Dynamic contrast enhanced MRI in clinical and basic researches: differentiating vertebral pathologic fracture, tumor targeting molecular imaging, and early assessment of anti-angiogenic treatment response
Date Issued
2011
Date
2011
Author(s)
Chen, Wei-Tsung
Abstract
Clinical (part 1) and basic researches (part 2, 3) were included in this thesis. By using dynamic contrast enhanced (DCE) MRI, we first demonstrated its ability for revealing hemodynamic changes in vertebral compression fractures, and successfully differentiated pathologic form benign vertebral compression fracture by analyzing the blood perfusion patterns and parameters. We established an effective and easy way for the diagnosis of pathologic vertebral compression fracture in cases with equivocal conventional MR findings. This is valuable when the primary malignancy is not known by the patient or physicians. If the pathologic fractures are misdiagnosed, the proper treatment timing will be delayed.
We also found an interesting issue of the relationship between the vertebral blood perfusion status and aging process. We noticed that the older our patients, the lower the bone marrow blood perfusion degree, revealed by DCE MRI. To validate this finding, we analyzed DCE MRI data from 60 subjects with varied age in both genders, and found a significant negative correlation between vertebral marrow blood perfusion and aging, this phenomenon was especially noticeable in female subjects.
According to above findings, we hypothesized that there might be a correlation between atherosclerosis and marrow blood perfusion. A sex- and age- matched study was proposed. We selected patients whose internal carotid artery intemal thickness was larger than 1mm from a database of 2245 patients who received carotid artery ultrasonography in our hospital, once a thick IMT subject was included in this study, another subject was selected with normal IMT from the same database under sex- and age matched policy. Totally 43 sex- an age- matched pairs were included in this study. Out results showed a significant negative correlation between internal carotid intemal thickness and marrow blood perfusion.
We also noticed that the fatty marrow deposition progressed with aging process, and hypothesized that the lipid ratio within bone marrow might have a correlation with marrow blood perfusion. MR spectroscopy was used to analyze MRS data from 50 female subjects to reveal the relationship between the marrow lipid water ratio and marrow blood perfusion, and a significant negative correlation between marrow blood perfusion and marrow lipid water ratio was proven.
In the clinical research portion, we first developed an easy and reliable method to differentiate pathologic vertebral compression fracture from osteoporotic fracture, by analyzing the blood perfusion patterns. Furthermore, we evaluated the vertebral marrow blood perfusion phenomenon with aging, atherosclerosis and marrow lipid water ratio, such relationships were not explored in the literature. Our results lead us to hypothesize that there is a link between marrow blood perfusion and osteoporosis, which is an important issue in aging medicine. In later studies, professor Shih demonstrated that there is a positive correlation between bone mineral density and marrow blood perfusion. This finding implied that ‘ischemia’ might be an important factor related to osteoporosis.
In the basic research portion, the aim of our study was to use DCE MRI combine with receptor-targeted MRI contrast medium to detect molecular signatures in tumors. We first successfully synthesized a folate conjugated, Gd-DTPA loaded polyethylene glycol (PEG) dendrimer, as a folate receptor (FR) targeted contrast medium. We observed hemodynamic changes of FR positive and FR negative tumors in living mouse DCE MR imaging. Our results showed that the conjugation of molecular ligand to a carrier loaded with Gd-DTPA is feasible for receptor targeted MR imaging.
This methodology not only turned a non-specific MR contrast medium into a receptor specific MR contrast agent, but also had the advantage of MR signal magnification, but adding multiple Gd-DTPA onto a dendrimer, hence, the sensitivity of this receptor contrast medium will increase. The T1 relaxicity of Gd-DTPA was 2.9(mM S)-1，however, the T1 relaxicity of the FR targeted contrast medium was 53.2(mM S)-1, which was 18.3 fold higher.
In the third part of the thesis, we demonstrated that the cRGD conjugated contrast medium can attached to the cell surface of the integrin αvβ3 expressing U87 MG in cellular attachment experiments; we also showed the targeting ability of this integrin αvβ3 targeting contrast medium in living animals, by using DCE MRI. The 30-min contrast washout percentage derived form DCE MRI showed that the integrin αvβ3 targeting contrast medium stayed longer in sites of tumor angiogenesis. If we used cRAD conjugated contrast medium as a control drug, in stead of RGD domain, the persistent contrast enhancement phenomenon was disappeared. However, in the anti-integrin αvβ3 monoclonal antibody or anti-VEGF monoclonal antibody studies, the persistent contrast enhancement phenomenon was disappeared, and a rapid contrast washout pattern was observed rapidly following the anti-angiogenetic therapy, even before the tumor volume decreased, which was observed 10 days after the start of anti-angiogenetic therapy. We confirmed our hypothesis, i.e., receptor targeted MR imaging was achievable and can be used in early assessment of target therapy, even in advance to tumor size decrease. Such ability is beyond any present medical imaging modalities.
In conclusion, we have demonstrated the clinical application of DCE MRI for differentiating pathologic vertebral compression fracture. The ability of DCE MRI is reinforced by using receptor targeting MR contrast medium. We have not only demonstrated the ability of folate receptor and integrin αvβ3 targeting conjugates in vitro and in vivo, but also showed its superior ability in the early assessment of anti-angiogenic therapy. Our findings will bring important impacts for future MR molecular imaging and clinical cancer treatment strategies.
Subjects
dynamic contrast enhanced MRI
blood perfusion
compression fracture
molecular imaging
folate receptor
angiogenesis
integrin αvβ3
anti-angiogenic therapy
SDGs
Type
thesis
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