title: A novel magnetic approach to enhance the efficacy of cell-based gene therapies.
abstract: Attempts have been made to use various forms of cellular vectors to deliver therapeutic genes to diseased tissues like malignant tumours. However, this approach has proved problematic due to the poor uptake of these vectors by the target tissue. We have devised a novel way of using magnetic nanoparticles (MNPs) to enhance the uptake of such 'therapeutically armed' cells by tumours. Monocytes naturally migrate from the bloodstream into tumours, so attempts have been made to use them to deliver therapeutic genes to these sites. However, transfected monocytes injected systemically fail to infiltrate tumours in large numbers. Using a new in vitro assay for assessing monocyte extravasation, we show that the ability of transfected human monocytes to migrate across a human endothelial cell layer into a 3D tumour spheroid is markedly increased when cells are pre-loaded with MNPs and a magnetic force is applied close to the spheroid. Furthermore, systemic administration of such 'magnetic' monocytes to mice bearing solid tumours led to a marked increase in their extravasation into the tumour in the presence of an external magnet. This new magnetic targeting approach could be used to increase the targeting, and thus the efficacy, of many cell-based gene therapies in vivo.
authors.affiliation: Tumour Targeting Group, Academic Unit of Pathology, University of Sheffield Medical School, Sheffield, UK.
authors.forename: M
authors.initials: M
authors.lastname: Muthana
authors.forename: S D
authors.initials: SD
authors.lastname: Scott
authors.forename: N
authors.initials: N
authors.lastname: Farrow
authors.forename: F
authors.initials: F
authors.lastname: Morrow
authors.forename: C
authors.initials: C
authors.lastname: Murdoch
authors.forename: S
authors.initials: S
authors.lastname: Grubb
authors.forename: N
authors.initials: N
authors.lastname: Brown
authors.forename: J
authors.initials: J
authors.lastname: Dobson
authors.forename: C E
authors.initials: CE
authors.lastname: Lewis
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007501:Iron; D008280:Magnetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000378:metabolism*; D053758:Nanoparticles; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D010587:Phagocytosis; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D049452:Green Fluorescent Proteins; D007501:Iron