The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a 68Ga-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin

Molecules

Zohreh Varasteh¹  Ulrika Rosenström³  Irina Velikyan¹  Bogdan Mitran¹  Mohamed Altai⁴  Hadis Honarvar⁴  Maria Rosestedt¹  Gunnar Lindeberg³  Jens Sörensen⁴  Mats Larhed²  Vladimir Tolmachev⁴ 

[1] Preclinical PET Platform, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden;Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Uppsala SE-751 23, Sweden;Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden;Biomedical Radiation Sciences, Department of Radiology, Oncology and Radiation Sciences, Faculty of Medicine, Uppsala University, Uppsala SE-751 85, Sweden

关键词: bombesin analog;    PEG;    GRPR;    antagonist;    molecular imaging;    breast cancer;    prostate cancer;    BT-474;    PC-3 cells;   

DOI  :  10.3390/molecules190710455

来源: mdpi

【 摘 要 】

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 (PEG₂) spacer (NOTA-PEG₂-RM26) and labeled with ⁶⁸Ga 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 ^natGa-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 ⁶⁸Ga-NOTA-PEG₃-RM26 showed lower liver uptake. Biodistribution of ⁶⁸Ga-NOTA-PEG₃-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 ⁶⁸Ga-NOTA-PEG₃-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.

【 授权许可】

CC BY   
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