A Zwitterionic-Shielded Carrier with pH-Modulated Reversible Self-Assembly for Gene Transfection

Abstract

Cationic vectors are ideal candidates for gene delivery thanks to their capability to carry large gene inserts and their scalable production. However, their cationic density gives rise to high cytotoxicity. We present the proper designed core-shell polyplexes made of either poly(ethylene imine) (PEI) or poly(2-dimethylamino ethyl methacrylate) (PDMAEMA) as the core and zwitterionic poly(acrylic acid)-block-poly(sulfobetaine methacrylate) (PAA-b-PSBMA) diblock copolymer as the shell. Gel retardation and ethidium bromide displacement assays were used to determine the PEI/DNA or PDMAEMA/DNA complexation. At neutral pH, the copolymer serves as a protective shell of the complex. As PSBMA is a nonfouling block, the shell reduced the cytotoxicity and enhanced the hemocompatibility (lower hemolysis activity, longer plasma clotting time) of the gene carriers. PAA segments in the copolymer impart pH sensitivity by allowing deshielding of the core in acidic solution. Therefore, the transfection efficiency of polyplexes at pH 6.5 was better than at pH 7.0, from β-galactosidase assay, and for all PAA-b-PSBMA tested. These results were supported by more favorable physicochemical properties in acidic solution (zeta potential, particle size, and interactions between the polymer and DNA). Thus, the results of this study offer a potential route to the development of efficient and nontoxic pH-sensitive gene carriers.

Polyethylenimine-based nanocarriers in co-delivery of drug and gene: a developing horizon

“…Cationic vectors are ideal candidates for gene delivery due to their ability to transfer large genes and scalable production [23]. The synthesis of cationic materials (polymers, lipids) to self-assemble with pDNA based on electrostatic interactions has been significantly improved [24].…”

“…In neutral pH, polymer acts as a protective shell of the complex. Therefore, the results of this study provide a pathway for improving the efficiency and non-toxic properties of pH-sensitive gene carriers [23]. In 2017, Park et al, constructed PLGA nanoparticles coated with Polycistronic SOX5, SOX6 and SOX9 genes for mesenchymal human stem cell chondrogenesis.…”

Biodegradable zwitterionic sulfobetaine polymer and its conjugate with paclitaxel for sustained drug delivery

“…Integrated zwitterion moieties, instead of mixed oppositely charged moieties, were incorporated with the biodegradable main-chains to guarantee electrically-neutral zwitterionic properties of the resulting materials without requiring additional synthetic control. With an anionic sulfonate group and a cationic trimethyl ammonium group, sulfobetaine (SB) was further selected as the zwitterion because of its superhydrophilicity [48–50]. Paclitaxel (PTX), a potent clinic anticancer drug, was chosen as a representative drug in our design of the polymer-drug conjugate [51].…”

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“…Thus, understanding the chemical structure of the polymer's ionizable moieties, and their respective pK a are indispensable for the design and synthesis of appropriate pH-sensitive DDS [112]. Moreover, attempts have been made to alleviate much concerned cytotoxicity of synthesized NPs by conjugating it with PEG or with any of the zwitterionic polybetaines [113][114][115][116][117]. Further studies are still on to nullify its cytotoxicity, if any.…”