優勢重點領域拔尖計畫-分子生醫影像研究中心/子計畫三：新世代核磁共振生醫分子影像之研發

2011-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/683092摘要：分子生醫影像為利用非侵入影像的方式研究活體生物細胞內的正常或病理狀態下的組織結構，即時反映生物體生理、病理變化的成像技術，對於目前的醫學研究具有相當之重要性，它為疾病病程的即時監測、基因治療的追蹤、藥物療效評測、提供了嶄新的道路。其技術具有巨大的科研及市場潛力，近年來世界各國都投入了巨額經費，進行開發研究。磁振分子影像核心實驗室之設立，主要為與核磁共振相關之研究，現階段我們將擴展執行中之小鼠肺癌模型之核磁共振分子影像研究。其內容將包含動態顯影灌流MRI影像來評估腫瘤之血管新生，擴散影像來評估腫瘤之細胞性(cellularity)並結合低磁場奈米標靶技術以辨識小動物腫瘤組織。為更進一步研究肺癌的治療評估與機轉，其後續實驗方向將針對腫瘤治療，深入探討其早期治療反應及療效，並研究於生物體內對於抗肺癌用藥之反應機制。主要內容為發展肺癌及其轉移的動物模式，利用動態顯影磁振造影之血管新生評估技術、開發同時具標定肺癌細胞及標定治療之多功能奈米磁振顯影劑(正子造影、磁振造影診斷、與誘發熱治療)、以及發展高訊雜比及高空間解析度之磁振造影技術，用來研究肺癌細胞與肺臟轉移小鼠模式於治療後之即時評估。並利用核醫藥物標記增加對於肺癌之細胞代謝與診斷的研究，同時利用放射線及藥物治療的方式來探討放射線引發之肺臟轉移現象與原發肺癌腫瘤血管新生的關係。結合上述技術之開發將可更進一步提供病灶分子病理資訊並設計多功能甚或智慧型標靶藥劑使醫師得以即時知道用藥之效能與投遞分布情形以計劃最佳化治療策略。在磁振造影之分子影像擷取部份，此核心將整合跨領域的磁振造影技術，包括擴散磁振造影、微灌流磁振造影、顯微磁振造影以建立一個宏觀且領先的磁振分子影像造影技術。此外，本團隊將發展出高效率改良式的高速成像序列及高溫超導射頻線圈造影技術並使用具有強梯度磁場的顯微造影線圈及平行影像技術及其重建演算法，藉以大幅提升影像敏感度、解析度、訊雜比、及取像速度。為了適用於活體動物實驗，本計畫將結合上述改良造影技術於 3T (Tesla)以及7T 磁振造影系統並結合動物正子斷層掃瞄以建立小鼠實驗影像技術整合平台。有了此一最佳化之小動物平台，將有助於研究奈米顆粒顯影劑的對比特性、建立適合於磁振照影對比強化的肺癌動物模型之造影平台、並評估動態顯影之核磁共振照影技術與合成之奈米顆粒顯影劑之體內生物分佈及標記之功效。並且結合MRS(磁振頻譜)分析並定量顯影劑之劑量, 做為往後實驗定量分析之利器。此外利用 DEC-及DW-MRI技術，做為不同肺癌靶標治療藥物之抗血管新生及細胞凋零效果之活體評估，並嘗試由本研究中瞭解治療肺癌過程中，抗癌藥物之機轉。而後續即將添購之Animal CT 以及 C13 MRI，更可以及藉此多種技術平台，篩選有潛力之抗肺癌之藥物。並進一步探討由動物模式到臨床轉譯醫學(translational medicine)的可行性。而在加入hyperpolarized MRI-Lung 診斷方式，更可以提升MRI在肺空腔內影像之成像效果，將達到磁振造影技術推向下一個里程碑。同時我們亦發展針對磁振造影分子影像所使用奈米顯影劑的量化磁化率映像(quantitative susceptibility mapping )技術。其內容包括開發奈米顯影劑的定量方式、並且應用在腫瘤細胞或是其他大腦的出血性疾病上作定量分析。由於目前的磁振造影分子影像定量均是以外加強磁性奈米粒子(Ultrasmall Superparamagnetic Iron Oxide)來產生T2*加權的磁振影像對比，再利用相位的影像資料計算強磁性奈米粒子因為磁化率的不同所形成的磁場干擾，最後得到不同磁化率在空間中的分佈。並使用自動化的規範化(regularization)來降低人工假影(artifact)，來達到一良好對比的磁化率量化映像。最後，將此磁化率量化映像利用奈米顯影劑的仿體驗證，並且將其應用在活體動物腫瘤細胞的顯影劑定量分析。本核心預計在未來五年將發展(1) 動態顯影灌流MRI影像來評估腫瘤以及藥物傳遞後的生物資訊。(2)結合動物用CT成像設備，與本實驗室現有之7T MRI相互交叉比對與影像評估。(3)整合多種成像技術，將分子醫學推向更多生物資訊化之平台。(4)利用多種醫學影像(PET/CT/Optical)之儀器，在加入磁振造影技術評估缺血性疾病。(5)建立更完整且具療效之動物用放射線治療平台，將呈現更完整之診斷，進而應用於臨床病患。(6)將多種技術整合，經過各種實驗測試，最終可將此種技術轉移應用於臨床上，達成轉譯醫學之貢獻。<br> Abstract: Biomedical molecular imaging is the imaging technology that can detect desired specific biomarkers in vivo using various imaging modalities. It successfully combined molecular biology, nano-technology and clinical medicine to fulfill this purpose. This core not only provided animal and clinical disease models for early detection, diagnosis and effective treatment but also provide molecular, sub-cellular information, and functional dynamic imaging for biomedical processes. To achieve long-term dynamic detection of specific gene expression in vivo to understand the different periods, different gene expression under different circumstances, and to provide interaction of genes to meet molecular biology, cell biology and development of biomedical research requirements in the post-genomic era. The MRI core lab is established to develop MR related researches. Currently, we will expand our prior study of MR molecular imaging of mice lung cancer model. Dynamic contrast-enhanced (DCE) perfusion MR for evaluating tumor angiogenesis, diffusion weighted (DW) imaging for tumor cellularity and nanoparticle targeted contrast agent for specific receptors will be included. The future studies will be focused on the therapeutic of lung cancer and early development to contribute the cancer drug development. The first main approach is to reveal the mechanism of early development and metastasis