兩性幾丁聚醣-結晶二氧化矽混成分子:分子設計，自組裝行為，藥物載體設計

Abstract

藉由兩性幾丁聚醣(羧酸基改質親水端，長碳鏈改質疏水端)與矽烷基偶聯劑APTES，(3-Aminopropyl) triethoxysilane，以化學鍵結方式結合，成功地合成出一無機-有機混成分子，並同時具有在水溶液中自組裝的功能。我們經由FTIR與13C-, 29Si固態核磁共振儀鑑定此無機-有機混成分子之化學結構; 而在水溶液中自組裝行為則由臨界微胞濃度(Critical aggregation concentration)來觀察，發現其自組裝的行為與分子在水溶液中的濃度有關。其自組裝形成的奈米載體之外觀形貌由掃描式電子顯微鏡 (scanning electron microscopy, SEM)與穿透式電子顯微鏡 (transmission electron microscopy, TEM)來觀察，其粒徑大小則由DLS偵測。此有機-無機混成分子在水溶液環境中自組裝所形成的奈米微粒，由穿透式電子顯微鏡的影像，可觀察到層狀二氧化矽的結晶相，推測在此有機-無機混成分子所形成之奈米微粒，無機二氧化矽是以shell或layer-by-layer的形式存在，此二氧化矽層是以連續且高度整齊排列成4~6奈米之間的原子層，推測此連續且高度整齊排列二氧化矽的產生，與此混成分子在水溶液中自組裝的行為所導致有關，疏水的作用力誘引此混成分子中之原子自我組織成一整齊的排列方式。二氧化矽層在此混成奈米微粒中，扮演著物理屏障的角色，可以減少包覆之內容物隨著高分子在水溶液中膨潤現象的產生而擴散溢出。此二氧化矽層的存在，顯示了一潛在的新可能性。此新型的有機-無機混成分子可藉由其自組裝的特性，提供一簡易的藥物包覆途徑，且可達到良好的包覆效果，因此可利用在藥物分子的包覆與傳遞之應用。此以疏水性抗癌藥物CPT為模型進行包覆，達到極佳的包覆率(>90%)；進一步更發現藥物包覆效率與釋放情形受濃度與溫度之影響，亦與價接之二氧化矽量有關。此無機-有機混成分子具有良好的生物相容性以及cell uptake的能力，除了對正常細胞有極低的毒性，且能快速的進入細胞體內；對肺癌與乳癌細胞亦作了部分探討。

An organic-inorganic hybrid molecule, which was synthesized by anchoring a silane coupling agent, (3-aminopropyl)triethoxysilane, to an amphiphatic carboxymethyl-hexanoyl chitosan (termed as CHC) previously-developed from this lab, was demonstrated an adjustable self assembling capability in aqueous solution. The chemical structure of this novel hybrid molecule was characterized by FTIR and 13C-, 29Si-nuclear magnetic resonance. The self-assemble behavior of the hybrid macromolecules was characterized by critical aggregation concentration (CAC) measurements which demonstrated a concentration-dependent assembly behavior. Structural morphology of the hybrid nanoparticles was investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scatter (DLS). A crystalline silica layer of ~6 nm in thickness was microscopically observed with a silica-CHC-silica layer-like architecture forming the hybrid nanoparticles. Such a highly-ordered silica lattice has been one of the most interesting phenomena ever reported forming under ambient, aqueous environment. Formation of the continuous crystalline silica layer also proved a cross-linker-free irreversible self-assembly behavior of the hybrid molecule compared with existing chitosan-based composite macromolecules. The hybrid macromolecule showed excellent encapsulation efficiency greater than 91% for an anti-cancer, hydrophobic molecule, (S)-(+)-Camptothecin. Its outstanding cytocompatibility and efficient cellular internalization towards the ARPE-19 cell line, associated with its structural stability under diluted condition, suggest a promising nanovehicle for drug delivery application.