雙硫化功能性矽基材於 藥物釋放與生物感測之應用

Abstract

過去十年，矽奈米材料在生物醫學發展上得到了極大的關注，在藥物投遞的領域更是百家爭鳴，為了提升載體的功能性並順應特定疾病治療的需求，針對不同組織、腫瘤細胞、微環境 (pH差異、氧化還原電位、酵素)的投藥機制都已被開發。多數的研究團隊是將具上述功能性應答的分子修飾於材料的表面，或修飾有機官能基(烷類、烯類或苯環)在矽骨架中製造孔洞的結構增加材料的載藥量。此外，也有些團隊製作矽/金屬複合性材料，利用金屬特殊的光學性質或磁性來增加材料的應用性，然而現階段卻沒有團隊將這些功能性的分子直接設計在矽材料的骨架之中。在此研究中，我們將雙硫鍵導入矽基材的結構，合成具氧化還原應答功能之矽奈米材料(redox-responsive silica nanoparticles, ReSiN)，使得矽奈米粒子可以在還原態的環境下自降解，並同時釋放出材料上的藥物分子。在具抗藥性的人類肉瘤細胞 (MES-SA/dx5)中，還原自降解矽奈米球可以降低細胞中的穀胱甘肽含量，增強抗癌藥物在抗藥性肉瘤細胞中的毒殺效果。在植物菸草細胞 (BY-2, tobacco cells)的研究中，我們將螢光分子修飾在此可針對還原反應自降解的矽奈米球上，追蹤其傳遞應是經由胞飲作用(endocytosis)，會先與巨自噬路徑(macroautophagic pathway)胞器融合最後進入液泡。藉由追蹤細胞內的螢光分布，並且能分別出不同胞器間還原能力的差異。目前結果顯示具功能性骨架的矽奈米材料極具潛力，針對研究的需求可設計出不同的矽基材，在藥物投遞或生物感測領域的應用提供了一個新的方向。

Silica nanomaterial has been well developed and employed as promising drug delivery vehicles in the past decade. However, limited studies were dedicated to create a functional silica scaffold by changing the Si-O-Si frameworks. Herein, we demonstrated a novel redox-responsive silica scaffold, which could be disassembled upon stimuli of reducing agents. This novel strategy facilitated the biodegradability of the drug delivery nanocarrier and concurrently released the drugs in targeted cells. We also found the depletion of GSH by the disulfide-rich silica matrix enhanced the cytotoxicity of doxorubicin in drug-resistant cells (MES-SA/dx5). Moreover, we applied this system to intact plant cells (BY-2, tobacco cells) for redox potential sensing in specific cellular organelles. Our current results indicated that redox-responsive silica nanoparticles (ReSiN) were delivered via endocytosis pathway and merged with macroautophagic pathway before the fusion with central vacuole. By monitoring the fluorescence distribution in tobacco cells, the redox potential could be differentiated. Based on current success, unique types of silica matrix with specialized properties could be developed for diverse purposes via this strategy. Such functionalized silica scaffold exhibited the potential and new direction to future drug delivery and biosensing applications.