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Local Targeting of Malignant Gliomas by the Diffusible Peptidic Vector 1,4,7,10-Tetraazacyclododecane-1-Glutaric Acid-4,7,10-Triacetic Acid-Substance P

Authors' Affiliations: ¹ Clinic and Institute of Nuclear Medicine, ² Division of Radiological Chemistry, ³ Neurosurgical Clinic, ⁴ Molecular Neuro-Oncology Laboratory of the Department of Surgery and Research, ⁵ Neuroradiology, and ⁶ Neuropathology, University Hospitals, Basel, Switzerland; ⁷ European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany; and ⁸ Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland

Requests for reprints: Adrian Merlo, Neurosurgical Clinic, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland. Phone: 41-61-265-71-82; Fax: 41-61-265-71-38; E-mail: amerlo{at}uhbs.ch.

Purpose: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid ¹²⁵I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins.

Experimental Design: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg¹ of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC₅₀ of 0.88 ± 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, ⁹⁰Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, ¹⁷⁷Lut and ²¹³Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3.

Results: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation.

Conclusions: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.

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