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.
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.
Kneifel
Stefan
S
Clinic and Institute of Nuclear Medicine, University Hospitals, Basel, Switzerland.
Cordier
Dominik
D
Good
Stephan
S
Ionescu
Mihai C S
MC
Ghaffari
Anthony
A
Hofer
Silvia
S
Kretzschmar
Martin
M
Tolnay
Markus
M
Apostolidis
Christos
C
Waser
Beatrice
B
Arnold
Marlene
M
Mueller-Brand
Jan
J
Maecke
Helmut R
HR
Reubi
Jean Claude
JC
Merlo
Adrian
A
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*
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