Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma

Rameshwar Patil,1 Anna Galstyan,1 Zachary B Grodzinski,1 Ekaterina S Shatalova,1 Shawn Wagner,2 Liron L Israel,1 Hui Ding,1 Keith L Black,1 Julia Y Ljubimova,1,3 Eggehard Holler1 1Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Biomedical...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Patil R, Galstyan A, Grodzinski ZB, Shatalova ES, Wagner S, Israel LL, Ding H, Black KL, Ljubimova JY, Holler E
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	magnetic resonance imaging gd-dota structure variation blood-brain barrier tumor targeting accelerated diagnosis Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/858be7154d72495c962066a05d71b156
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:858be7154d72495c962066a05d71b156
record_format	dspace
spelling	oai:doaj.org-article:858be7154d72495c962066a05d71b1562021-12-02T13:12:32ZSingle- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma1178-2013https://doaj.org/article/858be7154d72495c962066a05d71b1562020-05-01T00:00:00Zhttps://www.dovepress.com/single--and-multi-arm-gadolinium-mri-contrast-agents-for-targeted-imag-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Rameshwar Patil,1 Anna Galstyan,1 Zachary B Grodzinski,1 Ekaterina S Shatalova,1 Shawn Wagner,2 Liron L Israel,1 Hui Ding,1 Keith L Black,1 Julia Y Ljubimova,1,3 Eggehard Holler1 1Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Oncology Translational Program, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USACorrespondence: Eggehard HollerNanomedicine Research Center, Department of Neurosurgery, Cedars Sinai Medical Center, 127 S. San Vicente Boulevard, Suite A8304, Los Angeles, CA 90048 Tel +1 310 423-6630Email eggehard.holler@cshs.orgBackground: Position of gadolinium atom(s) plays a key role in contrast enhancement of gadolinium-based contrast agents. To gain a better understanding of effects of distance of gadolinium in relation to the nanoconjugate platform, we designed and synthesized single- and multi-arm (“star”) gadolinium conjugates equipped with antibody and peptides for targeting. The contrast agents were studied for their tumor imaging performance in a glioma mouse model.Materials and Methods: Antibody- and peptide-targeted nano contrast agents (NCAs) were synthesized using polymalic acid platforms of different sizes. Gadolinium-DOTA and intermediates were attached as amides and targeting agents such as antibodies and peptides as thioethers. For in vivo experiments, we used human U87MG xenografts as glioma models. Magnetic resonance imaging (MRI) was performed on a Bruker BioSpec 94/20USR 9.4 T small-animal scanner. Delivery of contrast agents across the blood–brain barrier was studied by fluorescent microscopy.Results: All contrast agents accumulated into tumor and showed composition-dependent imaging performance. Peptide-targeted mini-NCAs had hydrodynamic diameters in the range 5.2– 9.4 nm and antibody-targeted NCAs had diameters in the range 15.8– 20.5 nm. Zeta potentials were in the range of – 5.4–− 8.2 mV and − 4.6–− 8.8 mV, respectively. NCAs showed superior relaxivities compared to MultiHance at 9.4 T. The signal enhancement indicated maximum accumulation in tumor 30– 60 minutes after intravenous injection of the mouse tail vein. Only targeted NCAs were retained in tumor for up to 3 hours and displayed contrast enhancement.Conclusion: The novel targeted NCAs with star-PEG features displayed improved relaxivity and greater contrast compared with commercial MultiHance contrast agent. The enhancement by mini-NCAs showed clearance of tumor contrast after 3 hours providing a suitable time window for tumor diagnosis in clinics. The technology provides a great tool with the promise of differential MRI diagnosis of brain tumors.Keywords: magnetic resonance imaging, Gd-DOTA, structure variation, blood–brain barrier, tumor targeting, accelerated diagnosisPatil RGalstyan AGrodzinski ZBShatalova ESWagner SIsrael LLDing HBlack KLLjubimova JYHoller EDove Medical Pressarticlemagnetic resonance imaginggd-dotastructure variationblood-brain barriertumor targetingaccelerated diagnosisMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 3057-3070 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	magnetic resonance imaging gd-dota structure variation blood-brain barrier tumor targeting accelerated diagnosis Medicine (General) R5-920
