title: Spatial Control of Gene Expression by Nanocarriers Using Heparin Masking and Ultrasound-Targeted Microbubble Destruction.
abstract: We developed a method to spatially control gene expression following nonviral delivery of DNA. This method includes surface-modifying DNA nanocarriers with heparin to inhibit passive gene transfer in both the target and the off-target tissues and using ultrasound-targeted microbubble destruction (UTMD) to selectively activate heparin-inhibited gene transfer at the target site. We observed that the engraftment of heparin onto the surface of cationic liposomes reduced off-target gene expression in the liver, a major site of nanoplex accumulation, by more than 700-fold compared to the nonheparinized PEGylated liposomes. We further observed that tumor-directed UTMD increased gene transfer with heparin-modified nanoplexes by more than 10-fold. This method augmented tumor-to-liver selectivity of gene expression by 4000-fold compared to controls. We conclude that heparinization of DNA nanocarriers in conjunction with localized activation of gene transfer by UTMD may enable greater spatial control over genetic therapy.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.|Department of Biomedical Engineering, College of Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Beata
authors.initials: B
authors.lastname: Chertok
authors.affiliation: Department of Chemical Engineering, MIT , Cambridge, Massachusetts 02139, United States.|David H. Koch Institute for Integrative Cancer Research, MIT , Cambridge, Massachusetts 02139, United States.|Institute for Medical Engineering & Science, MIT , Cambridge, Massachusetts 02139, United States.|Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: Department of Chemical Engineering, MIT , Cambridge, Massachusetts 02139, United States.|David H. Koch Institute for Integrative Cancer Research, MIT , Cambridge, Massachusetts 02139, United States.|Institute for Medical Engineering & Science, MIT , Cambridge, Massachusetts 02139, United States.|Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts 02139, United States.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: D004247:DNA; D015316:Genetic Therapy; D006493:Heparin; D008081:Liposomes; D045423:Microbubbles; D036103:Nanotechnology; D014162:Transfection
chemical_list: D008081:Liposomes; D006493:Heparin; D004247:DNA
keywords: gene delivery; gene nanocarriers; heparin surface masking; microbubbles; spatial control; tumor targeting; ultrasound