Folic Acid Modified Cationic γ-Cyclodextrin-oligoethylenimine Star Polymer with Bioreducible Disulfide Linker for Efficient Targeted Gene Delivery

For an efficient folate-targeted delivery, while the interaction between the folate on the carriers and the folate receptor (FR) on the cells is necessary, the recovering and recycling of FR to maintain a high density level of FR on the cellular membrane is also important. Herein, we demonstrate a design and synthesis of a new star-shaped cationic polymer containing a γ-cyclodextrin (γ-CD) core and multiple oligoethylenimine (OEI) arms with folic acid (FA) linked by a bioreducible disulfide bond for efficient targeted gene delivery. The newly synthesized cationic polymer, named γ-CD-OEI-SS-FA, could be cleaved efficiently, and FA was readily released under reductive condition similar to intracellular environment. The γ-CD-OEI-SS-FA polymer was well-characterized and studied in terms of its gene delivery properties in FR-positive KB cells and FR-negative A549 cells under various conditions, in comparison with cationic polymers such as high molecular weight branched polyethylenimine (PEI), γ-CD-OEI star-shaped cationic polymer, γ-CD-OEI-FA polymer where FA was directed linked to the star polymer without disulfide linker. Our data have demonstrated that the new γ-CD-OEI-SS-FA gene carrier had low cytotoxicity and possessed capacity to target and deliver DNA to specific tumor cells that overexpress FRs, as well as functions to recover and recycle FRs onto cellular membranes to facilitate continuous FR-mediated endocytosis to achieve very high levels of gene expression. This study has expanded the strategy of FA-targeted delivery by combining the smart FR-recycling function to achieve the significant enhancement of gene expression. The new FA-targeted and bioreducible carrier may be a promising efficient gene delivery system for potential cancer gene therapy.