藥物動力研究的主要目的為增進藥物的效果，與降低藥物的副作用。因此，藥物運輸與釋放系統的研發，便是為了達到選擇性藥物釋放的目的；而於適當目標器官的局部藥物釋放，不僅能夠增加局部區域藥物的濃度，而且能夠減少其他器官接受不必要的藥物浸潤；因此這樣的技術發展，對於例如腫瘤的化學藥物治療方面，這種副作用極大的藥物投與，具有重要的意義。然而要達到上述之區域選擇性藥物釋放的目的，需要於體外有一個能控制藥物釋放的外場來進行。而於生物應用上，磁性控制為首選之外加控制場，而以磁性奈米粒子作為控制藥物釋放的標的。我們選擇二丁卡因(Dibucaine hydrochloride；DH+)作為包覆之標的藥物，其為一種具有三級胺結構之局部麻醉藥物；此外，它還可以作為酸檢指示劑。二丁卡因之學名為(2-butoxy-N-[2-(diethylamino)ethyl]-4-quinolinecarboxamide)，其於胺基上之質子可以為不帶電、一價或者是二價的型式，而與其所處之水溶液酸鹼值有關。我們選擇以細胞層級之藥物載體，包含紅血球ghost、大腸桿菌與乳酸菌等，來包覆二丁卡因藥物；並以紫外與可見光光譜(UV-vis)、核磁共振光譜(NMR)、螢光與磷光光譜、掃描式與穿透式電子顯微鏡，與熱重量分析等技術作藥物載體之包覆分析。其中由於二丁卡因具有雙環之奎寧(quinoline)結構，其核磁共振訊號出現於化學位移δ=7-9之間，而紫外與可見光光譜之訊號則出現於300-350 nm處，與其他藥物載體之訊號不同，可作為載體藥物包覆之判斷。而於熱重量分析中，二丁卡因則於290℃處裂解。另外於螢光光譜之分析中，我們則可以得知經由紅血球包覆，而進入其膜內的二丁卡因為不帶電的情形，而藥物釋放後之二丁卡因則呈現一價的型式，證實紅血球不只是進行物理性質的包覆，也會造成包覆藥物於其化學構形上之變化。最後我們並以350 nm之波長處的紫外與可見光光譜數值，進行載體之包覆與藥物釋放等定量分析，實驗結果發現紅血球載體呈現一級之藥物釋放曲線，且無突釋現象與延遲釋放之反應。我們也合成奈米磁性粒子作為藥物之區位選擇性釋放控制，並將其包覆於紅血球之內，且以穿透式電子顯微鏡觀察其晶格，呈現面心立方結構。經由以上結果，我們期待本研究可作為未來之選擇性藥物釋放設計的參考。

Drug efficiency and side effect minimization are very important in pharmaceutical research. Thus researches for drug delivery systems in selected target organ loading could prolong the survival for the later stage cancer managements. To achieve this goal, drug carriers controlled by external forces needs to be designed, and magnetic field seems to be the most suitable external force to provide drug-releasing control in biological systems. In this study, an anesthetic agent, dibucaine•HCl (DH+) is encapsulated in ghost of the red blood cells as a drug delivery system. Dibucaine (2-butoxy-N-[2-(diethylamino)ethyl]-4-quinolinecarboxamide) is a tertiary amine local anesthetic drugs, and we have used it for membrane change transfer study. It represents the neutral free base form of the anesthetic, containing a quinoline analog and an amide group. Dibucaine can also exist as a monocation in which the aliphatic tertiary amine N is protonated and/or a dication in which the aromatic N is also protonated. The equilibrium of dibucaine free base (D), monocation (DH+), and dication (DH22+) dibucaines depends on the pH in the medium. Local anesthetics can also exist as hydrogen-bonded and aggregate species depending on the nature of their solubilizing environments (polar/nonpolar solvent, biomembranes, lipids, proteins, cells, etc.).
	Encapsulation of dibucaine•HCl (DH+) by ghost red blood cells within magnetic nanoparticles inside in our study is characterized then by the optical spectroscopic analysis of FTIR, Raman, NMR, and emission/excitation analysis. The results indicated that photophysical properties of neutral (uncharged or free base), protonated (charged), hydrogen-bonded, and aggregate species of the encapsulated local anesthetics are quite different and clearly distinguishable from one another. The binding sites, via aliphatic tertiary amine N, amide O, and/or aromatic N are visible from FTIR, Raman, and NMR spectra.
	The drug uptake amount and uptake rate into the cells were analyzed by UV-visible spectroscopy recorded and read at 350 nm (a strong absorption peak for dibucaine). The quantitative results show that the uptake of drug displays a linear relationship with the amount of the dried substrates (e.g., RBC) used up to 4 mg. The rate of increasing the drug uptake is shown to level off at 4.8 mg/ml for DH+ species.  The thermal stability of the drug-encapsulated cells was investigated by thermogravimetric analysis (TG/DTA). SEM/TEM were used to view the possible cell morphology changes upon the encapsulation and complexty of drugs.
	Chemotherapy seems to be the only choice in the late, or even terminal stage cancer management with metastasis. Thus elevation of its efficiency by drug delivery system improvement may reduce drug resistance and prolong survival. Hope this kind of drug carrier design can provide some hints toward drug delivery system promotions.

