pH-Responsive Natural Polymeric Gene Delivery Shielding System Based on Dynamic Covalent Chemistry

A novel pH-responsive system based on aldehyde-bearing dextran derivatives (ODEX or FDEX) was designed to use as gene carrier shielding. Through pH sensitive Schiff base bonds between amino groups of PEI (in PEI/DNA polyplex) and aldehyde groups of dextran derivatives, PEI/DNA polyplex could be shielded and further condensed to obtain an effectively decreasing ζ-potential with smaller size. Schiff base bonds were pH-responsive, which were relatively stable in neutral environment but were deformed in slightly acidic and acidic environments. Through use of this characteristic, the PEI/DNA polyplex was effectively shielded during circulation in the body, and upon arrival at the tumor, the slightly acid pH triggered the breaking of Schiff base bonds to expose the positive PEI/DNA polyplex, which further interacted with tumor cell membranes, achieving efficient gene expression. Use of such characteristics could effectively address the high transfection efficiency versus stability dilemma of gene carriers. FDEX/PEI/DNA nanoparticles not only mediate higher cellular uptake and transfection efficiency in vitro but also effectively accumulate in tumors with gene expression in vivo higher than that of the ODEX analogues. As a result, this pH-responsive system is a promising strategy for cancer therapy.