Bioreducible polyether-based pDNA ternary polyplexes: balancing particle stability and transfection efficiency

Polyplex particles formed with plasmid DNA (pDNA) and Pluronic P85-block-poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (P85-b-P[Asp(DET)]) demonstrated highly effective transfection ability compared to PEG-based block cationomer, PEG-b-P[Asp(DET)]. Ternary polyplexes comprising PEG-b-P[Asp(DET)], poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)-b-P[Asp(DET)] (P(EPE)-b-P[Asp(DET)]) used as an analog of P85-b-P[Asp(DET)], and pDNA were prepared in this work aiming at maintaining adequate transfection efficiency while solving the stability issues of the P85-b-P[Asp(DET)] polyplexes. Furthermore, a bioreducible P(EPE)-SS-P[Asp(DET)] possessing a redox potential-sensitive disulfide linkage between the P(EPE) polymer and the cationic block was used as a substitute for P(EPE)-b-P[Asp(DET)] during ternary complex formation to investigate whether the transfection ability of the ternary polyplex system could be enhanced by triggered release of P(EPE) polymers from the polyplexes. The ternary complexes showed significant improvement in terms of stability against salt-induced aggregation compared to binary complexes, although the gene delivery ability dropped with the amount of PEG-b-P[Asp(DET)] used for complexation. By manipulating the difference in redox potential between the extracellular and intracellular environments, the reducible ternary complexes achieved higher transfection compared to the non-reducible polyplexes; moreover, the reducible polyplexes exhibited comparable stability to the non-reducible ones. These results suggest that reducible ternary complexes could provide satisfactory transfection efficiency without comprising the colloidal stability of the particles.