| 摘要: | 近年來，隨著醫療技術的急速進步，治療疾病的方法日益多元。其核心目標在於為受疾病所苦的患者提供恢復健康之有效途徑。許多疾病的預防與治療都仰賴精確的藥物給予方式。然而，藥物在體內運輸的過程中常面臨著諸多挑戰，例如: 藥物本身難以溶解於水、易降解、溶解度低、生物相容性不佳以及受體內生物屏障阻隔引發的加速藥物代謝等問題，這些因素直接影響著臨床治療的成效。因此，如何更有效且安全地將藥物傳遞至腫瘤細胞，成為值得深入探討的議題。觀察引入四硫化物 (BTES) 的 50 nm pexMON-PEG/PEI 能否在高含量 GSH且低 pH 值環境下能進行降解，讓奈米粒子在癌細胞環境中展現氧化還原應答之特性，成功作為控制藥物釋放的材料。為了提升材料降解效果，我們將癸烷 (Decane) 作為擴孔反應劑，並且利用四乙氧基矽烷（Tetraethoxysilane, TEOS）作為二氧化矽之來源，並將雙[3-(三乙氧基甲矽烷基)丙基] (Bis[3-(triethoxysilyl) propyl] tetrasulfide) (簡稱 BTES) 引入材料溶液中。疏水瞬間同時發生縮合反應，另外在材料表面修飾聚乙二醇（Polyethylene glycol, PEG) 提高材料的溶解度並減少聚集現象與修飾聚醚?亞胺 (Polyetherimide , PEI) 增加細胞吞噬，製備出 50 奈米擴孔之中孔洞有機二氧化矽奈米粒子由聚乙二醇與聚醚?亞胺進行表面修飾 (50 nm Pore Expanded Mesoporous Organosilica Nanoparticles modified with PEG and PEI , 50nm pexMON-PEG/PEI) 。另外，將阿黴素（Doxorubicin）抗癌藥物搭載到pexMON-PEG/PEI 中，進行後續之藥物釋放測試，並通過 4T1 乳腺癌細胞進行一系列的體外細胞實驗。我們透過不同的材料鑑定方法，比較 MSN-PEG/PEI （無擴/無四硫化物）、 pexMSN-PEG/PEI（擴孔/無四硫化物）與 pexMON-PEG/PEI（擴孔/有四硫化物） 之材料特性差異。值得留意的是，在藥物釋放實驗中，隨著 BTES 的引入， pexMON-PEG/PEI在10 mM GSH 環境中的裂解速度呈現提升趨勢，這表明 BTES成功引入到材料骨架中。同時，利用螢光顯微鏡觀察到，4T1 細胞對 pexMON-PEG/PEI 材質的吞噬效果更為顯著。另外，在藥物釋放實驗中，Dox@pexMON-PEG/PEI 在高水平 GSH 環境下出現較快釋放 Dox 的現象。螢光顯微鏡影像也表示 Dox@pexMON-PEG/PEI 對於 4T1 細胞核擁有較明顯的 DNA 損傷。pexMON-PEG/PEI 是一種具備氧化還原應答特性的材料，能夠與腫瘤細胞內高含量的 GSH 反應，而釋放所搭載的藥物。這種獨特的環境感知藥物釋放功能顯著提升了藥物運送至目標位置的可控性和精準性。透過利用這一特性，能夠在腫瘤環境內精準釋放藥物，提高治療效果，為精準醫療和腫瘤治療領域帶來重要的潛在價值。
In recent years, with the rapid advancement of medical technology, the methods for treating diseases have become increasingly diverse. The core objective is to provide effective pathways to restore health for patients suffering from illnesses. The prevention and treatment of many diseases rely on precise drug delivery methods. However, the transportation of drugs within the body often faces numerous challenges, such as drugs being difficult to dissolve in water, prone to degradation, low solubility, poor biocompatibility, and accelerated drug metabolism due to barriers within the biological system. These factors directly impact the efficacy of clinical treatment. Therefore, the exploration of how to more effectively and safely deliver drugs to tumor cells has become a topic worthy of in-depth investigation.Observing whether the incorporation of tetrasulfide (BTES) into 50 nm pexMON PEG/PEI allows for successful degradation in environments with high GSH content and low pH, enabling the nanoparticles to display redox-responsive characteristics in the cancer cell environment. This is intended to establish its efficacy as a material for controlling drug release. To enhance the material degradation efficiency, we employed decane as a pore expanding agent and utilized tetraethoxysilane (TEOS) as the source of silica. Additionally, we introduced bis[3-(triethoxysilyl) propyl] tetrasulfide (BTES) into the material solution. Hydrophobic condensation reactions occurred simultaneously during the material synthesis. Furthermore, we surface-modified the material with polyethylene glycol (PEG) to improve solubility and reduce aggregation, and with polyetherimide (PEI) to enhance cellular uptake. This resulted in the preparation of 50 nm pore-expanded mesoporous organosilica nanoparticles, denoted as 50 nm pexMON PEG/PEI. Subsequently, the anticancer drug doxorubicin was loaded into pexMON PEG/PEI, and drug release tests were conducted. A series of in vitro cell experiments were performed using 4T1 breast cancer cells.Through various material characterization methods, we compared the material characteristics of MSN-PEG/PEI (non-expanded/no tetrasulfide), pexMSN-PEG/PEI (expanded/no tetrasulfide), and pexMON-PEG/PEI (expanded/with tetrasulfide). It is noteworthy that, in drug release experiments, the introduction of BTES resulted in an increased degradation rate of pexMON-PEG/PEI in a 10 mM GSH environment, indicating the successful incorporation of BTES into the material framework. Concurrently, fluorescence microscopy revealed a more pronounced engulfment of pexMON-PEG/PEI by 4T1 cells. Furthermore, in drug release experiments, Dox@pexMON-PEG/PEI exhibited a faster doxorubicin release in a high GSH environment. Fluorescence microscopy images also indicated that Dox@pexMON PEG/PEI caused more noticeable DNA damage to the nuclei of 4T1 cells.
pexMON-PEG/PEI is a material endowed with redox-responsive characteristics, capable of reacting with the high levels of glutathione (GSH) present within tumor cells to release the loaded drug. This unique environment-sensitive drug release functionality significantly enhances the controllability and precision of drug delivery to the target site. By leveraging this feature, precise drug release within the tumor environment can be achieved, thereby improving therapeutic efficacy. This imparts important potential value to the fields of precision medicine and tumor treatment. |
