title: FGFR-targeted gene delivery mediated by supramolecular assembly between β-cyclodextrin-crosslinked PEI and redox-sensitive PEG.
abstract: A new redox-sensitive poly(ethylene glycol) (PEG)-based gene vector specially designed to target fibroblast growth factor receptors (FGFRs) was developed by host-guest supramolecular complexation. The new vector was designed as follows: 1) A host segment was consisted of β-cyclodextrin-crosslinked low molecular polyethylenimine (PEI) conjugated with MC11 peptide (MQLPLATGGGC) that can target FGFRs, being termed as MC11-PEI-β-cyclodextrin (MPC); 2) A guest segment is consisted of PEG and adamantyl group linked by a disulfide bond, the adamantyl-SS-PEG (Ad-SS-PEG); and 3) PEGylation of MPC by supramolecular complexation between MPC and Ad-SS-PEG to generate MPC/Ad-SS-PEG polycation, where the PEG chains can stabilize the DNA polyplexes extracellularly but can be readily cleavable intracellularly. It was found that the MPC/Ad-SS-PEG complexes could efficiently condense pDNA into nanoparticles around 100-200 nm, and were able to effectively stabilize polyplexes against salt- or BSA-induced aggregation. The MPC/Ad-SS-PEG polyplexes were more readily to dissociate with the aid of heparin in the presence of 5 mm DTT. In vitro gene transfection and cytotoxicity experiments in different carcinoma cell lines expressing FGFRs showed that MPC/Ad-SS-PEG could mediate significantly higher transfection efficiency than MPC complexed with adamantyl-PEG (MPC/Ad-PEG), which has no disulfide linkage and is non-PEG-detachable. Furthermore, confocal laser scanning microscopy study indicated that MPC/Ad-SS-PEG polyplexes could mediate much more efficient endosomal escape than stably shield MPC/Ad-PEG polyplexes at 12 h post-transfection. Importantly, MPC/Ad-SS-PEG was also able to efficiently mediate tumor-targeted gene delivery in the tumor-bearing mouse model after systemic injection in vivo. These results suggest that the MPC/Ad-SS-PEG systems could be a safe and efficient non-viral vector for FGFR-mediated targeted gene delivery for cancer gene therapy.
authors.affiliation: Department of Bioengineering, Faculty of Engineering, National University of Singapore,7 Engineering Drive 1, Singapore 117574, Singapore.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ping
authors.forename: Qida
authors.initials: Q
authors.lastname: Hu
authors.forename: Guping
authors.initials: G
authors.lastname: Tang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D005260:Female; D005822:Genetic Vectors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D014162:Transfection; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D010455:Peptides; D017468:Receptors, Fibroblast Growth Factor; D047392:beta-Cyclodextrins; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D004247:DNA