spellingShingle	magnetic resonance imaging gd-dota structure variation blood-brain barrier tumor targeting accelerated diagnosis Medicine (General) R5-920 Patil R Galstyan A Grodzinski ZB Shatalova ES Wagner S Israel LL Ding H Black KL Ljubimova JY Holler E Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma
description	Rameshwar Patil,1 Anna Galstyan,1 Zachary B Grodzinski,1 Ekaterina S Shatalova,1 Shawn Wagner,2 Liron L Israel,1 Hui Ding,1 Keith L Black,1 Julia Y Ljubimova,1,3 Eggehard Holler1 1Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Oncology Translational Program, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USACorrespondence: Eggehard HollerNanomedicine Research Center, Department of Neurosurgery, Cedars Sinai Medical Center, 127 S. San Vicente Boulevard, Suite A8304, Los Angeles, CA 90048 Tel +1 310 423-6630Email eggehard.holler@cshs.orgBackground: Position of gadolinium atom(s) plays a key role in contrast enhancement of gadolinium-based contrast agents. To gain a better understanding of effects of distance of gadolinium in relation to the nanoconjugate platform, we designed and synthesized single- and multi-arm (“star”) gadolinium conjugates equipped with antibody and peptides for targeting. The contrast agents were studied for their tumor imaging performance in a glioma mouse model.Materials and Methods: Antibody- and peptide-targeted nano contrast agents (NCAs) were synthesized using polymalic acid platforms of different sizes. Gadolinium-DOTA and intermediates were attached as amides and targeting agents such as antibodies and peptides as thioethers. For in vivo experiments, we used human U87MG xenografts as glioma models. Magnetic resonance imaging (MRI) was performed on a Bruker BioSpec 94/20USR 9.4 T small-animal scanner. Delivery of contrast agents across the blood–brain barrier was studied by fluorescent microscopy.Results: All contrast agents accumulated into tumor and showed composition-dependent imaging performance. Peptide-targeted mini-NCAs had hydrodynamic diameters in the range 5.2– 9.4 nm and antibody-targeted NCAs had diameters in the range 15.8– 20.5 nm. Zeta potentials were in the range of – 5.4–− 8.2 mV and − 4.6–− 8.8 mV, respectively. NCAs showed superior relaxivities compared to MultiHance at 9.4 T. The signal enhancement indicated maximum accumulation in tumor 30– 60 minutes after intravenous injection of the mouse tail vein. Only targeted NCAs were retained in tumor for up to 3 hours and displayed contrast enhancement.Conclusion: The novel targeted NCAs with star-PEG features displayed improved relaxivity and greater contrast compared with commercial MultiHance contrast agent. The enhancement by mini-NCAs showed clearance of tumor contrast after 3 hours providing a suitable time window for tumor diagnosis in clinics. The technology provides a great tool with the promise of differential MRI diagnosis of brain tumors.Keywords: magnetic resonance imaging, Gd-DOTA, structure variation, blood–brain barrier, tumor targeting, accelerated diagnosis
format	article
author	Patil R Galstyan A Grodzinski ZB Shatalova ES Wagner S Israel LL Ding H Black KL Ljubimova JY Holler E
author_facet	Patil R Galstyan A Grodzinski ZB Shatalova ES Wagner S Israel LL Ding H Black KL Ljubimova JY Holler E
author_sort	Patil R
title	Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma
title_short	Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma
title_full	Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma
title_fullStr	Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma
title_full_unstemmed	Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma
title_sort	single- and multi-arm gadolinium mri contrast agents for targeted imaging of glioblastoma
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/858be7154d72495c962066a05d71b156
work_keys_str_mv	AT patilr singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma AT galstyana singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma AT grodzinskizb singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma AT shatalovaes singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma AT wagners singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma AT israelll singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma AT dingh singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma AT blackkl singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma AT ljubimovajy singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma AT hollere singleandmultiarmgadoliniummricontrastagentsfortargetedimagingofglioblastoma
_version_	1718393395412467712

Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma

Ejemplares similares