臺灣博碩士論文加值系統

本研究利用氨水沉積法將具有超順磁性的氧化鐵 (superparamagnetic iron oxide；SPIO)奈米點妝點 (decorate)於披覆氫氧基磷灰石無機殼層的微脂體表面上，形成所謂 MHA-liposome磁性殼層結構，其具有超音波釋控載體與與磁振造影對比劑的多重功能，研究中利用 XRD、SQUID及 TEM來鑑定其結構與特性，並探討披覆 MHA殼層對於背景滲漏特性、超音波敏感性及磁振造影所造成的影響，研究中發現：在微脂體外披覆無機殼層可以降低藥物的背景滲漏；而經由超音波釋放實驗得知，MHA-liposome 對於高頻率 (1-3 MHz)、低功率 (0.2-1 watt/cm2)之醫療診斷用的超音波具有響應性，且 MHA-liposome對於高頻率 (1-3 MHz)超音波的敏感度比未經過改質的微脂體高，另一方面，MHA-liposome在磁振造影下具有 T2加權影像對比，在受到超音波刺激後遲緩率差值( r2* - r2)下降，因此，MHA-liposome不只可以作為 MR影像導引的超音波釋藥載體，更可以用影像的改變來偵測載體的釋放情形。

In this study, a novel remote-triggered drug carrier with superparamagnetic characteristic demonstrated a prompt response to the ultrasound with diagnosis frequency (1-3 MHz) and power density (0.2-1 watt/cm2) was successfully synthesized. The remote-triggered drug carrier exhibited a core/shell structure which was prepared via coating a thin layer of magnetic-hydroxyapatite onto liposome (MHA-liposome) through the ammonia decomposition route. The MHA-liposome was characterized by XRD, SQUID and TEM observation. The effects of MHA coating on the background leakage, ultrasound response, and MR signal were investigated. It was found that the core/shell structure could be efficiently triggered by ultrasound with high frequency (1 and 3 MHz). In addition, the inorganic coating layer significantly resisted the background leakage compared to unmodified liposome. These results suggested that the molecules encapsulated in the novel MHA-liposome core/shell structure can be released in a highly controllable manner through the use of ultrasound stimulus. On the other hand, it was found that the ultrasonically triggered vehicle could exhibit T2 contrast in MR images by coating magnetic-HA. Most importantly, the r2* - r2 value of MHA-coated liposome decreased after sonication, suggesting that the proposed vehicle could be used not only as a MR-guided drug vehicle capable of ultrasonically triggered release but also as a MR reporter to probe ultrasonic triggering.

目錄
謝誌 I
中文摘要 II
ABSTRACT IV
目錄 VII
圖目錄 VIII
表目錄 IX
第一章 緒論 1
1.1前言 1
1.2藥物載體設計 2
1.3 超音波介紹 4
1.4 磁振造影 5
1.4.1 磁振造影的介紹 5
1.4.2 磁振造影的原理 7
1.4.3 磁振造影之遲緩現象 8
1.4.4 顯影劑的種類 10
1.4.5 影響磁振造影對比劑顯影的因素 12
1.5 磁性材料介紹及應用 13
1.5.1 氧化鐵 13
1.5.2 磁性氫氧基磷灰石 14
1.6 影像導引藥物載體 15
1.7 微脂體 16
1.7.1 微脂體介紹 17
1.7.2 以微脂體作為藥物載體之文獻回顧 18
1.8 研究動機 20
第二章 儀器設備及藥品 22
2.1 儀器設備 22
2.2藥品 23
第三章 實驗方法 24
3.1 製備微脂體 24
3.2 製備HA-liposome 24
3.3 製備MHA-liposome(1X)(10X) 24
3.4穿透式電子顯微鏡 26
3.5 X光繞射儀 27
3.6 藥物釋放 27
3.6.1 長時間藥物釋放實驗 27
3.6.2 超音波藥物釋放實驗 28
3.6.3 超音波敏感性測試 29
3.7 磁振造影實驗 29
3.7.1 T2-加權影像 29
3.7.2 超音波刺激對於磁振造影影像的影響 31
3.8 磁滯曲線分析 32
第四章 結果與討論 33
4.1 載體的結構分析 33
4.2 載體磁性質 38
4.3 背景滲漏實驗 39
4.4 MHA-liposome(1x)在頻率1 MHz及3MHz超音波觸發下的藥物釋放行為
40
4.5 MHA-liposome(10X)在頻率1 MHZ及3MHZ超音波觸發下的藥物釋放行為 43
4.6 奈米氧化鐵顆粒含量對於超音波釋藥的影響 44
4.7 超音波敏感性測試 47
4.8 磁振造影遲緩率之分析 49
4.9 奈米氧化鐵顆粒含量對於遲緩率的影響 51
4.10 超音波刺激對於顯影的影響 55
4.11 磁滯曲線與遲緩率的關係 59
4.12 體外超音波造影測試 62
4.13 體內超音波造影測試 64
第五章 結論 67
第六章 未來展望 68
參考文獻 70

