標題: 包覆順鉑之功能性藥物載體的合成與生物分析 應用於肺癌治療
Synthesis and Characterization of Magnetically Targeted Cisplatin-loaded Carriers for Lung Cancer Therapy
作者: 曾苡瑄
Tseng, Yi-Hsuan
陳三元
Chen, San Yuan
材料科學與工程學系奈米科技碩博士班
關鍵字: 癌症;順鉑;聚乙烯醇;聚丙烯酸;磁導引;cancer;cisplatin;polyvinyl alcohol;polyacrylic acid;magnetic guidance
公開日期: 2014
摘要: 順鉑為現今癌症化療第一線用藥之一,特別是頭頸部癌以及非小型細胞肺癌,然而在臨床上的應用雖然極為廣泛, 它本身造成嚴重的的副作用像是腎毒性和不專一的生物分佈像是與膜蛋白結合使其在治療過程中面對了不少挑戰。在2011年有文獻提出了SPI-077這個同為包覆順鉑的藥物載體在臨床試驗因未能彰顯其療效而於臨床第二期被迫停止,探究主因為順鉑從載體釋放效率不佳而未能證明其療效。而本篇論文的研究重點在於開發功能性的磁性藥物載體(CDDP-PAA-Nanocomposite)以改善上述缺點。此具有磁性的奈米級藥物載體,搭配物理性磁引導,預期能大量累積藥物載體於腫瘤部位,達成優異的治療功效。 本次研究中,我們將高生物相容性的聚乙烯醇(polyvinyl alcohol, PVA)、以及賦予了載體擁有磁性的超順磁性氧化鐵(superparamagnetic iron oxide, SPIO)奈米粒子設計合成載體。以簡單的雙乳化方式將藥物物理性的包覆在內。由於順鉑是偏水相的藥物,我們在包覆藥物時同時以高分子聚丙烯酸(polyacrylic acid, PAA)化學性地利用負電荷吸附順鉑,是為了增加藥物包覆率並同時避免順鉑過早釋放。藥物載體大小分佈在一百五十到兩百奈米之間,並在接續藥物釋放實驗中探討聚丙烯酸對於順鉑由載體釋放扮演了一個延緩釋放的角色,故選擇之,並以A549人類肺線癌細胞作為接續細胞和動物實驗的模型。從細胞實驗中,證實了磁引導能大幅提升藥物載體進入細胞並驗證了此藥物載體的安全性。 在動物實驗方面,首先探討毒性,由於順鉑是由肝臟代謝,腎臟排泄。由血液生化以及病理切片證明了藥物有了載體保護並於體內緩慢釋放,大幅減低了對代謝器官的毒性;而由藥物動力學的實驗也直接說明了載體藥物大幅提升藥物的半衰期並延長了在血液循環的時間。上述的結果,更由接續生物分佈的實驗結果雙重證明,並解釋了毒性降低是由於藥物由載體包覆,體積遠大於腎小管能夠吸收代謝的範圍。反之於純藥物在短時間內大量被腎臟代謝而造成腎小管的壞死。最後在療效的部分,載體藥物搭配磁引導,更是將它抑制腫瘤的角色發揮的璃淋盡致。
Cisplatin (CDDP) is one of the most potent chemotherapy agents, displaying significant clinical activity against a variety of solid tumors [1, 2]. However, a major clinical limitation of this drug is its side effects in normal tissues, prominently toxicity in the kidneys [3] and nonspecific biodistribution [4, 5]. The primary aim of this study is to develop a special delivery system to improve the aforementioned shortcoming. Here, we designed a novel nanocarrier for tumor therapy, which composed of polyvinyl alcohol (PVA), superparamagnetic iron oxide (SPIO) nanoparticles and polyacrylic acid (PAA), which electrostatic interact with CDDP[6]. Both of CDDP and PAA were encapsulated into the inner core by the simple double emulsion method. Blood biochemical analysis and histopathological studies revealed that CDDP-PAA-NC significantly reduced nephrotoxicity. Compared to free CDDP, prolonged blood circulation time and improved biodistribution were observed of CDDP-PAA-NC delivery in vivo. Furthermore, with an external magnet, CDDP-PAA-NC tended to show greater antitumor activity in A549 tumor bearing mice without body weight loss compared to that of CDDP.
URI: http://140.113.39.130/cdrfb3/record/nctu/#GT070151610
http://hdl.handle.net/11536/75586
Appears in Collections:Thesis