本研究利用固態脂質奈米粒子作為奈米載體，並同時搭載化療藥物阿黴素 (DOX, doxorubicin) 以及p53穩定藥物硫辛酸 (LA, α-lipoic acid) 用於大腸直腸癌的化學治療，透過結合化學治療與穩定p53蛋白以促進細胞凋亡的產生，進而提升大腸直腸癌的化療效果。
研究中以二次乳化法製備固態脂質奈米粒子，並將DOX及LA結合所形成的複合物 (Complex) 包覆於奈米粒子的疏水核心中，並藉由靜電作用力於表層修飾上mouse serum albumin (MSA)。在細胞實驗中，透過螢光顯微鏡顯示奈米載體可透過胞吞作用進到CT26細胞內，並於溶酶體中瓦解釋放出搭載的化療藥物DOX。在細胞毒性測試中證明在同樣濃度的藥物之下，同時搭載DOX及LA能達到更好的細胞毒殺效果，並且透過觀察p53蛋白的表達、細胞凋亡蛋白的活化，以及GSK-3β的表現，證明研究中所使用的硫辛酸能夠穩定p53，降低大腸癌細胞對於化學治療上的抗拒性，進而增強化學治療的效果。未來如有機會應用在大腸癌的動物模型上，則可針對MSA修飾的標靶特性探討其可靶向腫瘤血管組織的假設，並期望有更好的細胞攝取載體的能力。

Colorectal cancer stands as one of the most common cancer and second most deadly cancer worldwide. Numerous studies on the therapeutic effectiveness of nanoparticles against colorectal cancer have been reported. However, effective and efficient treatment method is still not available. One of the main issues with chemotherapy for colorectal cancer (CRC) is therapy resistance which severely reduces treatment effectiveness and affects patients' prognoses. α-lipoic acid in combination with chemotherapy drugs is shown to have synergistic effect against tumors by reducing therapy resistance. In this study, we develop a solid lipid nanoparticle-based drug delivery system for treating colorectal cancer by co-loading chemotherapeutic drug doxorubicin (DOX) and α-lipoic acid (LA) as a p53 stabilizer. Our study proved enhanced effectiveness of chemotherapy by combining doxorubicin with α-lipoic acid, synergistically promoting cell apoptosis. The solid lipid nanoparticles were prepared by a double emulsion method. The hydrophobic core of the nanoparticles was loaded with the complex that formed by binding DOX and LA, further we use mouse serum albumin (MSA) to modify the surface of our nanoparticles to achieve colloidal stability.
Doxorubicin/α-lipoic acid co-loaded solid lipid nanoparticles (DLSLNs) enter CT26 cells via endocytosis and release DOX within the lysosomes. Cell viability assay proved that the co-loading of DOX and LA achieved better cytotoxic effects at the same DOX concentration. This result was further supported by the expression of the p53 protein, activation of apoptosis-related proteins, and the expression of GSK-3β. The use of α-lipoic acid in this study stabilizes the p53 protein, reduces resistance of colorectal cancer cells to chemotherapy, and enhances the efficacy of chemotherapy. Further this study is aimed to investigate the targeting properties of MSA modified nanoparticles and to achieve improved cellular uptake and its anticancer properties for targeting tumor vascular tissue. This nanotherapeutic system holds a potential to be used in animal model.

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