4.6 Article

In vivo Evaluation of an Engineered Cyclotide as Specific CXCR4 Imaging Reagent

期刊

CHEMISTRY-A EUROPEAN JOURNAL
卷 23, 期 58, 页码 14469-14475

出版社

WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201702540

关键词

CXCR4; cyclotides; GPCR; molecular imaging; PET

资金

  1. National Institutes of Health Research [R01-GM113363, R01-CA166131, P30-CA006973, P50-CA103175]
  2. Department of Defense Congressionally Directed Medical Research Programs in Lung Cancer Grant [LC150051]
  3. Breast Cancer Grant [BC121957]
  4. BROAD Medical Research Program-Crohn's and Colitis Foundation of America [483566]
  5. Lupus Research Institute
  6. Whittier Foundation
  7. Alexander and Margaret Stewart Trust
  8. CDMRP [LC150051, 893440] Funding Source: Federal RePORTER

向作者/读者索取更多资源

The CXCR4 chemokine receptor plays a key regulatory role in many biological functions, including embryonic development and controlling leukocyte functions during inflammation and immunity. CXCR4 has been also associated with multiple types of cancers where its overexpression/activation promotes metastasis, angiogenesis, and tumor growth and/or survival. Furthermore, CXCR4 is involved in HIV replication, as it is a co-receptor for viral entry into host cells. Altogether, these features make CXCR4 a very attractive target for the development of imaging and therapeutic agents. Here, the in vivo evaluation of the MCoTI-based cyclotide, MCo-CVX-5c, for the development of imaging agents that target CXCR4 is reported. Cyclotide MCo-CVX-5c is a potent CXCR4 antagonist with a remarkable in vivo resistance to biological degradation in serum. A [Cu-64]-DOTA-labeled version of this cyclotide demonstrated high and significant uptake in U87-stb-CXCR4 tumors compared to the control U87 tumors. Furthermore, protracted imaging studies demonstrated radiotracer retention in the U87-stb-CXCR4 tumor at 24 h post injection. Uptake in U87-stb-CXCR4 tumors could be blocked by unlabeled MCo-CVX-5c, showing high in vivo specificity. These results demonstrate the in vivo specificity and retention of a bioactive molecularly targeted cyclotide and highlight the potential of bioactive cyclotides for the development of new imaging agents that target CXCR4.

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