結合癌症診斷與磁熱化療之氧化鐵奈米藥物載體開發

Abstract

大腸直腸癌目前已是全球人類死亡的重大疾病之一，而國內隨著經濟之進步、飲食習慣之西化，大腸直腸癌之發生率亦隨之增加，約有三分之一的大腸直腸癌患者於診斷時即已發生轉移。而目前大腸直腸癌惡化的元兇乃是因病患體內有一群惡性度極高的腫瘤幹細胞，研究也證實腫瘤幹細胞能造成癌症復發、轉移，以及對藥物產生多重抗藥性的結果。本計畫即是開發一結合診斷與高溫療法、化療之高生物相容性奈米藥物載體以應用於大腸直腸癌與腫 瘤幹細胞之診斷與治療上。本計畫所使用的奈米藥物載體系統是以超順磁磁性奈米粒子 (Superparamagnetic iron oxide nanoparticles)為核心，做為大腸直腸癌診斷與高溫治療之工具，並層層披覆上高生物相容性之 Poly(sodium styrene sulfonate)、化療藥物 Irinotecan (CPT-11)與人類血清白蛋白，並利用 anti-human prominin-1 (PROM1/CD133) monoclonal antibodies 作為此奈米藥物載體對大腸直腸癌標靶治療之標記，以增加直腸腫瘤幹細胞與腫瘤細胞對奈米藥物載體的攝入。故可藉此奈米藥物載體提高化療藥物於血液之半衰期、降低病患之副作用與提高大腸直腸癌熱療與化療之效果。

Colorectal cancer is now one of the major diseases in the world. With westernized diet in Taiwan, the incidence of colorectal cancer increases. For cancer stem cell therapy, CD133 (prominin-1) is a theoretical cancer stem cell (CSC) marker for colorectal cancer and is a proposed therapeutic target. Cells with CD133 overexpression have demonstrated enhanced tumor-initiating ability and tumor relapse probability. To resolve the problem of chemotherapy failure, we will develop a magnetite-based nanomedicine using loco-regional hyperthermia combined with chemotherapy. The targeting carrier has a magnetite nanoparticle (superparamagnetic iron oxide nanoparticles, SPIO) core and a layer-by-layer polyelectrolyte molecule shell that carries irinotecan (CPT-11) and anti-human prominin-1 (PROM1/CD133) monoclonal antibody for cancer stem cell-specific targeting. Besides as a contrast agent for MRI, this nanomedicine plays as an important role to relay the externally delivered radiofrequency energy for tumor hyperthermia. Locoregional heat can trigger a drug release from the carrier as it directly damages tumor cells and cancer stem cells. .Finally, the use of this nanomedicine can improve the half-life of chemotherapy drugs in the blood and reduce the side effect, and is significantly more efficacious than hyperthermia or chemotherapy alone for colorectal cancer therapy.