目錄
謝誌………………………….…………………………………………………….…..ii
摘要………………………………………………………...………………….……...iii
目錄………………………………………………………………….………..……..viii
附圖 ................................................................................…………............................xii
附表..................................................................................………….................….....xvii

第一章：緒論

研究目的：晚期惡性腫瘤之醫療處置與藥物設計…………………………………1
	前言………………………………………………………………………………1
	晚期惡性腫瘤之回顧……………………………………………………………2
		基質金屬蛋白酶……………………………………………………………4
		血小板源生長因子之結構與訊息傳遞……………………………………6
		轉型生長因子-β之結構與訊息傳遞……………………………………...7
		血管新生作用與其對惡性腫瘤之影響…………………………………..10
	化學治療的限制與挑戰………………………………………………………..13

第二章：藥物動力學與載體設計

	藥物動力學簡介………………………………………………………………..14
	藥物輸送系統的設計…………………………………………………………..18
	藥物載體之種類………………………………………………………………..20
		微胞藥物載體……………………………………………………………..20
		高分子藥物載體…………………………………………………………..22
		分子層級藥物載體………………………………………………………..27
		細胞層級藥物載體………………………………………………………..32
	藥物釋放類型及釋放動力學…………………………………………………..34
		擴散型藥物釋放，包含儲槽式與整體式釋放類型………………………34
		溶蝕或化學反應式藥物釋放……………………………………………..35
		澎潤式藥物釋放…………………………………………………………..36
		滲透式藥物釋放…………………………………………………………..37
	Fick’s第一定律…………………………………………………………………38
	零階、一階及t1/2-的藥物釋放模型……………………………………………40
		零階藥物釋放模型………………………………………………………..40
		一階藥物釋放模型………………………………………………………..40
		t1/2-藥物釋放模型…………………………………………………………41
	時間延遲與突釋現象…………………………………………………………..43
		時間延遲…………………………………………………………………..43
		突釋現象…………………………………………………………………..43
利用經過加工去除血紅素之人類紅血球作為藥物載體…………………………..44
	人類紅血球細胞膜之結構……………………………………………………..45
	紅血球細胞膜之加工與製備…………………………………………………..47
藥物輸送系統之磁性控制…………………………………………………………..49
	磁性生成機制…………………………………………………………………..49
	磁性材料之種類………………………………………………………………..50
	磁性材料的生物應用…………………………………………………………..52

第三章：實驗設計與步驟

以二丁卡因作為目標包覆藥物……………………………………………………..57
實驗材料與方法………………………………………………………………..60
	實驗儀器…………………………………………………………………..60
	菌株與血球來源…………………………………………………………..60
	實驗藥品…………………………………………………………………..61
	培養基與藥品配置………………………………………………………..62
大腸桿菌與乳酸菌之培養過程………………………………………………..63
	細菌藥物載體製備方法…………………………………………………..64
經由滲透壓控制加工處理人類紅血球做為藥物攜帶之載體………………..65
載體與其包覆藥物之螢光與磷光光譜分析…………………………………..66
定量分析：藥物封裝與釋放之測試…………………………………………..67
	不同載體質量下的藥物包覆量…………………………………………..67
紅血球之藥物釋放測試…………………………………………………..68
奈米金粒子之製備……………………………………………………………..69
磁性奈米粒子之製備…………………………………………………………..70