圖目錄
圖 1-1 當RF脈衝開啟，氫原子吸收能量改變方向………………………………6
圖 1-2 當RF脈衝關閉，氫原子釋放能量並回到原來方向上 7
圖 1-3 T1恢復曲線，RF脈衝關閉，Z方向分量恢復至原來方向。 8
圖 1-4 T2恢復曲線，RF脈衝關閉，X-Y平面上方向上分量回歸至零。 9
圖 1-5 釓嵌合物的分子結構。…………………………………………………….11
圖 1-6 微脂體再包覆現象示意圖。 17
圖 3-1 實驗流程示意圖。 25
圖 3-2 磁振造影樣品裝置圖。 30
圖 4-1 載體受磁鐵作用前後之狀態。 35
圖 4-2 載體之TEM圖。 36
圖 4-3 載體之XRD圖譜。 37
圖 4-4 載體之磁滯曲線。 38
圖 4-5 載體之背景滲漏特性。 40
圖 4-6 MHA-liposome(1x) 在超音波作用之下之藥物釋放曲線。 41
圖 4-7 載體在受到超音波觸發前後之TEM圖。 42
圖 4-8 MHA-liposome(10x) 在超音波作用之下之藥物釋放曲線。 43
圖 4-9 MHA-liposome(1x)及MHA-liposome(10x)在1 MHz超音波觸發之藥物釋放比較圖。 45
圖 4-10 MHA-liposome(1x)及MHA-liposome(10x)在3 MHz超音波觸發之藥物釋放比較圖。 45
圖 4-11 超音波對於MHA-liposome(1x)及MHA-liposome(10x)的影響示意圖。 46
圖 4-12 載體的超音波敏感度比較。 48
圖 4-13 載體的T2加權影像。 50
圖 4-14 載體濃度與遲緩率的關係。 50
圖 4-15 MHA-liposome(1x)及MHA-liposome(10x)的T2加權影像。 52
圖 4-16 MHA-liposome(1x)及MHA-liposome(10x)的r2關係圖。 52
圖 4-17 MHA-liposome(1x)及MHA-liposome(10x)的T2*加權影像。 53
圖 4-18 MHA-liposome(1x)及MHA-liposome(10x)的r2*關係圖。 53
圖 4-19 MHA-liposome(1x)及MHA-liposome(10x)的r2、r2*與M之關係。 54
圖 4-20 MHA-liposome(1x)在超音波刺激前後的遲緩率變化圖。 57
圖 4-21 MHA-liposome(10x)在超音波刺激前後的遲緩率變化圖。 58
圖 4-22 MHA-liposome(1x)及MHA-liposome(10x)在超音波刺激前後之磁滯曲線 60
圖 4-23 MHA-liposome(1x)及MHA-liposome(10x)之DR與DM關係。 60
圖 4-24 MHA-liposome(1x)於生物體外之超音波造影圖。 62
圖 4-25 MHA-liposome(1x)於生物體內之超音波造影圖。 64

表目錄
表 1-1 造影技術的優缺點比較 6
表 3-1 樣品實驗條件及名稱 25
表 3-2 造影參數 31

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