多功能奈米載體用於癌症治療有效性之評估

Abstract

多功能奈米載體在近幾年之研發及應用相當廣泛，因其具有可與其他療法合併治療之特性，其他療法如化學治療、放射線同位素治療、標靶治療、光熱治療、抑制劑治療等。 本論文主要使用多功能奈米載體-奈米微胞分別進行三個部分之試驗研究。第一部分為多功能奈米微胞標誌放射線同位素再包覆化療藥物Doxorubicin應用於肝癌治療評估。運用放射性同位素錸-188(半衰期16.9個小時)具有的85% β-射線進行腫瘤的放射線治療及其15% γ-射線可用於偵測藥物於動物活體之體內外分佈情形。治療結果顯示若錸-188合併化療藥物之組別對於腫瘤可達到最佳之抑制，可大幅增加腫瘤細胞的細胞壞死及凋亡。 第二部分為酪胺酸激酶抑制劑合併化療藥物SN38應用於大腸直腸癌治療，此研究是將酪胺酸激酶抑制劑Sunitinib與化療藥物SN38同時包覆於奈米微胞內，Sunitinib具有改變腫瘤內為環境之性質，而SN38為大腸癌治療之化療藥物CPT-11之有效成分物質，兩者對病患皆具有不良之副作用，故將兩種藥物同時包覆在奈米微胞中，預期可降低抑制劑及強效之化療藥物之副作用，提升對於腫瘤治療之效果。療效試驗結果顯示奈米微胞包覆Sunitinib與SN38可以有效的抑制腫瘤的生長並減低副作用。 第三部分為標靶藥物診斷應用及其結合光熱療法用於大腸直腸癌治療。此部分又分為兩個研究主題，一為標靶藥物之診斷研究，此部分之研究為預先試驗，內容包括對三種大腸直腸癌腫瘤細胞(HCT-116、HT-29及SW-620)之標靶能力測試及放射線同位素In-111標誌臨床用藥爾必得舒(Cetuximab)進行體內外生體分佈之驗證試驗，驗證結果Cetuximab標靶HCT-116細胞之效果最好。二為Cetuximab標誌於包覆光感藥物IR780奈米微胞之動物光熱治療試驗。試驗結果驗證，具標靶能力之Cetuximab/IR780奈米微胞可以增加光感藥物對腫瘤抑制效果。

The multi-functional nanocarrier has many researches and application widely in recent years, which can combine with other therapy method. The combination of chemotherapy, radiotherapy, targeting therapy photodynamic therapy and tyrosine kinase inhibitor therapy had been a therapy method for cancer treatments. Main of this dissertation was used muti-functional nanocarrier- micelles for three parts researches. The first part is therapeutic applications of micelles combination of chemotherapy (Doxorubicin) and radiotherapy (rhenium-188, 188Re) in hepatocellular carcinoma. 188Re (t1/2=16.9 hours) decays by 15% gamma emission and by 85% beta emission for in vivo, ex vivo biodistribution and therapeutic applications. The multifunctional micelles loaded with Dox and labeled with 188Re were developed to synergistically inhibit tumor cell growth and enhance necrosis and apoptosis. The second part is therapeutic efficacy of chemotherapy drug (SN38) and tyrosine kinase inhibitor (Sunitinib) co-loading micelles in colorectal cancer. Sunitinib has the effect of change the environment within the tumor. The active form of CPT-11 as SN38 has higher cytotoxicity than CPT-11, which could have an excellent anticancer effect. We expect that low dose of SN38 combined with tyrosine kinase could enhance the antitumor effect and reduce the side effect of chemotherapy. The third part is targeting drug for diagnosis and combined with near-infrared dye for enhanced photothermal therapy in colorectal cancer two studies. Study one is pre-study, which include binding effect of three colorectal cancer cells (HCT-116, HT-29 and SW-620) and 111In-cetuximab as a diagnostic agent by accessible epidermal growth factor (EGF) receptor targeting in colorectal carcinoma. Results showed high EGF receptor expression and uptake in HCT-116 colorectal tumors. Study two is EGF receptor targeted micelles containing near-infrared dye (IR780) for photothermal therapy in colorectal cancer. The Cetuximab/IR-780/micelles could enhance the antitumor effects by photothermal therapy in colorectal cancers.