第四章：實驗結果與討論

定性分析：藥物封裝偵測與分析……………………………………………………72
	掃描式電子顯微鏡觀察………………………………………………………..72
		掃描式電子顯微鏡下之載體與其包覆藥物……………………………..74
	穿透式電子顯微鏡觀察………………………………………………………..77
		穿透式電子顯微鏡下之載體與其包覆藥物……………………………..78
紫外與可見光光譜……………………………………………………………..81
	載體與其包覆藥物之紫外與可見光光譜分析…………………………..84
核磁共振光譜…………………………………………………………………..88
	載體與其包覆藥物之紫外與核磁共振光譜分析………………………..91
	熱重量分析……………………………………………………………………..95
		載體與其包覆藥物之熱重量分析………………………………………..95
	螢光與磷光光譜分析…………………………………………………………101
		載體與其包覆藥物之螢光與磷光光譜分析……………………………103
定量分析：藥物封裝與釋放之測試……………………………………………….109
	各種細胞層級藥物載體之封裝效率比較……………………………………109
紅血球之藥物釋放測試………………………………………………………113
以紅血球載體包覆奈米磁性粒子…………………………………………………114

第五章：結論與未來展望

實驗步驟討論………………………………………………………………………116
藥物包覆機制………………………………………………………………………116
藥物釋放機制與其模型……………………………………………………………120
奈米磁性粒子之包覆………………………………………………………………120
臨床應用與討論……………………………………………………………………120
未來展望……………………………………………………………………………121


