution On Aminoglycoside-Based Polymers: Plasmid Delivery and Transgene Expression

Authors 

Pushpavanam, K. S. - Presenter, Arizona State University
Miryala, B., Arizona State University
Potta, T., Marlyn Nutraceuticals
Rege*, K., Arizona State University
Tian, Y., Arizona State University



Cationic polymers are attractive candidates for transgene delivery and expression since they are considered to be safer alternatives to viral delivery vehicles.  Amphiphilic polymers that combine cationic character with hydrophobicity are hypothesized to possess  high efficacies for nucleic acid condensation and uptake across cellular membranes. Here, we report the design, synthesis, characterization and transgene expression efficacies of lipid-substituted aminoglycoside polymers. A library of 54 lipid-polymer conjugates was synthesized by N-acylation of the free amines present in the polymers. Aminoglycoside-polymers were derivatized with three different acid chlorides based on C6, C14, and C18 chains. The extent of the lipid substitution was dependent on the lipid-polymer stoichiometry, and the conjugates were characterized using 1H NMR and FTIR spectroscopy. Parallel screening of the conjugates led to identification of several leads that demonstrated higher transgene expression efficacies in several cancer cells, when compared to the parental polymers and poly(ethylene imine), a current polymeric standard for transgene expression. Transgene expression efficacy was dependent on the extent of lipid substitution, as well as the chain length of the lipid substituted. The influence of the various physicochemical properties including polyplex size, zeta potential, and DNA binding on transgene expression efficacies were investigated. This study indicates that lipid substitution on aminoglycoside-based polymers results in high levels of transgene expression compared to unsubstituted polymers. Taken together, these materials show significant promise in non-viral transgene delivery, and may be attractive for gene therapy applications.

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