摘要:肺癌在台灣及其他工業化國家最常見之癌症死亡原因之一,且肺癌之臨床特徵為不易早期診
斷,常早期發生轉移,並常有手術後復發之情況。就目前的治療成效,非小細胞肺癌對放射線治療及
化學治療之反應也較差。臨床對於肺癌病患治療成效評估主要是以腫瘤大小的量測及血液中CEA,
CA-153, CA-199 等生物標記作為依據,但利用傳統醫學影像量測腫瘤尺寸及血液生物標記並不易於
評估早期治療效果。於前期研究計劃中本團隊已針對非小細胞肺癌之動物模式進行腫瘤生成、在奈米
標定技術發展上已可於非小細胞肺癌之動物模型進行體內標定,並於腫瘤區域之T2 加權影像產生
25%的訊號衰減,此一體內標定並已延伸應用於口腔癌動物模型的影像偵測。
為更進一步研究肺癌的治療評估與機轉,本計畫針對腫瘤治療,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,並利
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。
本研究計畫將利用兩種肺癌轉移的動物模式作為研究標的:其一為受放射線治療誘發肺癌轉移
的動物模式(C57BL/6 品系),其腫瘤細胞為Lewis lung carcinoma(LLC-LM);其二為SCID 之動物模式,
其腫瘤細胞為CL1-0、CL1-5、與Mock 189 來探討腫瘤轉移形成機轉。在針對細胞分子表現特異性
鑑別之奈米顯影劑的發展平台部份,可藉由測試修改奈米表面以改良並同時具有正子斷層掃瞄與磁振
造影之對比顯影的效果。藉由發展新型態之奈米粒子作為吸收近紅外光誘發熱治療之雙效奈米藥物。
根據過去的文獻報導,αvβ3 為新生血管之表面受器,其可被RGD-4C 特異標定其腫瘤新生血管。而
同時EFGR(Epidermal growth factor receptor)為一腫瘤生長激素表面受器,其功能可被抗EGFR 抗體抑
制,因此未來將進一步連結抗腫瘤及新生血管特異性表面抗原分子,如EGFR 及RGD-4C,以作為融
合標的投遞之導向器及攻擊武器於一體之多功製劑。
在磁振造影之分子影像擷取部份,此計畫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。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。以及藉此技術平台,篩選有潛力之抗肺癌之藥物。
本研究整合一流之生醫及理工研究團隊以從事動態顯影、奈米顯影粒子、顯微磁振造影、及動
物正子斷層掃瞄等結合上中下游之整合研究建立活體動態追蹤動物腫瘤治療評估及轉移過程的分子
影像模式,分析放射線引發肺癌肺臟轉移過程中血管新生與缺氧誘發因子的動態表現情況,以釐清血
管新生與缺氧誘發因子對應其標靶藥物在抑制小鼠腫瘤肺部轉移治療之應用潛力,以期密切的交流互
動及研究成果達成預期研究目標,提升在國際上的能見度,達到生醫分子磁振造影技術之領先地位。
Abstract: Lung cancer is the major leading etiology of cancer-related death in the world. There are many different treatment strategies of lung cancer, including surgery, chemotherapy, targeted therapy, radiation therapy,
radiofrequency tumor ablation, photodynamic therapy, cryotherapy or combination. Clinical evaluation of treatment response of lung cancer depends mainly on measurement of tumor size in imaging study and serum biomarkers for tumor burden such as CEA, CA-153, CA-199, etc.. Early treatment response may precede the change of tumor size which is not usually perceptible on conventional imaging technology. The serum biomarker level is also subjective to the tumor burden which is not usually reliable. During investigation and clinical practice, we have to know the possible response of a cancer to non-operative treatments as early as possible for predicting their treatment effect, and for understanding the exact mechanisms of anti-cancer treatments in vivo. Therefore, the development of a surrogate to evaluate cancer treatment response before the change of tumor size is very important and potentially promising. It has been found that the tumor metastasis involves cell invasion, anti-anchorage-dependent apoptosis, specific tissue
part adhesion, and angiogenesis. The current in vivo animal model with metastasis is confounded by
multi-factorial impact. The stable metastasis model controlled by univariate factor is not widely available.
Therefore, using established animal model of metastatic lung cancer will be more valuable to explore the characters and mechanisms of developing lung metastasis. In this project, we will use dynamic
contrast-enhanced (DCE) and diffusion-weighted MRI (DW-MRI) for evaluating tumor response in
non-small cell lung cancer (NSCLC) and Lewis lung carcinoma (LLC-LM) mouse models to variable
anti-cancer therapy, including chemotherapy, photothermal therapy, and radiation treatment. Recently, DCE MRI has been considered an in vivo surgogate of angiogenesis and DW-MRI has been reported important in detecting the change of cellularity and early tumor response such as apoptosis. With our experiences of DCE-MRI and DW-MRI, we are capable to apply these technologies in our established mice models. For specifically recognized cancer cells, we have developed synthesis of iron oxide nanoparticles with excellent stability, biocompatibility, and interface for additional biochemical modifications. With the nanoparticle technology, we will not only improve the synthesis and modifications of iron oxide nanoparticle to achieve
better contrast and targeting effect, but also develop the nanomaterials with micro-PET-enhancement and photothermal-therapeutic-trigger properties for investigating the mechanism of lung cancer metastasis and cancer therapy. Furthermore, for combined molecular expression specific cancer targeting and therapy, bioconjugation of nanoparticles with anti-EGFR (epidermal growth factor receptor) monoclonal antibody and RGD-4C peptides will be performed, and the materials will be evaluated whether or not an increased signal contrast and hence high detection rate could be achieved for early detection of metastatic lesions.
To achieve high quality molecular MR imaging, we will develop 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.
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 pulmonary
carcinoma mouse model in vivo. This integrated molecular imaging platform could potentially be extended to clinical practice and promote the personalized healthcare system regarding to different mechanisms of treatment of human lung cancer and metastasis as well as the early treatment response.