臺灣博碩士論文加值系統

本研究有兩個主要部分。第一部分探討七層塔萃取物對骨肉瘤的效果。骨肉瘤（Osteosarcoma; OS）是一種骨癌。這種腫瘤的百分之八十是有轉移性，它可以擴散到肺部或肝臟。為了提高生存率，儘管有副作用，骨肉瘤患者的通常需接受化療。由此可見，目前迫切需要更多對人骨肉瘤的治療藥物。近日，發現七層塔萃取物（Ocimumgratissimum aqueous extract; OGE ）有抗腫瘤活性。由於它的抗氧化特性導致了對治療方法的廣泛研究 我們利用藥物基因分析來探討 OGE 對人骨肉瘤 U2- OS 和 HOS 細胞。生長的影響。細胞活力，西方墨點和流式細胞分析法進行了解 OGE 對人骨肉瘤的細胞活力，藥物基因組學分析則包括基因微陣列(cDNA microarray)和 RT-PCR 試驗。細胞活力檢測發現，OGE 顯著地降低 U2- OS 和 HOS 細胞的存活率，且有劑量依賴性。它會增加 U2-OS 和 HOS 細胞皺縮、sub-G1 片段和 caspase 3 的活化作用， 進而誘導細胞凋亡，但對於人成骨(human osteoblast hFOS) 細胞不影響。基因微陣列實驗結果顯示，細胞週期調控和細胞凋亡相關因子及細胞增殖標誌物的表達，都被 OGE 影響而修飾其表達。 RT-PCR 分析也證實 OGE 治療會調降 SKA2 和 BUB1B，並調昇 PPP1R15A、SQSTM1、HSPA1B 和 DDIT4 由。研究 OGE 抗癌活性發現一些潛在的靶基因，表明OGE 是一種對於治療人骨肉瘤很有前途的藥物。

第二部分研究了萬古黴素/幾丁聚醣(vancomycin/chitosan)複合沉積在 post poroushydroxyapatite (HA) coated Ti6Al4V 鍍層的藥物控制釋放。通過電化學沈積技術，將萬古黴素/幾丁聚醣複合物（vancomycin/chitosan）沈積在 Ti6Al4V 基材，在浸泡試驗中由於極性水分子對於氫鍵鍵結的快速破壞，顯示在幾個小時內，80 ％的藥物已經崩解釋放出來。因此，為了控制藥物的釋放，將萬古黴素/幾丁聚醣複合物使用電化學沈積技術電解沉積於 post porous hydroxyapatite (HA) coated Ti6Al4V 來試驗，結果發現在一開始的萬古黴素藥物釋放量可以控制達到 55％，然後從第 1 天到第 5 天，有 20％左右的穩定釋放。到 6 天之後，有一個較慢的釋放最後的 25％。抑菌試驗發現，HA 的鍍層可以持續一個月以上 30mm 直徑的抑菌圈。這表現優於無 HA 的鍍層，因為無 HA的鍍層會在 21 天之後逐漸失去了抑菌圈。此外，細胞培養顯示 vancomycin-chitosan/HA複合鍍層增強的細胞增殖、細胞分化和成骨細胞礦化作用。我們的研究發現這樣的鍍層將有助於永久性植入物的骨整合。另外兔子骨髓炎動物模型的研究結果也明白顯示，該鍍層有助於骨髓炎的預防和治療。

The study has two main parts. The first part of the study explored the effect of Ocimum gratissimum aqueous extract on osteosarcoma. Osteosarcoma (OS) is a type of bone cancer. Eighty percent of this tumor is metastatic; it can be spread to the lungs or liver. To increase survival rate, patients with OS usually undergo chemotherapy, despite its side effects. Evidently, there is an urgent need for therapeutic drug for human osteosarcoma. Recently, Ocimum gratissimum aqueous extract (OGE) has been observed to have anti-tumor activity. The finding regarding its antioxidant properties has resulted in extensive research on therapeutic strategies. In the first part of the study, pharmacogenomics analyses were performed to explore the effect of OGE on human osteosarcoma U2-OS and HOS cell growth. Cell viability, western blot and flow cytometry analysis were performed before performing pharmacogenomics analyses for the effect of OGE on human osteosarcoma U2-OS and HOS cell growth, including cDNA microarray and RT-PCR assays. Cell viability assays revealed that OGE significantly and dose-dependently decreased the viability of U2-OS and HOS cells. Increases in cell shrinkage, Sub-G1-fragments and the activation of caspase 3 indicated that OGE induced cell apoptosis in U2-OS and HOS cells. There was no change in human osteoblast hFOS cells. cDNA microarray assay demonstrated that the expression of cell cycle regulators, apoptosis-related factors and cell proliferation markers were all modified by OGE treatment. RT-PCR analysis also confirmed down-regulation of SKA2 and BUB1B, and up-regulation of PPP1R15A, SQSTM1, HSPA1B and DDIT4 by OGE treatment. The finding of anticancer activity in OGE and the identification of some potential target genes suggest that OGE is a promising therapeutic drug for human osteosarcoma.

The second part of the study investigated the drug-controlled release of vancomycin/chitosan composite deposited on post porous hydroxyapatite coated Ti6Al4V implant. By means of electrochemical technology, the vancomycin–chitosan composite was originally deposited on Ti4Al4V through the hydrogen bonds and the deprotonation. The rapid destruction of the hydrogen bonding between them by polar water molecules during immersion tests revealed 80% drug burst in a few hours. Thus, to control the drug release, the post porous hydroxyapatite (HA) coated Ti4Al4V was prepared for the subsequent electrolytic deposition of vancomycin–chitosan composite. It was observed that the initial burst was reduced to 55%. Then from day 1 to day 5, there was a steady release about 20%, and after day 6, there was a slower release of the retained 25%. It was also observed that a bacterial inhibition zone diameter of 30 mm could last for more than a month in antibacterial tests. This outperformed the coated specimen without HA, which gradually lost an inhibition zone after 21 days. Moreover, the cell culture suggested that the vancomycin–chitosan/HA composite coated had enhanced the proliferation, the differentiation and the mineralization of the osteoblast-like cell. The finding suggests that the investigated coating would benefit the osteointegration on permanent implants. The results of the rabbit infection animal model also indicated that the coating helped the pro-phylaxis and therapy of osteomyelitis.

Acknowledgement i
Chinese Abstract ii
English Abstract iii
List of Tables vi
List of Figures vii
List of Appendix xi
Chapter 1: Introduction 1
Chapter 2: Experimental Procedure for the First Part of the Study 24
Chapter 3: Experimental Procedure for the Second Part of the Study 28
Chapter 4: Results and Discussion
4.1. Results and Discussion for the First Part of the Study 32
4.2. Results and Discussion for the Second Part of the Study 37
Chapter 5: Conclusion 41
References 43

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