|Molecular MRI Monitoring of Therapy & Disease|
|Thermosensitive Polymer-Modified Liposome as a
Multimodal and Multifunctional Carrier for MRI and Optical Imaging:
Tumor Detection, Visualization of Triggered Drug Release, and
Ichio Aoki1, Misao Yoneyama1, Jun Hirose2, Yuzuru Minemoto3, Takayoshi Koyama3, Sadahito Aoshima4, Jeff Kershaw1, Kenji Kono2, Yukihito Ishizaka3, Iwao Kanno1
1National Institute of Radiological Sciences, Chiba, Japan; 2Osaka Prefecture University, Osaka, Japan; 3International Medical Center of Japan, Tokyo, Japan; 4Osaka University, Osaka, Japan
A liposomal drug-delivery-system (DDS) will be help to avoid the side effects of chemotherapy by releasing anticancer drug at the tumor site. To improve the liposomal-DDS, we developed a multimodal thermo-sensitive polymer-modified liposomes (MTPL) and added new factors, long-term stability of the liposome in-vivo, passive accumulation in the tumor, and multimodal observation with MRI and optical imaging. The purpose of this study was to investigate whether 1) MRI and optical imaging can visualize MTPL accumulation in the tumor, 2) MTPL allows visualization of the drug-release after being triggered by mild-heating, and 3) MTPL can provide anti-tumor effects after treatment.
Trifluoromisonidazole (TFMISO) as Imaging Agent of
Hypoxia in Solid Tumors - An In Vivo 19F MR Study
Ellen Ackerstaff1, Khushali Kotedia1, Mihai Coman1, Kristen L. Zakian1, Sean A. Burke1, Sean D. Carlin1, Joseph O'Donoghue1, Clifton C. Ling1, Jason A. Koutcher1
1Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Tumor hypoxia may influence treatment response and outcome. Thus, we investigated the potential of Trifluoromisonidazole (TFMISO) to measure hypoxia in solid tumors by in vivo 19F MRS and MRSI in two animal models of cancer breathing either air or 100% oxygen. Intratumoral TFMISO concentration increased with tumor growth in the MCa tumor model irrespective of amount of oxygen applied. In the R3327-AT model, intratumoral TFMISO levels were only moderately influenced by tumor growth but seemed to decrease in response to breathing of 100% oxygen in tumors below ~600mm3. Our results suggest that TFMISO may be useful for tumor hypoxia imaging by MR.
|MRI-Guided Targeting of Magnetic
Nanoparticles in an Orthotopic 9L Gliosarcoma Brain Tumor Model
Beata Chertok1, Allan E. David1, Bradford A. Moffat2, Brian D. Ross1, Victor C. Yang1
1University of Michigan, Ann Arbor, Michigan, USA; 2University of Melbourne, Melbourne, Australia
This study investigated the utility of MRI to guide the alignment of a brain tumor lesion with magnetic field gradient to improve on specificity of magnetic nanoparticle accumulation within the tumor by an externally applied magnetic field in orthotopic 9L glioma model.
MR Molecular Imaging of Neovasculature May Predict
Response to Antiangiogenic Therapy in Animal Cancer Models
Anne H. Schmieder1, Patrick M. Winter1, Todd A. Williams1, John S. Allen1, Grace Hu1, Huiying Zhang1, Shelton D. Caruthers1, 2, Samuel A. Wickline1, Gregory M. Lanza1
1Washington University School of Medicine, St Louis, Missouri, USA; 2Philips Medical Systems, Andover, Massachusetts, USA
Noninvasive high-resolution MR molecular imaging can provide a unique tool to characterize and quantify neovasculature in tumors. 3D neovascular mapping in mice implanted with MDA435 tumors revealed sparse neovascularity, which was further decreased with α5β1-targeted but not αvβ3-targeted antiangiogenic treatment. However, MDA435 tumor size was unaffected by either regimen, suggesting that MDA435 xenograft tumor growth has little dependence on angiogenesis, unlike previous results in the rabbit Vx2 model. These data illustrate the prognostic opportunities afforded by noninvasive high-resolution MR molecular imaging that may be clinically relevant in establishing personalized therapy regimens.
In Vivo Intracellular PO2
Measurements of Perfluorocarbon Labeled 9L Glioma Cells
Deepak K. Kadayakkara1, Lisa K. Pusateri1, Hongyan Xu1, Jelena M. Janjic1, Eric T. Ahrens1, 2
1Carnegie Mellon University, Pittsburgh, Pennsylvania, USA; 2Pittsburgh NMR Centre for Biomedical Sciences, Pittsburgh, Pennsylvania, USA
In vivo oximetry of tumor tissues by MRI has enormous potential for preclinical evaluation of new therapeutics. Existing 19F relaxometry methods measure the pO2 of the tumor cells indirectly from the sequestered perfluorocarbon nanoparticles in the tumor periphery following systemic administration. In this study, we demonstrate the feasibility of measuring the direct intracellular pO2 of 9L gliosarcoma cells in the rat brain using 19F MRS. The 9L glioma cells were labeled with perfluoro-15-crown-5 ether (CE) prior to implantation and pO2 was measured using 19F T1 relaxation. The method will be used to study the real-time dynamics of tumor cell metabolism before and after the delivery of therapeutics.
