合成包覆中孔洞氧化矽奈米顆粒之海藻酸微米顆粒 應用於穩定釋放以及標靶化學治療

Synthesis of Mesoporous Silica Nanoparticle Encapsulated Alginate Microparticles for Sustained Release and Targeting Chemotherapy

廖祐德(Yu-Te Liao)

指導教授 ： 吳嘉文

國立臺灣大學/工學院/化學工程學研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.02657

摘要

本論文著重於合成包覆中孔洞氧化矽之海藻酸微米顆粒（MSN@Alg），並且將MSN@Alg應用於穩定釋放以及標靶化療。我們以空氣動力噴霧法為基礎合成MSN@Alg，在此系統下我們藉由調控海藻酸合成濃度、海藻酸流量、氣體流量、噴嘴與氯化鈣槽之距離以及氯化鈣槽之轉速來等不同之參數以合成不同的海藻酸微米顆粒粒徑與型態。舉例來說，當海藻酸合成濃度為1%，海藻酸流量為0.5 mL/min，氣體流量為500 mbar，噴嘴與氯化鈣槽之距離為6 cm，氯化鈣槽之轉速為300 r.p.m時，在海藻酸溶液中加入0.3%之中孔洞氧化矽（MSN），可成功合成出分布集中直徑約為20 um之球型之包覆中孔洞氧化矽海藻酸微米顆粒。接著在海藻酸表面修飾RGD胜肽鏈用於針對特定細胞，並提升藥物治療效果。
以羅丹明6G（rhodamine 6G，R6G）為模擬藥物比較MSN以及MSN@Alg兩者在不同海藻酸濃度以及不同磷酸緩衝液濃度時的吸附以及釋放特性曲線。隨著海藻酸以及磷酸量的改變MSN@Alg具有不同的釋放曲線，當磷酸緩衝液（10 mM）與MSN@Alg之比例為2 毫升比1毫克時具有較佳的穩定釋放效果，而其釋放時間可延長至20天（在此條件下MSN只能維持約10小時的延長釋放）。
將阿黴素（Dox）搭載於MSN內部後，比較有無標靶性質的材料對於具有無標靶受體之細胞的治療效果。由細胞存活率可知，即使載體濃度提高到10 mg/mL對於正常細胞以及癌細胞皆不具有明顯生物毒性（存活率大於80%）。當載體具有標靶配體時，其對於具有標靶受體的癌細胞（HepG2）之治療效果提升約3.5倍；而對於不具有標靶受體之癌細胞（BT20）之治療效果則無明顯差異。

關鍵字

海藻酸 ； 中孔洞氧化矽奈米顆粒 ； 穩定釋放 ； 細胞標定

並列摘要

This study reports the synthesis of mesoporous silica nanoparticles encapsulated alginate microparticles (MSN@Alg) for sustained release and targeting chemotherapy. The MSN@Alg was synthesized by air dynamical atomization, and the effects of several critical factors including concentration of alginate solution, flow rate of alginate solution, flow rate of air, the distance between nozzle and calcium bath, and stirring rate of calcium on the particle size of the synthesized MSN@Alg were investigated. For example, an uniformly distributed, spherical MSN@Alg with 20 um in diameter could be successfully produced when the reaction conditions were chosen as follows: the concentration of alginate solution was 1%, the flow rate of alginate solution was 0.5 mL/min, the flow rate of air was 500 mbar/cm2, the length between nozzle and calcium bath was 6 cm, and the rate of stirring of calcium bath was 300 r.p.m. with 0.3% MSN.
For studying the sustained release properties of the MSN@Alg, rhodamine 6G (R6G) was used as a model drug, and we compared the release properties of R6G/MSN and R6G/MSN@Alg by using different concentrations of alginate, concentrations and volumes of PBS buffer solutions. The sustained release behavior of the R6G/MSN@Alg system can be prolonged to 20 days with an optimal condition of 1 mg R6G/MSN@Alg to 2 mL PBS (10 mM).
For specific targeting chemotherapy, an anti-cancer drug, doxorubicin (Dox), was used to loaded into MSN@Alg, and a RGD-based peptide was functionalized onto the surface of MSN@Alg for the purpose of specific targeting. The results showed that the intracellular drug delivery efficiency was greatly enhanced (i.e, 3.5 folds) for the Dox/MSN@Alg/RGD drug delivery system.

並列關鍵字

alginate ； mesoporous silica nanoparticle ； sustained release ； cell specific targeting

參考文獻

1 Slowing, I. I., Vivero-Escoto, J. L., Wu, C.-W. & Lin, V. S. Y. Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv. Drug Delivery Rev. 60, 1278-1288, (2008).

2 Zhang, C. M. et al. Self-activated luminescent and mesoporous strontium hydroxyapatite nanorods for drug delivery. Biomaterials 31, 3374-3383, (2010).

3 Doshi, N. & Mitragotri, S. Designer Biomaterials for Nanomedicine. Adv. Funct. Mater. 19, 3843-3854, (2009).

4 Bangham, A. D. & Horne, R. W. Negative staining of phospholipids and their structural modification by surface-active agents as observed in electron microscope. J. Mol. Biol. 8, 660-&, (1964).

5 Matsumoto, T. et al. Modification of apatite materials for bone tissue engineering and drug delivery carriers. Curr. Med. Chem. 14, 2726-2733, (2007).