Use of polyglutamic acids to reduce uptake of radiometal-labeled minigastrin in the kidneys.
Uptake of radiolabeled peptides in the kidneys may obscure abdominal tumors in radiopeptide scintigraphy. This problem is much more pronounced in peptide receptor radionuclide therapy (i.e., radiopeptide therapy), possibly leading to renal damage or even failure. Cationic peptide uptake in the kidneys can be reduced by the application of cationic amino acids, such as lysine or arginine. The aim of this study was to develop a suitable method to reduce anionic peptide uptake in the kidneys. (111)In-Diethylenetriaminepentaacetic acid dGlu(1)-minigastrin ((111)In-DTPA-dGlu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2)) was chosen as a model compound with a sequence of 6 negatively charged glutamic acids in a chain and an additional aspartic acid.


METHODS
TT (human medullary carcinoma cells)-bearing nu/nu mice of the Institute of Cancer Research genotype received intraperitoneal injections of different chain lengths and weights of glutamic acids, aspartic acids, and derivatives of glutamic acids. Uptake in tumors and organs was determined and compared with the values for untreated control mice.


RESULTS
Accretion of (111)In-DTPA-dGlu(1)-minigastrin in the kidneys could be reduced by up to 90%. The uptake values for all other organs and the tumors were not affected. These results were obtained with a chain of 5 or more glutamic acids, whereas uptake in kidneys was affected not at all or only slightly with poly-d-glutamic or polyaspartic acids and with Glu(x) (x = 1-4).


CONCLUSIONS
These studies indicated a specific blocking of uptake by Glu(5) sequences in the kidneys. Application of polyglutamic acids is a new, successful method of reducing uptake of negatively charged peptides in the kidneys during radiopeptide therapy.
Béhé
Martin
M
Department of Nuclear Medicine, Philipps-University of Marburg, Baldingerstrasse, D-35043 Marburg, Germany. behe@staff.uni-marburg.de
Kluge
Gerald
G
Becker
Wolfgang
W
Gotthardt
Martin
M
Behr
Thomas M
TM
D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D018276:Carcinoma, Medullary / Q000378:metabolism; D005260:Female; D005755:Gastrins / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007205:Indium Radioisotopes; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011099:Polyglutamic Acid / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D013964:Thyroid Neoplasms / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D005755:Gastrins; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D011099:Polyglutamic Acid; C008530:minigastrin; D001224:Aspartic Acid