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Research Articles: Therapeutics

Enhancement of tumor thermal therapy using gold nanoparticle–assisted tumor necrosis factor- delivery

Departments of ¹ Mechanical Engineering, ² Therapeutic Radiology, ³ Electrical Engineering, ⁴ Biomedical Engineering, and ⁵ Urology, University of Minnesota, Minneapolis, Minnesota and ⁶ CytImmune Sciences, Inc., Rockville, Maryland

Requests for reprints: Robert J. Griffin, Radiation Biology Section, Department of Radiation Oncology, University of Minnesota Medical School, Minneapolis, MN 55455. Phone: 612-626-6064; Fax: 612-626-6245. E-mail: griff007{at}umn.edu

Abstract

Tumor necrosis factor- (TNF-) is a potent cytokine with anticancer efficacy that can significantly enhance hyperthermic injury. However, TNF- 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-) with incorporated TNF- payload (several hundred TNF- molecules per nanoparticle) to maximize tumor damage and minimize systemic exposure to TNF-. SCK mammary carcinomas grown in A/J mice were treated with 125 or 250 µg/kg PT-cAu-TNF- alone or followed by local heating at 42.5°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- 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- or PT-cAu-TNF-. Tumor perfusion, imaged by contrast enhanced ultrasonography, on days 1 and 5 after treatment revealed perfusion defects after the injection of PT-cAu-TNF- 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--coated gold nanoparticles when given i.v. at the proper dosage and timing. [Mol Cancer Ther 2006;5(4):1014–20]

Grant support: Grants DAMD 17-03-1-0432 (R.K. Visaria) and DAMD 17-01-1-33 (E.S. Ebbini), NIH CA44114 (R.J. Griffin and C.W. Song), Biomedical Engineering Institute-University of Minnesota (J.C. Bischof).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/21/05; revised 12/25/05; accepted 2/15/06.

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