of lung cancer in animal model. By using the dynamic contrast enhanced MR imaging (DCE) and angiographic imaging, specific target of nanoparticle (PET, MR and thermotherapy) and high resolution/low noise MR technique, it will be a high impact research for the disclosing of lung cancer metastasis and therapeutic efficiency. To reveal cellular metabolism and diagnosis of lung cancer, we will combine the multiple modalities, including nuclear medicine, radiotherapy and drug efficiency, to improve this study. In summary, as we describe above, multiple modalities could be converged to a useful knowledge, paralleled by molecular pathological informatics. Those information will provide the diagnosis, specific targeting and pharmacodynamic-kinetics distribution for optimizing the strategy of therapeutic in clinical application. In the part of MR imaging acquisition, this core lab will apply interdisciplinary MR techniques, including diffusion tensor image, diffusion weighted image and high-resolution microscopic MR, to develop macroscopic and first-leading MR technique. Multimodality imaging is an emerging field for diagnosis and treatment planning. As shown in recent experiences of PET-CT using different isotopes, the functional information of nuclear medicine is well demonstrated on detailed CT images and shown of successful clinical implementation. To achieve high quality molecular MR imaging, we have developed high temperature superconducting RF coil with strong imaging gradient insert and parallel acquisition to ensure excellent signal-to-noise ratio, high resolution, and fast acquisition in this project. An integrated multi-modality approach using DCE-MRI, DW-MRI, microscopic molecular MRI using smart contrast agents and micro-PET imaging, will provide a full-spectrum functional evaluation with updated technology. These approaches will be very valuable to characterize both in vitro and in vivo mice models of NSCLC and metastatic lung cancer. To have quantitative molecular imaging capability, we have also worked on susceptibility imaging for USPIO (Ultrasmall Superparamagnetic Iron Oxide). An automatic regularized algorithm has to be implemented to eliminate artifact to achieve good contrast images. This quantitative susceptibility mapping will be validated and applied in quantifying tumor cell number and in vivo animal study. With this study, we will be able to establish an advanced MR and PET animal platform for functional and molecular imaging to probe the underlined mechanisms of angiogenesis and metastasis of mouse cancer model in vivo. This integrated molecular imaging platform could be extended to clinical practice and promote the personalized healthcare system for treatment of human cancer and metastasis In these five years, the aims of MRI core lab are (1) to develop DCE MRI for assessment of lung cancer mice model in variable of drugs and treatment protocol; (2) to establish microCT imaging platform for functional analysis; (3) to develop fusion and multiparametric functional imaging; (4) to explore the possibility of hypoxia MR imaging with correlation of other imaging modalities such as PET and/or optical imaging; (5) radiotherapy and medical Translation; and (6) Quantitative identification of MR imaging.腫瘤超極化磁振造影定量分析磁振頻譜轉譯醫學Tumorhyperpolarized MRIquantitative susceptibility mappingMRStranslational medicine優勢重點領域拔尖計畫-分子生醫影像研究中心/子計畫三：新世代核磁共振生醫分子影像之研發