利用一產氧系統提升小紅莓化療的效果

Development of an Oxygen Generating System to Enhance Chemotherapeutic Efficacy of Doxorubicin

林雯慧(LIM, WOON HUI)

指導教授 ： 宋信文

國立清華大學/工學院/化學工程學系/碩士(2014年)

摘要

摘要

肝細胞癌，簡稱肝癌，是目前最常見的肝臟惡性腫瘤，也是全世界好發的癌症之一。肝癌最理想的是能夠早期發現，早期接受治療。目前臨床上的治療，像是化學治療，放射線治療等都無法根治，主要原因是復發的機會很高。這些療程都無法完全將癌細胞殺死的原因是癌細胞內部嚴重缺氧，癌細胞在缺氧環境的抗藥性高。缺氧會引導抗藥性，主要是因為部分的抗癌藥物會藉由氧氣來產生自由基，這些自由基會攻擊細胞來達到治療效果；在缺氧環境下，無法產生足夠的自由基，進而無法達到預期的療效。因此，我們藉由一產氧系統來減緩癌細胞內部的缺氧情形，降低藥物因為缺氧而造成的治療阻力，進而提升治療效果。此產氧系統是利用褐藻酸钠和鈣離子的交聯來包覆過氧化鈣和過氧化氫酶形成微球體；過氧化鈣與水接觸後會開始分解，過氧化氫在過氧化氫酶的催化下會大量地產生氧氣。此系統採用的是體外實驗 (in vitro)，並在兩個環境下進行細胞實驗，即有氧環境及缺氧環境。此交聯10分鐘的微球體具有長時間釋放氧氣的能力，維持了28個小時的釋放時間。從實驗結果得知缺氧環境確實會降低癌細胞對藥物的敏感度，因此氧氣在癌症的治療上扮演了一個關鍵的角色，氧氣越充足，產生的自由基越多，進而殺死越多的癌細胞。根據實驗結果顯示，隨著微球體的量越多，提供的氧氣越充足，成功地提高了癌細胞在缺氧環境下的致死率，降低了藥物因缺氧而造成的治療阻力，提升化學治療效果。綜合本研究的實驗結果，此產氧系統在癌症治療上是一種頗有潛力的治療方法。

關鍵字: 缺氧、抗藥性、產氧系統、降低治療阻力，提升化療的效果

關鍵字

缺氧 ； 抗藥性 ； 產氧系統 ； 降低治療阻力 ； 提升化療的效果

並列摘要

ABSTRACT

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer. General chemotherapy and radiotherapy offer somewhat unsatisfactory responsiveness, the overall recurrence rate is very high, this could be attributed to the chemotherapeutic resistance that results from tumor hypoxia. Recently, hypoxia has been described as an important factor to chemotherapeutic resistance, owing to the redox state, meaning that oxygen (O2) is required to generate ROS to be maximally cytotoxic. To address the above issue, an oxygen generating system was fabricated using alginate, having calcium peroxide as the oxygen generating source, which decompose hydrogen peroxide and release oxygen when contact with water. The decomposition rate could be increased by the addition of catalase, a common enzyme found in nearly all living organisms. This novel system was performed under two controlled conditions, normoxia and hypoxia. Optimization of microspheres, cytotoxicity of material and condition of the system were carried out specifically based on the responses observed from in vitro studies using Hep3B cells as a candidate. Microspheres are capable of sustainably release oxygen over 24 hours while the best cross-linking time during the gelation was found to be 10 minutes. It was observed that cells maintained high viability under hypoxic condition and found that doxorubicin-induced oxyradicals play a vital role in the development of drug resistance. However, this oxygen generating system has successfully reduced the chemotherapeutic resistance which induced by hypoxia and enhanced the chemotherapeutic efficacy of doxorubicin. These results suggest that the developed oxygen generating system is a highly promising approach in maximizing the therapeutic effectiveness with minimal side effects.

Keywords: hypoxia; chemotherapeutic resistance; oxygen generating system; redox cycle of doxorubicin; enhancement of the chemotherapeutic efficacy

並列關鍵字

hypoxia ； chemotherapeutic resistance ； oxygen generating system ； redox cycle of doxorubicin ； enhancement of the chemotherapeutic efficacy

參考文獻

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