Chemokine receptor 4 targeted protein MRI contrast agent for early detection of liver metastases

Shanshan Tan; Hua Yang; Shenghui Xue; Jingjuan Qiao; Mani Salarian; Khan Hekmatyar; Yuguang Meng; Rao Mukkavilli; Fan Pu; Oluwatosin Y Odubade; Wayne Harris; Yan Hai; Melinda L Yushak; Vanessa M Morales-Tirado; Pardeep Mittal; Phillip Z Sun; David Lawson; Hans E Grossniklaus; Jenny J Yang

doi:10.1126/sciadv.aav7504

Chemokine receptor 4 targeted protein MRI contrast agent for early detection of liver metastases

Sci Adv. 2020 Feb 7;6(6):eaav7504. doi: 10.1126/sciadv.aav7504. eCollection 2020 Feb.

Authors

Shanshan Tan¹, Hua Yang², Shenghui Xue³, Jingjuan Qiao¹, Mani Salarian¹, Khan Hekmatyar⁴, Yuguang Meng⁵, Rao Mukkavilli⁶, Fan Pu¹, Oluwatosin Y Odubade¹, Wayne Harris⁷, Yan Hai⁸, Melinda L Yushak⁷, Vanessa M Morales-Tirado⁹, Pardeep Mittal¹⁰, Phillip Z Sun⁵, David Lawson⁷, Hans E Grossniklaus², Jenny J Yang^{1

11}

Affiliations

¹ Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
² Department of Ophthalmology, Emory University, Atlanta, GA 30322, USA.
³ InLighta Biosciences LLC, Atlanta, GA 30303, USA.
⁴ Bioimaging Research Center, University of Georgia, Athens, GA 30602, USA.
⁵ Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
⁶ Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
⁷ Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
⁸ Department of Mathematics and Statistics, Georgia State University, Atlanta, GA 30303, USA.
⁹ Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
¹⁰ Department of Radiology and Imaging, Augusta University, Augusta, GA 30912, USA.
¹¹ Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.

Abstract

Liver metastases often progress from primary cancers including uveal melanoma (UM), breast, and colon cancer. Molecular biomarker imaging is a new non-invasive approach for detecting early stage tumors. Here, we report the elevated expression of chemokine receptor 4 (CXCR4) in liver metastases in UM patients and metastatic UM mouse models, and development of a CXCR4-targeted MRI contrast agent, ProCA32.CXCR4, for sensitive MRI detection of UM liver metastases. ProCA32.CXCR4 exhibits high relaxivities (r ₁ = 30.9 mM^-1 s^-1, r ₂ = 43.2 mM^-1 s^-1, 1.5 T; r ₁ = 23.5 mM^-1 s^-1, r ₂ = 98.6 mM^-1 s^-1, 7.0 T), strong CXCR4 binding (K _d = 1.10 ± 0.18 μM), CXCR4 molecular imaging capability in metastatic and intrahepatic xenotransplantation UM mouse models. ProCA32.CXCR4 enables detecting UM liver metastases as small as 0.1 mm³. Further development of the CXCR4-targeted imaging agent should have strong translation potential for early detection, surveillance, and treatment stratification of liver metastases patients.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers*
Contrast Media* / chemistry
Disease Models, Animal
Early Detection of Cancer
Gene Expression
Humans
Liver Neoplasms / diagnostic imaging*
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology
Magnetic Resonance Imaging* / methods
Mice
Models, Molecular
Molecular Imaging*
Neoplasm Metastasis
Protein Binding
ROC Curve
Receptors, CXCR4 / chemistry
Receptors, CXCR4 / genetics
Receptors, CXCR4 / metabolism*
Reproducibility of Results
Structure-Activity Relationship

Substances

Biomarkers
CXCR4 protein, human
Contrast Media
Receptors, CXCR4

Abstract

Publication types

MeSH terms

Substances

Grants and funding