title: Enhancement of tumor thermal therapy using gold nanoparticle-assisted tumor necrosis factor-alpha delivery.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is a potent cytokine with anticancer efficacy that can significantly enhance hyperthermic injury. However, TNF-alpha is systemically toxic, thereby creating a need for its selective tumor delivery. We used a newly developed nanoparticle delivery system consisting of 33-nm polyethylene glycol-coated colloidal gold nanoparticles (PT-cAu-TNF-alpha) with incorporated TNF-alpha payload (several hundred TNF-alpha molecules per nanoparticle) to maximize tumor damage and minimize systemic exposure to TNF-alpha. SCK mammary carcinomas grown in A/J mice were treated with 125 or 250 microg/kg PT-cAu-TNF-alpha alone or followed by local heating at 42.5 degrees C using a water bath for 60 minutes, 4 hours after nanoparticle injection. Increases in tumor growth delay were observed for both PT-cAu-TNF-alpha alone and heat alone, although the most dramatic effect was found in the combination treatment. Tumor blood flow was significantly suppressed 4 hours after an i.v. injection of free TNF-alpha or PT-cAu-TNF-alpha. Tumor perfusion, imaged by contrast enhanced ultrasonography, on days 1 and 5 after treatment revealed perfusion defects after the injection of PT-cAu-TNF-alpha alone and, in many regions, complete flow inhibition in tumors treated with combination treatment. The combination treatment of SCK tumors in vivo reduced the in vivo/in vitro tumor cell survival to 0.05% immediately following heating and to 0.005% at 18 hours after heating, suggesting vascular damage-mediated tumor cell killing. Thermally induced tumor growth delay was enhanced by pretreatment with TNF-alpha-coated gold nanoparticles when given i.v. at the proper dosage and timing.
authors.affiliation: Department of Mechanical Engineering, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Rachana K
authors.initials: RK
authors.lastname: Visaria
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Brent W
authors.initials: BW
authors.lastname: Williams
authors.forename: Emad S
authors.initials: ES
authors.lastname: Ebbini
authors.forename: Giulio F
authors.initials: GF
authors.lastname: Paciotti
authors.forename: Chang W
authors.initials: CW
authors.lastname: Song
authors.forename: John C
authors.initials: JC
authors.lastname: Bischof
mesh_terms: D000818:Animals; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006046:Gold; D006979:Hyperthermia, Induced; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D051379:Mice; D049329:Nanostructures; D012413:Rubidium / Q000493:pharmacokinetics; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D006046:Gold; D012413:Rubidium