Synthetic non-viral vectors for gene therapy are appealing alternatives to viral vectors, which give high levels of transfection but pose serious health risks. The complex nature of DNA delivery to live cells necessitates the rational design of non-viral vectors to achieve levels of transfection comparable to highly evolved viruses. The versatility and tunability of polymer chemistry lends itself to the synthesis of well-defined DNA delivery vehicles equipped with functionality for cellular and nuclear targeting, degradation, endosomal escape, modulation of polymer-DNA binding, and stability. This presentation will describe a theoretical- experimental approach to the design of comb polymers with cationic oligopeptides and zwitterionic groups pendent to a polycyclooctene backbone. Cationic oligopeptides, including oligolysines and the Simian Virus SV-40 nuclear localization sequence PKKKRKV, complex DNA into nanoscopic particles, termed ‘polyplexes’, and zwitterions modulate polymer-DNA binding strength. Atomistic and coarse-grained simulations examine the effects of polymer structure and composition on DNA binding strength and direct the design of new polymers with improved DNA complexation properties. In transfection experiments in SKOV3 cells, comb polymers with PKKKRKV groups attached to the polymer backbone at the valine (V) residue (rNLS) outperformed the commercial benchmark reagents, Lipofectamine 2000 and JetPEI, and exhibited favorable cell viability characteristics.

Comb polymers for non-viral gene delivery

249th National Meeting (2015)

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