Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach

The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for th...

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Autores principales:	Marta Braga, Chee Hau Leow, Javier Hernandez Gil, Jin H. Teh, Laurence Carroll, Nicholas J. Long, Meng-Xing Tang, Eric O. Aboagye
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5fcceb31271645ffa7d7b464bf6bd2c7
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spelling	oai:doaj.org-article:5fcceb31271645ffa7d7b464bf6bd2c72021-11-25T06:19:43ZInvestigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach1932-6203https://doaj.org/article/5fcceb31271645ffa7d7b464bf6bd2c72021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601444/?tool=EBIhttps://doaj.org/toc/1932-6203The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for therapeutic stratification and monitoring. PET agents enjoy the most success, but more cost-effective and radiation-free approaches such as ultrasound (US) imaging could represent an attractive alternative. In this work, we developed a targeted microbubble (MB) for imaging of vascular CXCR4 expression in cancer. A CXCR4-targeted MB was developed through incorporation of the T140 peptide into the MB shell. Binding properties of the T140-MB and control, non-targeted MB (NT-MB) were evaluated in MDA-MB-231 cells where CXCR4 expression was knocked-down (via shRNA) through optical imaging, and in the lymphoma tumor models U2932 and SuDHL8 (high and low CXCR4 expression, respectively) by US imaging. PET imaging of [18F]MCFB, a tumor-penetrating CXCR4-targeted small molecule, was used to provide whole-tumor CXCR4 readouts. CXCR4 expression and microvessel density were performed by immunohistochemistry analysis and western blot. T140-MB were formed with similar properties to NT-MB and accumulated sensitively and specifically in cells according to their CXCR4 expression. In NOD SCID mice, T140-MB persisted longer in tumors than NT-MB, indicative of target interaction, but showed no difference between U2932 and SuDHL8. In contrast, PET imaging with [18F]MCFB showed a marked difference in tumor uptake at 40–60 min post-injection between the two tumor models (p<0.05). Ex vivo analysis revealed that the large differences in CXCR4 expression between the two models are not reflected in the vascular compartment, where the MB are restricted; in fact, microvessel density and CXCR4 expression in the vasculature was comparable between U2932 and SuDHL8 tumors. In conclusion, we successfully developed a T140-MB that can be used for imaging CXCR4 expression in the tumor vasculature.Marta BragaChee Hau LeowJavier Hernandez GilJin H. TehLaurence CarrollNicholas J. LongMeng-Xing TangEric O. AboagyePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marta Braga Chee Hau Leow Javier Hernandez Gil Jin H. Teh Laurence Carroll Nicholas J. Long Meng-Xing Tang Eric O. Aboagye Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach
description	The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for therapeutic stratification and monitoring. PET agents enjoy the most success, but more cost-effective and radiation-free approaches such as ultrasound (US) imaging could represent an attractive alternative. In this work, we developed a targeted microbubble (MB) for imaging of vascular CXCR4 expression in cancer. A CXCR4-targeted MB was developed through incorporation of the T140 peptide into the MB shell. Binding properties of the T140-MB and control, non-targeted MB (NT-MB) were evaluated in MDA-MB-231 cells where CXCR4 expression was knocked-down (via shRNA) through optical imaging, and in the lymphoma tumor models U2932 and SuDHL8 (high and low CXCR4 expression, respectively) by US imaging. PET imaging of [18F]MCFB, a tumor-penetrating CXCR4-targeted small molecule, was used to provide whole-tumor CXCR4 readouts. CXCR4 expression and microvessel density were performed by immunohistochemistry analysis and western blot. T140-MB were formed with similar properties to NT-MB and accumulated sensitively and specifically in cells according to their CXCR4 expression. In NOD SCID mice, T140-MB persisted longer in tumors than NT-MB, indicative of target interaction, but showed no difference between U2932 and SuDHL8. In contrast, PET imaging with [18F]MCFB showed a marked difference in tumor uptake at 40–60 min post-injection between the two tumor models (p<0.05). Ex vivo analysis revealed that the large differences in CXCR4 expression between the two models are not reflected in the vascular compartment, where the MB are restricted; in fact, microvessel density and CXCR4 expression in the vasculature was comparable between U2932 and SuDHL8 tumors. In conclusion, we successfully developed a T140-MB that can be used for imaging CXCR4 expression in the tumor vasculature.
format	article
author	Marta Braga Chee Hau Leow Javier Hernandez Gil Jin H. Teh Laurence Carroll Nicholas J. Long Meng-Xing Tang Eric O. Aboagye
author_facet	Marta Braga Chee Hau Leow Javier Hernandez Gil Jin H. Teh Laurence Carroll Nicholas J. Long Meng-Xing Tang Eric O. Aboagye
author_sort	Marta Braga
title	Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach
title_short	Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach
title_full	Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach
title_fullStr	Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach
title_full_unstemmed	Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach
title_sort	investigating cxcr4 expression of tumor cells and the vascular compartment: a multimodal approach
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5fcceb31271645ffa7d7b464bf6bd2c7
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Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach

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