The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a Ga-68-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin
2014 (English)In: Molecules, ISSN 1420-3049, Vol. 19, no 7, 10455-10472 p.Article in journal (Refereed) Published
The overexpression of gastrin-releasing peptide receptor (GRPR) in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7-triazacyclononane-N, N', N ''-triacetic acid (NOTA) via a diethyleneglycol (PEG(2)) spacer (NOTA-PEG(2)-RM26) and labeled with Ga-68 can be used for imaging of GRPR-expressing tumors. In this study, we evaluated if a variation of mini-PEG spacer length can be used for optimization of targeting properties of the NOTA-conjugated RM26. A series of analogs with different PEG-length (n = 2, 3, 4, 6) was synthesized, radiolabeled and evaluated in vitro and in vivo. The IC50 values of Ga-nat-NOTA-PEG(n)-RM26 (n = 2, 3, 4, 6) were 3.1 +/- 0.2, 3.9 +/- 0.3, 5.4 +/- 0.4 and 5.8 +/- 0.3 nM, respectively. In normal mice all conjugates demonstrated similar biodistribution pattern, however Ga-68-NOTA-PEG(3)-RM26 showed lower liver uptake. Biodistribution of Ga-68-NOTA-PEG(3)-RM26 was evaluated in nude mice bearing PC-3 (prostate cancer) and BT-474 (breast cancer) xenografts. High uptake in tumors (4.6 +/- 0.6% ID/g and 2.8 +/- 0.4% ID/g for PC-3 and BT-474 xenografts, respectively) and high tumor-to-background ratios (tumor/ blood of 44 +/- 12 and 42 +/- 5 for PC-3 and BT-474 xenografts, respectively) were found already at 2 h p.i. of Ga-68-NOTA-PEG(3)-RM26. Results of this study suggest that variation in the length of the PEG spacer can be used for optimization of targeting properties of peptide-chelator conjugates. However, the influence of the mini-PEG length on biodistribution is minor when di-, tri-, tetra- and hexaethylene glycol are compared.
Place, publisher, year, edition, pages
2014. Vol. 19, no 7, 10455-10472 p.
bombesin analog, PEG, GRPR, antagonist, molecular imaging, breast cancer, prostate cancer, BT-474, PC-3 cells
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-231315DOI: 10.3390/molecules190710455ISI: 000340036200108PubMedID: 25036155OAI: oai:DiVA.org:uu-231315DiVA: diva2:744286