title: 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.
abstract: OBJECTIVE
  Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid (125)I 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.
  
  
  METHODS
  We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC(50) 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, (90)Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and (213)Bi 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.
authors.affiliation: Clinic and Institute of Nuclear Medicine, University Hospitals, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kneifel
authors.forename: Dominik
authors.initials: D
authors.lastname: Cordier
authors.forename: Stephan
authors.initials: S
authors.lastname: Good
authors.forename: Mihai C S
authors.initials: MC
authors.lastname: Ionescu
authors.forename: Anthony
authors.initials: A
authors.lastname: Ghaffari
authors.forename: Silvia
authors.initials: S
authors.lastname: Hofer
authors.forename: Martin
authors.initials: M
authors.lastname: Kretzschmar
authors.forename: Markus
authors.initials: M
authors.lastname: Tolnay
authors.forename: Christos
authors.initials: C
authors.lastname: Apostolidis
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Marlene
authors.initials: M
authors.lastname: Arnold
authors.forename: Jan
authors.initials: J
authors.lastname: Mueller-Brand
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Adrian
authors.initials: A
authors.lastname: Merlo
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D005260:Female; D005910:Glioma / Q000532:radiotherapy*; D006573:Heterocyclic Compounds, 1-Ring / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D015183:Restriction Mapping; D013373:Substance P / Q000031:analogs & derivatives* / Q000235:genetics / Q000627:therapeutic use*; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C513199:substance P, 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-arginyl(1)-; D013373:Substance P