TY - JOUR
T1 - Improved magnetic resonance molecular imaging of tumor angiogenesis by avidin-induced clearance of nonbound bimodal liposomes
AU - Van Tilborg, Geralda A.F.
AU - Mulder, Willem J.M.
AU - Van Der Schaft, Daisy W.J.
AU - Reutelingsperger, Chris P.M.
AU - Griffioen, Arjan W.
AU - Strijkers, Gustav J.
AU - Nicolay, Klaas
N1 - Funding Information:
Abbreviations: ICP-AES, inductively coupled plasma atomic emission spectrometry; ICP-MS, inductively coupled plasma mass spectrometry; avidin-2-B4F, avidin-2-biotin-4-fluorescein Address all correspondence to: Geralda A.F. van Tilborg, Eindhoven University of Technology, NLaag B2.03, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands. E-mail: g.a.f.v.tilborg@tue.nl 1This study was funded in part by the BSIK program entitled Molecular Imaging of Ischemic Heart Disease (project number BSIK03033) and by the EC – FP6-project DiMI, LSHB-CT-2005-512146. This study was performed in the framework of the European Cooperation in Scientific and Technical Research (COST) D38 Action Metal-Based Systems for Molecular Imaging Applications. Received 25 July 2008; Revised 29 September 2008; Accepted 13 October 2008 Copyright © 2008 Neoplasia Press, Inc. All rights reserved 1522-8002/08/$25.00 DOI 10.1593/neo.08858
PY - 2008/12
Y1 - 2008/12
N2 - Angiogenic, that is, newly formed, blood vessels play an important role in tumor growth and metastasis and are a potential target for tumor treatment. In previous studies, the αvβ3 integrin, which is strongly expressed in angiogenic vessels, has been used as a target for Arg-Gly-Asp (RGD)-functionalized nanoparticulate contrast agents for magnetic resonance imaging-based visualization of angiogenesis. In the present study, the target-to-background ratio was increased by diminishing the nonspecific contrast enhancement originating from contrast material present in the blood pool. This was accomplished by the use of a so-called avidin chase, which allowed rapid clearance of nonbound paramagnetic RGD-biotin-liposomes from the blood circulation. C57BL/6 mice, bearing a B16F10 mouse melanoma, received RGD-functionalized or untargeted biotin-liposomes, which was followed by avidin infusion or no infusion. Precontrast, postcontrast, and postavidin T 1-weighted magnetic resonance images were acquired at 6.3 T. Postcontrast images showed similar percentages of contrast-enhanced pixels in the tumors of mice that received RGD-biotin-liposomes and biotin-liposomes. Post avidin infusion this percentage rapidly decreased to precontrast levels for biotin-liposomes, whereas a significant amount of contrast-enhanced pixels remained present for RGD-biotin-liposomes. These results showed that besides target-associated contrast agent, the circulating contrast agent contributed significantly to the contrast enhancement as well. Ex vivo fluorescence microscopy confirmed association of the RGD-biotin-liposomes to tumor endothelial cells bothwith and without avidin infusion, whereas biotin-liposomes were predominantly found within the vessel lumen. The clearance methodology presented in this study successfully enhanced the specificity of molecular magnetic resonance imaging and opens exciting possibilities for studying detection limits and targeting kinetics of site-directed contrast agents in vivo.
AB - Angiogenic, that is, newly formed, blood vessels play an important role in tumor growth and metastasis and are a potential target for tumor treatment. In previous studies, the αvβ3 integrin, which is strongly expressed in angiogenic vessels, has been used as a target for Arg-Gly-Asp (RGD)-functionalized nanoparticulate contrast agents for magnetic resonance imaging-based visualization of angiogenesis. In the present study, the target-to-background ratio was increased by diminishing the nonspecific contrast enhancement originating from contrast material present in the blood pool. This was accomplished by the use of a so-called avidin chase, which allowed rapid clearance of nonbound paramagnetic RGD-biotin-liposomes from the blood circulation. C57BL/6 mice, bearing a B16F10 mouse melanoma, received RGD-functionalized or untargeted biotin-liposomes, which was followed by avidin infusion or no infusion. Precontrast, postcontrast, and postavidin T 1-weighted magnetic resonance images were acquired at 6.3 T. Postcontrast images showed similar percentages of contrast-enhanced pixels in the tumors of mice that received RGD-biotin-liposomes and biotin-liposomes. Post avidin infusion this percentage rapidly decreased to precontrast levels for biotin-liposomes, whereas a significant amount of contrast-enhanced pixels remained present for RGD-biotin-liposomes. These results showed that besides target-associated contrast agent, the circulating contrast agent contributed significantly to the contrast enhancement as well. Ex vivo fluorescence microscopy confirmed association of the RGD-biotin-liposomes to tumor endothelial cells bothwith and without avidin infusion, whereas biotin-liposomes were predominantly found within the vessel lumen. The clearance methodology presented in this study successfully enhanced the specificity of molecular magnetic resonance imaging and opens exciting possibilities for studying detection limits and targeting kinetics of site-directed contrast agents in vivo.
UR - http://www.scopus.com/inward/record.url?scp=57349155015&partnerID=8YFLogxK
U2 - 10.1593/neo.08858
DO - 10.1593/neo.08858
M3 - Article
C2 - 19048124
AN - SCOPUS:57349155015
SN - 1522-8002
VL - 10
SP - 1459
EP - 1469
JO - Neoplasia
JF - Neoplasia
IS - 12
ER -