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Real-time, Image-Guided, Convection-Enhanced Delivery of Interleukin 13 Bound to Pseudomonas Exotoxin

Authors' Affiliations: ¹ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke; ² Division of Bioengineering and Physical Science, Office of Research Services; and ³ Radioimmune and Inorganic Chemistry Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; ⁴ Department of Neurosurgery, University of Florida, Gainesville, Gainesville, Florida; and ⁵ Department of Neurosurgery, Georgetown University, Washington, District of Columbia

Requests for reprints: Russell R. Lonser, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Room 5D37, Building 10, 10 Center Drive, Bethesda, MD 20892-1414. Phone: 301-496-5728; Fax: 301-402-0380; E-mail: lonserr{at}ninds.nih.gov.

Purpose: To determine if the tumor-targeted cytotoxin interleukin 13 bound to Pseudomonas exotoxin (IL13-PE) could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution in real-time using a surrogate magnetic resonance imaging tracer, we used convection-enhanced delivery to perfuse rat and primate brainstems with IL13-PE and gadolinium-bound albumin (Gd-albumin).

Experimental Design: Thirty rats underwent convective brainstem perfusion of IL13-PE (0.25, 0.5, or 10 µg/mL) or vehicle. Twelve primates underwent convective brainstem perfusion of either IL13-PE (0.25, 0.5, or 10 µg/mL; n = 8), co-infusion of ¹²⁵I-IL13-PE and Gd-albumin (n = 2), or co-infusion of IL13-PE (0.5 µg/mL) and Gd-albumin (n = 2). The animals were permitted to survive for up to 28 days before sacrifice and histologic assessment.

Results: Rats showed no evidence of toxicity at all doses. Primates showed no toxicity at 0.25 or 0.5 µg/mL but showed clinical and histologic toxicity at 10 µg/mL. Quantitative autoradiography confirmed that Gd-albumin precisely tracked IL13-PE anatomic distribution and accurately showed the volume of distribution.

Conclusions: IL13-PE can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and over clinically relevant volumes using convection-enhanced delivery. Moreover, the distribution of IL13-PE can be accurately tracked by co-infusion of Gd-albumin using real-time magnetic resonance imaging.

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