整合多重影像對比劑之合成與特性研究

Abstract

影像的技術極限往往限制了癌症的診斷與治療。根據臨床經驗指出，癌症早期診斷可以提升治癒或延長病人壽命的機率。多重影像技術的使用更克服了單一影像技術無法為診斷上提供完整資訊的限制。核磁共振造影技術( magnetic resonance imaging, MRI ) 正是一種適合用於體內腫瘤成像的技術；光學影像技術可以提供我們高靈敏度且非侵入性的腫瘤早期診斷資訊。具有生物相容性的多功能目標化磁性奈米粒子探針可以改變磁振造影技術的訊號強度，近紅外光的螢光染料及屬於生物系統的部位可以提供高靈敏度及空間解析度的生物體影像。然而，目前最主要的挑戰在於如何保持標靶部位的藥物性質，例如抗體治療的特性。由於磁性奈米粒子具有強的T2核磁共振造影對比效果，因此很廣泛地被利用在生物醫學領域中。近年來，超順磁奈米氧化鐵粒子 ( superpapramagnetic iron oxide nanoparticle) 合成方法中的非水相熱裂解法受到強烈地關注，由於此種合成方法可以控制磁性奈米粒子的各種重要的特性，例如：粒徑大小、磁性參雜、磁晶相及表面狀態。為了獲得最好的磁性特性，常使用尖晶石結構的亞鐵鹽類，其一般結構通式為MFe2O4，其中M為錳 ( Mn )、鐵 ( Fe )、鈷 ( Co ) 或鎳 ( Ni ) 的二價陽離子。近年來的研究指出，MnFe2O4奈米粒子是上述提及的尖晶石亞鐵鹽類中，具有最大的磁化率及最低的生物細胞毒性之化合物。然而，非水相熱裂解法最主要的缺點在於合成過程中會在粒子表面鍍上一層疏水性層，因此，利用後修飾的步驟，可提高磁性奈米粒子於生物系統水溶液中的穩定度及其分散性。單株抗體 ( monoclonal antibody ) 的重大突破大大提升了臨床上單株抗體使用的安全性，例如： Cetuximab是以受體 ( receptor ) 為基礎的臨床標靶治療藥物，被使用在治療大腸癌轉移 ( metastatic colorectal cancer, MCRC ) 及鱗狀上皮細胞癌 ( squamous cell carcinoma of head/neck cancers SCCHN )，其屬於嵌合型單株抗體，對表皮生長因子受體 ( epidermal growth factor receptor, EGFR ) 具有特異性，研究指出Cetuximab利用與細胞外的EGFR結合而鎖住表皮生長因子 ( Epidermal Growth Factor, EGF ) 及轉化生長因子 ( Transforming Growth Factor-β, TGF-β ) 的結合受體，干擾訊息傳遞，使得細胞週期停止，最終導致細胞凋亡。

Technological limitations of imaging modality often hold back diagnosis and therapy of cancer. According to extensive clinical experience, early diagnosis may lead to cure or at least offer extended life to the patient. Generally, structural and functional information are required to get the complete insight of the cause and progress of cancer. The limitations of single imaging modality which cannot provide all the information in the diagnosis can be overcome by the synergistic utilization of multiple imaging modalities. Magnetic resonance imaging (MRI) is ideally suited for imaging tumor buried deep inside the body. Fortunately, optical imaging technique enables us to non-invasively visualize the early events in tumor formation with high sensitivity. A multimodal target specific probe consisting of a biocompatible magnetic nanoparticle capable of altering the MR signal intensity, and a NIR fluorochrome and a biological moiety can provide high sensitivity and spatial resolution in vivo imaging. However the major challenge is to maintain the pharmokinetics property of the targeting moiety such as an antibody possessing therapeutic properties. Magnetic nanoparticles have found widespread application in biomedical area due to its strong negative contrast effects in T2-weighted MR imaging. Recently, non-hydrolytic thermal-decomposition method, one of the methods of SPIO nanoparticles synthesis has drawn intense attention. It allows synthetic control of some important features of magnetic nanoparticle, such as size, magnetic dopants, magneto-crystalline phases, and surface states. In order to meet the excellent magnetic property, spinel metal ferrites have drawn much attention. The general formula for spinel metal ferrites is MFe2O4, where M is +2 cation of Mn, Fe, Co or Ni. A recent study has shown that MnFe2O4 NPs have the highest mass magnetization value and low cytotoxicity among MFe2O4 mentioned above. These two properties makes MnFe2O4 nanoparticle highly attractive for ultrasensitive MR imaging probe. The major drawback of nonhydrolytic thermal-decomposition method causes a hydrophobic coating on the particle surface. Consequently, post synthesis processing is required to achieve high colloidal stability and dispersibility in aqueous biofluids. Significant breakthrough in the establishment of monoclonal antibody (MAb) technology has lead to the availability of effective and clinically safe monoclonal antibodies. One such receptor-based targeted therapy clinically used for the treatment of metastatic colorectal cancer (MCRC) and squamous cell carcinoma of head/neck cancers (SCCHN) is Cetuximab. It is chimeric monoclonal antibody and specific for the epidermal growth factor receptor (EGFR). Studies have shown that Cetuximab can block the binding of both EGF and TGF-β to their receptors through binding to the extracellular domain of EGFR. Thereby, interrupts the signaling cascade that ultimately leads to cell cycle arrest and induction of apoptosis. Recent studies have demonstrated Cetuximab can be potentially employed for targeted drug delivery to tumor site, and has been the focus of a number of studies involving in vivo evaluation of EGFR. For instance, in vitro study has shown high cellular uptake of Cetuximab-conjugated fluorescent magnetic nanohybrid. Furthermore, a recent in vivo study demonstrates Cetuximab-conjugated magneto-fluorescent silica nanoparticles as effective agent for both MRI and optical imaging.