參考文獻……………………………………………………………………………122

附圖
圖一：血小板源生長因子的訊息傳遞路徑，包含了初級與次級傳遞。………………7
圖二：轉型生長因子-β的主要結構蛋白示意圖。………………………………………8
圖三：Smad 的結構示意圖。…………………………………………………………………8
圖四：多個Smad 可以區分為R-smad，Co-smad 與Anti-smad 三種。………………9
圖五：絲胺酸與蘇胺酸激酶受器的訊息傳遞示意圖。…………………………………9
圖六：血管新生作用進行的微環境。……………………………………………………10
圖七：經由酸性、缺氧環境與適當的生長因子催化，Ang-2 被大量製造分泌，並
且與Tie-2 結合而造成血管內皮結構的崩解。…………………………………………11
圖八：由於較低的氧氣濃度與一些血管新生因子的促進，例如上皮生長因子、血
管內皮生長因子、血小板源生長因子，以及轉型生長因子-β等，造成血管內皮
的前驅細胞增生分裂出更多的血管內皮細胞，並且形成新的血管結構。…………12
圖九：藥物由進入體內直到排泄出去過程的相關數理分析。………………………14
圖十：藥物由進入體內，直到代謝排出的過程中，藥物濃度於血漿(plasma)中的
變化量。………………………………………………………………………………………...15
圖十一：最小有效濃度(MEC)、最低毒害濃度(MTC)與血漿中之藥物濃度的關
係。………………………………………………………………………………………………16
圖十二：兩種不同目標的藥物設計：速效型(rapid release)與長效型(sustain release)
的藥物，其在血漿中濃度隨著時間變化的關係圖。……………………………………18
圖十三：藉由極性與非極性的分子間作用力(polar-nonpolar interactions)，同時具
有兩種性質的分子具有表面活性劑的性質，在臨界微胞濃度之上便可形成許多不
同種類的微胞(micelle)結構。………………………………………………………………21
圖十四：以HM-DEX 與HM-hydroxypropylcellulose 為高分子材料所合成之藥物載
體。………………………………………………………………………………………………23
圖十五：HM DEX-g-PEO10-C16的分子結構，與其溶於DMSO-d6的核磁共振光
譜。………………………………………………………………………………………………24
圖十六：利用微胞(micelle)合成的方式，以作為HM DEX-g-PEO10-C16材料，選
取適當的溶液濃度，將目標藥物包覆在高分子藥物載體的步驟。…………………25
圖十七：感溫性高分子N-isopropylacrylamide (NIPAAM)的分子結構。……………25
圖十八：感溫性高分子N-isopropylacrylamide (NIPAAM)藥物載體，隨溫度變化而
將內含之目標藥物釋出之機制。…………………………………………………………26
圖十九：三種不同的環糊精(cyclodextrin)其對應的分子結構，以及其分子內凹槽
的大小，這對應了其可以嵌合藥物分子的能力。………………………………………28
圖二十：β-環糊精與trans-dichloro(dipyridine)platinum(II) (DDP)之傅立葉轉換紅
外線光譜分析。………………………………………………………………………………30
圖二十一：β-環糊精(β-cyclodextrin)與trans-dichloro(dipyridine)platinum(II)
(DDP)之 1H核磁共振光譜分析。…………………………………………………………31
圖二十二：細胞膜由因外力造成缺損，而形成膜內外通道的過程。………………33
圖二十三：儲槽式(reservoir device)之藥物釋放模型。………………………………34
圖二十四：整體式(monolithic device)釋放模型之示意圖。…………………………35
圖二十五：溶蝕式之藥物釋放模型。……………………………………………………36
圖二十六：化學釋放類型之載體與其藥物釋放示意圖。……………………………36
圖二十七：膨潤式(swelling type)載體之藥物釋放說明。……………………………37
圖二十八：滲透式(osmosis type)之藥物釋放模型。……………………………………38
圖二十九：零階、一階及t1/2-釋放模型的藥物累積釋放量與時間關係圖。……41
圖三十：零階、一階及t1/2-釋放模型的藥物釋放速率與時間關係圖。………………42
圖三十一：時間延遲(time lag)與藥物突釋現象(burst effect)兩種現象，對於藥物累
積釋放速率的影響。…………………………………………………………………………43
圖三十二：位於紅血球內外膜上的磷脂質結構，以及其相關之嵌入蛋白分子。…46
圖三十三：利用電穿孔的方式，於紅血球表面製造人工通道以去除其內血紅素之電子顯微鏡觀察。……………………………………………………………………………48
圖三十四：通過一線圈的電流產生了一磁通密度為Ｂ的磁場Ｈ０，當一磁性
核心被放入線圈內時，其磁通密度較高。………………………………………………51
圖三十五：B-H 曲線在第二或四象限內能繪出的最大面積，為B-H 乘積之最大
值。………………………………………………………………………………………………52
圖三十六：鐵氧磁體(ferrites)為最常見的磁性陶瓷，它具有尖晶石型結晶結構，
是一種包含8個面心立方結構(FCC)次晶胞的結晶結構。……………...……………53
圖三十七：Fe3O4奈米磁性粒子之包覆高分子(PEG)製作過程。……………………54
圖三十八：Fe3O4奈米磁性粒子之傅立葉轉換紅外線光譜。………………………54
圖三十九：外層包覆高分子(PAA)之Fe3O4奈米磁性粒子，其熱重量損失分析。…55
圖四十：穿透式電子顯微鏡下之Fe3O4奈米磁性粒子，其大小約為數十奈米左
右。………………………………………………………………………………………………55
圖四十一：二丁卡因(Dibucaine)之化學結構。…………………………………………58
圖四十二：二丁卡因之價數(cation)，與其所處環境之酸鹼值(pH value)之間的關
係。………………………………………………………………………………………………59
圖四十三：以滲透壓法，控制去除紅血球內之血紅素與其他胞器之過程。……66
圖四十四：Fe3O4奈米磁性粒子之製備流程。…………………………………………72
