- 學位論文
開發用於遞送Tirapazamine之白蛋白奈米載體
Development of Tirapazamine-Loaded Albumin Nanoparticles
摘要
腫瘤缺氧(tumor hypoxia)在癌症進展中扮演關鍵角色，並且是造成腫瘤細胞抗藥性的重要機制之一，這不但是目前癌症治療的一大挑戰，也是預後不良的指標。由於腫瘤缺氧區域氧氣含量不足、癌細胞生長緩慢且血流供應較差，傳統的化學療法、放射線療法對於缺氧的腫瘤細胞往往療效有限，因此發展針對缺氧區域的治療方式有其必要性。缺氧活化前驅藥物(hypoxia-activated prodrug)能針對缺氧細胞產生選擇性毒性，而Tirapazamine (TPZ)即為其中一種，其在缺氧環境下能活化產生自由基，造成DNA斷裂而引發細胞死亡，此特性使TPZ被廣泛研究作為對抗腫瘤缺氧的治療方式。然而，TPZ在體內的半衰期短、容易被代謝，且在腫瘤中的累積量不足，因此臨床效果不如預期。因此在本研究中，以發展改善TPZ在體內的穩定性，增加腫瘤累積藥量，並且有利於臨床使用的劑型為目標。 本研究中利用銅離子與TPZ進行錯合，以促進TPZ的包覆。銅離子TPZ錯合物[Cu(TPZ)2]為疏水性物質，為增加Cu(TPZ)2的溶解度，我們進一步選用白蛋白(albumin)與Cu(TPZ)2形成奈米粒子(nanoparticles)，並優化白蛋白奈米粒子的製備過程，接著於in vitro實驗分析其儲存穩定性、血清穩定性、以及細胞毒殺效果。之後我們進一步以戊二醛(glutaraldehyde)將白蛋白奈米粒子交聯，改善其血清穩定性。最後在in vivo中初步探討ANP-Cu(TPZ)2的療效。
並列摘要
Tumor hypoxia remains one major challenge in treating solid tumor as it contributes to cancer progression and drug resistance. Conventional radiotherapy and chemotherapy have shown limited efficacy in treating hypoxia regions within solid tumor, indicating the importance of tumor hypoxia in cancer therapy. Tirapazamine (TPZ), a hypoxia-activated prodrug (HAP), produces toxic radicals that cause DNA breaks under hypoxic conditions. Despite its potential in selective cytotoxicity against hypoxic cells in tumor, clinical efficacy of TPZ is unsatisfactory due to its short half-life and rapid metabolism, rendering insufficient tumor accumulation. These obstacles indicate the need of better drug delivery system. Herein, we developed cupric-TPZ albumin nanoparticles [ANP-Cu (TPZ)2] with size of approximately 130 nm and high entrapment efficiency. Cupric ions were used to complex with TPZ to increase its hydrophobicity. Hydrophobic Cu(TPZ)2 was then encapsulated with albumin. In vitro analyses have shown that ANP-Cu(TPZ)2 display good storage stability and cytotoxicity. The serum stability of ANP-Cu(TPZ)2 was further improved by glutaraldehyde crosslinking. The therapeutic efficacy was further evaluated in mice bearing synergistic C26 tumor.