Comparative in vitro and in vivo evaluation of two 64Cu-labeled bombesin analogs in a mouse model of human prostate adenocarcinoma

Yi Shan Yang, Xianzhong Zhang, Zhengming Xiong, Xiaoyuan Chen

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Bombesin (BBN), an analog of human gastrin-releasing peptide (GRP), binds to the GRP receptor (GRPR) with high affinity and specificity. Overexpression of GRPR has been discovered in mostly androgen-independent human prostate tissues and, thus, provides a potential target for prostate cancer diagnosis and therapy. We have previously demonstrated the feasibility of the positron emission tomography (PET) imaging using 64Cu-1,4,7,10-tetraazadodecane-N,N′,N″,N″′-tetraacetic acid (DOTA)-[Lys3]BBN to detect GRPR-positive prostate cancer. In this study, we compared the receptor affinity, metabolic stability, tumor-targeting efficacy, and pharmacokinetics of a truncated BBN analog 64Cu-DOTA-Aca-BBN(7-14) with 64Cu-DOTA-[Lys3]BBN. Binding of each DOTA conjugate to GRPR on PC-3 and 22Rv1 prostate cancer cells was evaluated with competitive binding assay using 125I-[Tyr4]BBN as radioligand. In vivo pharmacokinetics was determined on male nude mice subcutaneously implanted with PC-3 cells. Dynamic microPET imaging was performed to evaluate the systemic distribution of the tracers. Metabolic stability of the tracers in blood, urine, tumor, liver and kidney was studied using high-performance liquid chromatography. The results showed that 125I-[Tyr4]BBN has a Kd of 14.8±0.4 nM against PC-3 cells, and the receptor concentration on PC-3 cell surface is approximately 2.7±0.1×106 receptors per cell. The 50% inhibitory concentration value for DOTA-Aca-BBN(7-14) is 18.4±0.2 nM, and that for DOTA-[Lys3]BBN is 2.2±0.5 nM. DOTA-[Lys3]BBN shows a better tumor contrast and absolute tumor activity accumulation compared to DOTA-Aca-BBN(7-14). Studies on metabolic stability for both tracers on organ homogenates showed that 64Cu-DOTA-[Lys3]BBN is relatively stable. This study demonstrated that both tracers are suitable for targeted PET imaging to detect the expression of GRPR in prostate cancer, while 64Cu-DOTA-[Lys3]BBN may have a better potential for clinical translation.

Original languageEnglish (US)
Pages (from-to)371-380
Number of pages10
JournalNuclear Medicine and Biology
Volume33
Issue number3
DOIs
StatePublished - Apr 2006
Externally publishedYes

Bibliographical note

Funding Information:
Supported, in part, by DOD Prostate Cancer Research Program (PCRP) New Investigator Award (NIA) DAMD1717-03-1-0143, National Cancer Institute (NCI) Grant R21 CA102123, National Institute of Biomedical Imaging and Bioengineering (NIBIB) Grant R21 EB001785, Department of Defense (DOD) Breast Cancer Research Program (BCRP) Concept Award DAMD17-03-1-0752, DOD BCRP IDEA Award W81XWH-04-1-0697, American Lung Association California (ALAC), the Society of Nuclear Medicine Education and Research Foundation, National Cancer Institute (NCI) Small Animal Imaging Resource Program (SAIRP) R24 CA93862, NCI In Vivo Cellular Molecular Imaging Center (ICMIC) grant P50 CA114747, and NCI Centers of Cancer Nanotechnology Excellence (CCNE) U54 grant. The production of Cu-64 at Washington University School of Medicine is supported by the NCI grant R24 CA86307.

Keywords

  • Bombesin
  • Cu
  • GRP Receptor
  • MicroPET
  • Prostate Cancer

Fingerprint

Dive into the research topics of 'Comparative in vitro and in vivo evaluation of two 64Cu-labeled bombesin analogs in a mouse model of human prostate adenocarcinoma'. Together they form a unique fingerprint.

Cite this