利用榖胱甘肽調制金奈米修飾中孔洞二氧化矽奈米球之藥物釋放

奈米載體的高比表面積可以提高水溶性不佳的藥物的溶解度，提高藥物的生物利用度及吸收力，並降低藥物的毒副作用、減少給藥次數，進而達到減少病患痛苦的目的；此外，有別於傳統傾瀉式藥物製劑，新型的奈米藥物載體應具備藥物控制釋放之功能，以精確控制藥物在到達標的器官或組織時釋放內容藥物的能力。基於中孔洞二氧化矽奈米球的諸多優點(具有高表面積、孔洞體積、易修飾性及生物相容性等)，本研究選用表面修飾胺基(amino group)的中孔洞二氧化矽奈米球做為載體，並透過氮金原子間微弱的親和力(6 kcal/mol)，將金奈米粒子當成矽球孔洞的阻塞劑，製備出金奈米修飾之中孔洞二氧化矽奈米球(Gold-Capped Mesoporous Silica Nanoparticles, GCMSN)做為奈米藥物載體。預期當GCMSN 進入細胞後，由於細胞內的榖胱甘太(Glutathione, GSH)濃度稍高，因此硫金原子的親和作用(47 kcal/mol)應可取代原本的氮金作用力，使得金奈米粒子從中孔洞二氧化矽奈米球上脫附下來，自動啟動控制釋放的扳機(不需外來光、電、熱等能量的輸入即可達到藥物釋放的目的)。初步的研究成果已證實，在穿透式電子顯微鏡鏡檢及螢光光譜儀偵測下，高濃度GSH(10 mM)確實可以促使金奈米粒子從中孔洞二氧化矽奈米球上脫附，而裝載於其內的螢光分子接著被順利釋放；此外，我們亦成功的將疏水性抗癌藥物裝載於GCMSN 中，而透過藥物傳遞及控制釋放，該奈米載體可大幅增強抗癌藥物對於人類肺腺癌細胞(Human Lung Epithelial Cells A549 ) 的毒殺力。研究中，我們同時亦發現，做為阻塞劑的金奈米粒子可選擇性地誘導癌細胞的氧化壓力上升，因而對癌細胞造成氧化傷害。因此，我們認為GCMSN 不但具備調節藥物釋放的能力，還能與抗癌藥物產生協同效應(synergistic effect),增強其對癌細胞的療效，大幅提高對癌細胞的毒殺力。因此本研究所合成的 GCMSN 具有相當大的潛力可以成為新一代的奈米藥物載體。

關鍵字

中孔洞二氧化矽奈米球；控制釋放；藥物傳遞

並列摘要

!""# # Abstract Unlike the traditional dose-dumping pharmaceutical preparations, nano-DDS (drug delivery system) with enhanced surface area not only are capable of transmitting hydrophobic drugs in vitro and in vivo with improved drug bioavailability/absorption, but also help to reduce dosage/side effects of drug. Mesoporous Silica Nanoparticles (MSNs) are known for its versatile advantages such as higher surface area, larger pore volume, tunable pore size and lower cytotoxicity. In this study, the gold nanoparticle (AuNP)-capped, amino-functionalized mesoporous silica nanoparticles (GCMSN) were fabricated as drug carriers, in which AuNPs were modified onto the MSNs via a weak gold-nitrogen bonding (6 kcal/mol) acting as gatekeeper. It was found in this study that, after cellular uptake of GCMSNs, the AuNPs were desorbed from MSNs due to the presence of a relatively higher concentration of intracellular glutathione (GSH, 10 mM), leading to the substitution of gold-thiol bonding (bonding affinity: 47 kcal/mol) for the former weak gold-nitrogen bonding. Such design enables the triggering of drug release from the nanocarriers without external energy (i.e., light/heat, electricity, or acoustic energy). The characterization of GCMSNs was investigated by Scanning/Transmission Electron Microscopy, Dynamic Light Scattering spectrometry, Zeta potential analyzer, UV-Vis/Fluorescence spectrometry, confocal microscopy, and powder X-ray diffraction analysis. In vitro studies show that our GCMSNs themselves were able to induce the oxidative stress in cancer cells, leading to higher cell death rate. Moreover, a hydrophobic anticancer drug (camptothecin, CPT) was encapsulated in the pore channels of GCMSNs, and the feasibility of practical drug delivery application was demonstrated in vitro . The controlled release of the anticancer drug shows excellent capability of killing human lung epithelial A549 cells . We thus concluded that Au-capped CPT-loaded MSNs not merely has the ability of controlling drug release, but also produces synergistic effect in treating cancer cells with less side effects and higher efficacy, which makes them a highly promising candidate as a new-generation nano-DDS carriers.

並列關鍵字

mesoporous silica nanoparticles ； control release ； drug delivery

參考文獻

A new family of mesoporous molecular sieves prepared with

MCM-41-type mesoporous silica nanoparticles on the endocytosis by human

Vectors for in Vivo Photodynamic Therapy of Cancer.

Annual Review of Bioche

of MCM-41-Type Mesoporous Silica Nanoparticles on the Endocytosis by

國際替代計量

利用榖胱甘肽調制金奈米修飾中孔洞二氧化矽奈米球之藥物釋放

主題瀏覽