MR-Visualization of Tumors in Mice by Dy-Loaded
Liposomes as T2*-Susceptibility Agents. Evidence for a Macrophage
Silvio Aime1, Daniela Delli Castelli1, Enzo Terreno1, Claudia Cabella2, Massimo Visigalli, Linda Chabaane, Stefania Lanzardo, Carla Carrera
1University of Turin, Turin, Italy; 2CRM Cracco Imaging S.p.A., Italy
Dy(III) loaded liposomes are T2* susceptibility agents that provide an excellent visualization of tumors. The lack of specific tumor uptake in vivo has been associated to the efficient removal of liposomes operated by tumor associated macrophages.
19F MRS Allows Quantitative Evaluation of
Anti-Angiogenic Therapy Delivered with Targeted Perfluorocarbon
Emily Alexandria Waters1, Ralph W. Fuhrhop1, John S. Allen1, Gregory M. Lanza1, Samuel A. Wickline1
1Washington University School of Medicine, Saint Louis, Missouri, USA
Once diagnosed, aortic valve disease can progress rapidly to critical stenosis requiring surgical valve replacement. We illustrate the use of molecularly targeted drug-bearing nanoparticles for both early diagnosis and therapy of experimental aortic stenosis (AS) by targeting the inflammatory angiogenic components of AS with the use of αv β 3-integrin binding perfluorocarbon nanoparticles. In this case MR spectroscopy of the unique 19F signal from the nanoparticles is used to quantify the extent of angiogenesis, which expresses the α;v β 3 integrin, and to measure the response to antiangiogenic drug therapy. We utilize a cholesterol-fed rabbit model of AS that exhibits gross thickening, macrophage infiltration, and angiogenesis with abundant α;v β 3 endothelial biomarkers that can be quantified with 19F MRS to report drug efficacy.
Correspondence of Magnetic Resonance Molecular
Imaging to Quantitative Determination of E- And P-Selectin Expression in
Albert Yongwon Jin1, Ursula I. Tuor2, Jaspreet Kaur1, Dave Rushforth2, S Boutry3, Tadeusz Foniok2, Robert N. Muller3, Boguslaw Tomanek2, Philip A. Barber1
1University of Calgary, Calgary, Canada; 2National Research Council of Canada, Calgary, Canada; 3University of Mons-Hainaut, Mons-Hainaut, Belgium
Endothelial activation following cerebral ischemia and reperfusion involves the expression of the adhesion molecules P- and E-selectin. In a model of transient focal cerebral ischemia and reperfusion, magnetic resonance molecular imaging using the selectin-specific contrast agent Gd-DTPA-B(sLeX)A demonstrated differences in the accumulation of targeted and non-targeted contrast within the ischemic hemisphere in P-selectin knockout mice compared to the wild-type. These differences were correlated to the quantitative determination of P- and E-selectin expression in the brain, and led to the novel observation that E-selectin is upregulated in the ischemic hemisphere following acute stroke in P-selectin-deficient mice.
Manganese Guided Cellular MRI of Human Embryonic Stem
Mayumi Yamada1, Paul T. Gurney1, Pratima Kundu1, Robert C. Robbins1, Phillip C. Yang1
1Stanford University, Stanford, California , USA
Human embryonic stem cells (hESC) have demonstrated the ability to restore the injured myocardium. MRI has emerged as one of the predominant imaging modalities using iron-oxide nanoparticles to localize the transplanted cells in the myocardium. However, fundamental biological information regarding the viability of the transplanted cells can not be monitored. In this study, we employed MnCl2 (manganese chloride) guided cellular MRI to determine viability of hESC.
|Single Cell Level Detection of Gadolinium-Labeled
Stem Cells Using a Clinical 3.0T MRI Scanner
Monique Regine Bernsen1, Amber Davinia Moelker1, Sandra T. van Tiel1, Gavin C. Houston2, Gabriel P. Krestin1, Piotr A. Wielopolski1
1Erasmus MC, Rotterdam, Netherlands; 2GE Healthcare, Den Bosch, Netherlands
The ability to track transplanted cells in vivo is considered a crucial point in the development and validation of cell-based therapy. To overcome some limitations of the negative contrast provided by labeling of cells with iron-oxide particles, we have developed an efficient labeling method for incorporation of Gd into cells. Using cationic lipid-based nano-particles (Gd-lipo) efficient labeling of stem cells was achieved allowing visualization of cells by positive contrast at single cell level. Also in vivo imaging of approximately 10.000 labeled cells injected in the myocardium of living syngenic cells was achieved.