Effect of monomer sequence of poly(histidine/lysine) catiomers on gene packing capacity and delivery efficiency

Abstract

Polymeric catiomers, which can mimic viruses for gene packing and delivery, have received considerable attention as nonviral vectors for gene therapy. Inspired by the critically important role of the sequence of structural units in various biomolecules, including DNA and protein, in this study, we intend to investigate how the monomer sequence of a polymeric catiomer affects its gene packing capacity and delivery efficiency. The well-documented poly(histidine-co-lysine) was chosen as the scaffold for gene carrier. Four reducible polycations (RPCs) based on sequence-regulated peptides monomers were synthesized. Chemical parameters (namely, composition and molecular weight) of four RPCs were controlled at comparable level except for the monomer sequence. All of the RPCs exhibited low cytotoxicity and effective DNA binding ability. However, these RPCs displayed distinct diversity from each other, especially in their ability of binding to DNA, buffering capacity and transfection efficiency. Using 293T cell as the mode, we found that the regulation of the monomer sequence of polycations could significantly affect their properties for gene delivery, with differences of 100 fold. The sequence effect might be correlated with different chain folding as well as physiochemical properties of RPCs/pDNA complexes, providing new insight for designing gene vector with promising prospects in gene therapy.