title: Supramolecular Aggregate as a High-Efficiency Gene Carrier Mediated with Optimized Assembly Structure.
abstract: For cancer gene therapy, a safe and high-efficient gene carrier is a must. To resolve the contradiction between gene transfection efficiency and cytotoxicity, many polymers with complex topological structures have been synthesized, although their synthesis processes and structure control are difficult as well as the high molecular weight also bring high cytotoxicity. We proposed an alternative strategy that uses supramolecular inclusion to construct the aggregate from the small molecules for gene delivery, and to further explore the relationship between the topological assembly structure and their ability to deliver gene. Herein, PEI-1.8k-conjugating β-CD through 6-hydroxyl (PEI-6-CD) and 2-hydroxyl (PEI-2-CD) have been synthesized respectively and then assembled with diferrocene (Fc)-ended polyethylene glycol (PEG-Fc). The obtained aggregates were then used to deliver MMP-9 shRNA plasmid for MCF-7 cancer therapy. It was found that the higher gene transfection efficiency can be obtained by selecting PEI-2-CD as the host and tuning the host/guest molar ratios. With the rational modulation of supramolecular architectures, the aggregate played the functions similar to macromolecules which exhibit higher transfection efficiency than PEI-25k, but show much lower cytotoxicity because of the nature of small/low molecules. In vitro and in vivo assays confirmed that the aggregate could deliver MMP-9 shRNA plasmid effectively into MCF-7 cells and then downregulate MMP-9 expression, which induced the significant MCF-7 cell apoptosis, as well inhibit MCF-7 tumor growth with low toxicity. The supramolecular aggregates maybe become a promising carrier for cancer gene therapy and also provided an alternative strategy for designing new gene carriers.
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University , Guangzhou 510632, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University , Guangzhou 510632, China.
authors.forename: Junkun
authors.initials: J
authors.lastname: Duan
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University , Guangzhou 510632, China.
authors.forename: Lingguang
authors.initials: L
authors.lastname: Cai
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University , Guangzhou 510632, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Ma
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University , Guangzhou 510632, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
mesh_terms: D018014:Gene Transfer Techniques; D010957:Plasmids; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D014162:Transfection
chemical_list: D011092:Polyethylene Glycols; D011094:Polyethyleneimine
keywords: MMP-9 shRNA delivery; assembly structure optimization; cancer therapy; gene carrier; host−guest interactions; supramolecular aggregate