圖四十五：於掃描式電子顯微鏡(SEM)成像中，二次電子與背向電子(backscatter
electrons)的形成原理。………………………………………………………………………74
圖四十六：掃描式電子顯微鏡下之紅血球載體。……………………………………75
圖四十七：掃描式電子顯微鏡下之大腸桿菌載體。…………………………………76
圖四十八：掃描式電子顯微鏡下之乳酸菌載體。……………………………………77
圖四十九：穿透式電子顯微鏡下之紅血球載體與包覆之奈米金粒子。…………78
圖五十：穿透式電子顯微鏡下之大腸桿菌載體。……………………………………79
圖五十一：穿透式電子顯微鏡下之乳酸菌載體。……………………………………81
圖五十二：數種常見之電子的躍遷型式。………………………………………………82
圖五十三：各種不同之電磁波與其波長範圍。…………………………………………83
圖五十四：一些常見於紫外與可見光光譜的分子結構，與其電子躍遷型式。…82
圖五十五：二丁卡因(Dibucaine hydrochloride)之紫外與可見光光譜。……………85
圖五十六：紅血球之 (A)二丁卡因藥物包覆前，(B)藥物包覆後的紫外與可見光光
譜。………………………………………………………………………………………………86
圖五十七：大腸桿菌之 (A)二丁卡因藥物包覆前，(B)藥物包覆後的紫外與可見光
光譜。…………………………………………………………………………………………87
圖五十八：乳酸菌之 (A)二丁卡因藥物包覆前，(B)藥物包覆後的紫外與可見光光
譜。………………………………………………………………………………………………88
圖五十九：常見化學結構之質子訊號與其化學位移。………………………………91
圖六十：於核磁共振訊號偵測下，不同質子個數的自轉-自轉耦合。……………92
圖六十一：二丁卡因(dibucaine hydrochloride)麻醉藥物溶於DMSO 中之1H核磁
共振光譜。……………………………………………………………………………………92
圖六十二：紅血球之 (A)二丁卡因藥物包覆前，(B)藥物包覆後的核磁共振光
譜。………………………………………………………………………………………………93
圖六十三：大腸桿菌之 (A)二丁卡因藥物包覆前，(B)藥物包覆後的核磁共振光
譜。………………………………………………………………………………………………94
圖六十四：乳酸菌之 (A)二丁卡因藥物包覆前，(B)藥物包覆後的核磁共振光
譜。………………………………………………………………………………………………95
圖六十五：二丁卡因(dibucaine hydrochloride)之熱重量分析結果。………………97
圖六十六：紅血球之熱重量分析圖。(A)為DH+藥物包覆前，而(B)為DH+藥物包
覆後之測量情形。……………………………………………………………………………98
圖六十七：大腸桿菌之熱重量分析圖。(A)為DH+藥物包覆前，而(B)為DH+藥物
包覆後之測量情形。………………………………………………………………………100
圖六十八：乳酸菌之熱重量分析圖。(A)為DH+藥物包覆前，而(B)為DH+藥物包
覆後之測量情形。…………………………………………………………………………101
圖六十九：電子處於激發態時，其能量的耗散過程。………………………………103
圖七十：Dibucaine hydrochloride；DH+的(A)室溫螢光光譜。(B) 77K 磷光光
譜。……………………………………………………………………………………………104
圖七十一：紅血球的(A)室溫螢光光譜。(B) 77K 磷光光譜。……………………105
圖七十二：包覆Dibucaine hydrochloride；DH+藥物的紅血球載體，其(A)室溫螢
光光譜。(B) 77K 磷光光譜。……………………………………………………………106
圖七十三：包覆Dibucaine hydrochloride (DH+)藥物的紅血球經藥物釋放兩小時
後，其(A)室溫螢光光譜。(B) 77K 磷光光譜。………………………………………108
圖七十四：紅血球藥物載體之數量(mg)，與紫外-可見光光譜之吸光度(350 nm)
的影響。………………………………………………………………………………………110
圖七十五：大腸桿菌載體之數量(mg)，與紫外-可見光光譜之吸光度(350 nm)的影
響。……………………………………………………………………………………………111
圖七十六：乳酸菌載體之數量(mg)，與紫外-可見光光譜之吸光度(350 nm)的影
響。……………………………………………………………………………………………112
圖七十七：於紅血球、大腸桿菌與乳酸菌等三種不同的藥物載體，其Dibucaine
hydrochloride (DH+)之包覆能力比較。…………………………………………………113
圖七十八：包覆Dibucaine hydrochloride (DH+)之紅血球載體，其藥物釋放隨時
間之變化關係圖。…………………………………………………………………………114
圖七十九：Fe3O4奈米磁性粒子外觀與其在掃描式、穿透式電子顯微鏡下之外
型。……………………………………………………………………………………………115
圖八十：以紅血球載體包覆Fe3O4磁性奈米粒子之穿透式電子顯微鏡觀察。…116
圖八十一：(A)DH+之螢光實驗光譜，(B)DH+之77K 磷光光譜，(C)紅血球之螢
光光譜，(D)紅血球包覆DH+之螢光光譜，(E)為由紅血球載體內所釋放之DH+
螢光光譜，(F)則為(E)之77K 磷光光譜。………………………………………………118
圖八十二：經由圖(A)中DH+吸光度之校正曲線，可以換算出載體內所含有DH+
之數量，如圖(B)與圖(C)所示。……………………………………………………………120
附表
表一：在腫瘤組織中可被分離偵測到的蛋白質水解酶，並且列出這些酵素的相關
活性。…………………………………………………………………………………………….3
表二：已發表之高分子作為藥物載體材料………………………………………………23
表三：環糊精的一般性質。…………………………………………………………………28
表四：二丁卡因(Dibucaine)之價數與其所處之生物體內環境之關係。……………60
表五：各螢光與磷光實驗之波峰值。……………………………………………………109
表六：各螢光與磷光實驗組之輻射半衰期(life-time)。………………………………109

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