title: Engineering clustered ligand binding into nonviral vectors: alphavbeta3 targeting as an example.
abstract: The development of techniques to efficiently deliver genes using nonviral approaches can broaden the application of gene delivery in medical applications without the safety concerns associated with viral vectors. Here, we designed a clustered integrin-binding platform to enhance the efficiency and targetability of nonviral gene transfer to HeLa cells with low and high densities of alpha(v)beta(3) integrin receptors. Arg-Gly-Asp (RGD) nanoclusters were formed using gold nanoparticles functionalized with RGD peptides and used to modify the surface of DNA/poly(ethylene imine) (PEI) polyplexes. DNA/PEI polyplexes with attached RGD nanoclusters resulted in either 5.4- or 35-fold increase in gene transfer efficiency over unmodified polyplexes for HeLa cells with low- or high-integrin surface density, respectively. The transfection efficiency obtained with the commercially available vector jetPEI-RGD was used for comparison as a vector without clustered binding. JetPEI-RGD exhibited a 1.2-fold enhancement compared to unmodified jetPEI in cells with high densities of alpha(v)beta(3) integrin receptors. The data presented here emphasize the importance of the RGD conformational arrangement on the surface of the polyplex to achieve efficient targeting and gene transfer, and provide an approach to introduce clustering to a wide variety of nanoparticles for gene delivery.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California at Los Angeles, Los Angeles, California 90024, USA.
authors.forename: Quinn K T
authors.initials: QK
authors.lastname: Ng
authors.forename: Marie K
authors.initials: MK
authors.lastname: Sutton
authors.forename: Pan
authors.initials: P
authors.lastname: Soonsawad
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Holland
authors.initials: H
authors.lastname: Cheng
authors.forename: Tatiana
authors.initials: T
authors.lastname: Segura
mesh_terms: D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D007097:Imines / Q000737:chemistry; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D011095:Polyethylenes / Q000737:chemistry
chemical_list: D007097:Imines; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011095:Polyethylenes; C505405:poly(ethylene imine); C047981:arginyl-glycyl-aspartic acid