中空中孔洞二氧化矽奈米顆粒具有高表面積、高孔體積、極佳生物相容性與可生物降解等優點，是一種極具潛力的藥物載體。然而，僅少數文獻探討二氧化矽溶解速率與細胞毒性間之關係。本論文以不同種類官能基 (胺基、磷酸基、羧酸基) 嫁接於中空中孔洞二氧化矽奈米顆粒MMT-2並調控修飾程度，研究官能基對溶解速率的影響。我們以模擬體液之緩衝液與細胞培養液作溶解實驗，因官能基會改變其所連接之矽原子的電子環境，且造成不同程度之立體障礙；這些官能基影響二氧化矽溶解反應的進行，而當官能基修飾量提高時，溶解速率下降。我們進一步比較溶解速率與細胞毒性結果，發現二氧化矽的溶解速率是影響細胞毒性的主要原因之一。另外，為展示MMT-2於藥物傳遞系統之應用，我們以支撐式脂雙層包覆MMT-2並攜帶標靶粒線體藥物DTPP，發現此複合物能有效包覆藥物，阻擋藥物預先流出。

Hollow mesoporous silica nanoparticles (HMSNs) have attracted significant attention, especially in biomedical field, due to the properties of large pore volume, high surface area, high biocompatibility and good biodegradability. However, few researches focused on the relationship between cytotoxicity and silica degradation behaviors, which is of importance from pre-clinical perspective. Herein we reported the degradation behaviors of MMT-2 and functionalized MMT-2 (amino-, phosphonate-, carboxylic acid-functionalized) in simulated body fluid and minimum essential medium with 10% fetal bovine serum. The functionalized MMT-2 presented a slower degradation fashion which was caused by the steric hindrance of organosilane and less electrophilicity of silicon atoms. The fast degradation behaviors and high modification extent of silica nanoparticles showed high toxicity in cellular assays (MCF-7).
To demonstrate that MMT-2 could serve as ideal carrier for mitochondria targeting drug decyltriphenylphosphonium bromide (DTPP), we designed a MMT-2 supported lipid bilayer, and it showed ideal drug encapsulation efficiency and little pre-leaking behavior.

目錄
第一章 緒論 1
1-1 中孔洞二氧化矽簡介 1
1-2 中孔洞二氧化矽奈米顆粒的合成 2
1-3 中空中孔洞二氧化矽奈米顆粒MMT-2 10
1-4 中孔洞二氧化矽奈米顆粒的表面修飾 17
1-5 中孔洞二氧化矽奈米顆粒的生醫應用 20
1-5-1 藥物載體的發展 20
1-5-2 中孔洞二氧化矽奈米顆粒對細胞的生理影響 23
1-5-3 粒線體與標靶粒線體藥物之簡介 27
1-6 研究動機 29
第二章 實驗部分 31
2-1 實驗藥品 31
2-2 MMT-2及MCM-41的合成 34
2-2-1 MCM-41的合成 34
2-2-2 MMT-2的合成 34
2-3 嫁接官能基於MCM-41及MMT-2 35
2-3-1 嫁接APTMS官能基 35
2-3-2 嫁接CTMS官能基 35
2-3-3 嫁接THPMP官能基 36
2-4 中孔洞二氧化矽在SBF或medium下的溶解 37
2-4-1 SBF與medium配置方法 37
2-4-2 以矽鉬藍法分析溶液中矽酸鹽含量 38
2-4-3 溶解實驗 39
2-5 合成DTPP loaded lipid-HM 39
2-6 DTPP loaded lipid-HM的藥物釋放實驗 40
2-7 材料鑑定與分析方法 41
2-7-1 X-ray粉末繞射法 41
2-7-2 29Si固態核磁共振光譜術 42
2-7-3 氮氣物理吸脫附法 42
2-7-4 熱重分析法 45
2-7-5 掃描式電子顯微鏡 46
2-7-6 穿透式電子顯微鏡 46
2-7-7 動態光散射法與界達電位分析 47
2-7-8 紫外可見分光光譜術 47
2-7-9 傅立葉紅外線光譜術 47
2-7-10感應耦合電漿質譜分析法 48
2-8 細胞實驗 48
2-8-1 細胞培養 48
2-8-2 細胞毒性實驗 49
2-8-3 細胞增殖分析 49
2-8-4 細胞實驗分析儀器 50
2-8-4-1 可見光讀盤儀 50
第三章 結果與討論 51
3-1 中孔洞二氧化矽奈米顆粒之合成 51
3-1-1 29Si固態核磁共振光譜與熱重分析 52
3-1-2 氮氣物理吸脫附鑑定 55
3-1-3 顆粒粒徑與表面電位 58
3-2 MMT-2於SBF之溶解速率研究 59
3-2-1 MMT-2與MCM-41對溶解速率之影響 61
3-2-2 修飾程度對溶解速率之影響 62
3-2-3 官能基對溶解速率之影響 64
3-2-4 嫁接官能基之MMT-2和MCM-41對溶解速率之影響 69
3-3 MMT-2於MEM+10%FBS中之溶解速率研究 71
3-3-1 MMT-2與MCM-41對溶解速率之影響 71
3-3-2 修飾程度對溶解速率之影響 72
3-3-3 官能基對溶解速率之影響 73
3-3-4 功能化MMT-2和MCM-41對溶解速率之影響 74
3-4 官能基與溶解速率對MCF-7細胞活性之研究 76
3-4-1 MMT-2與MCM-41對MCF-7細胞活性之影響 76
3-4-2 修飾程度對MCF-7細胞活性之影響 78
3-4-3 官能基對MCF-7細胞活性之影響 79
3-4-4 功能化MMT-2和MCM-41對MCF-7細胞活性之影響 80
3-5 DTPP loaded lipid-HM 82
3-5-1 外表面嫁接CDSMH官能基MMT-2之材料鑑定與分析 83
3-5-2 DTPP之定量 86
3-5-3 DTPP loaded lipid-HM之包覆效率與藥物釋放分析 88
3-5-4 DTPP loaded lipid-HM與free DTPP的細胞毒殺性 92
第四章 結論 95
第五章 參考文獻 97

五 參考文獻
[1] Ciesla, U.; Schüth, F. Microporous Mesoporous Mater. 1999, 27, 131-149.
[2] Yanagisawa, T.; Shimizu, T.; Kuroda, K.; Kato, C.Bull. Chem. Soc. Jpn. 1990, 63, 988-992.
[3] Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartuli, J. C.; Beck, J. S. Nature 1992, 359, 710-712.
[4] Schmidt, R.; Hansen, E. W.; Stoecker, M.; Akporiaye, D.; Ellestad, O. H. J. Am. Chem. Soc. 1995, 117, 4049-4056.
[5] Raman, N. K.; Anderson, M. T.; Brinker, C. J.Chem. Mater. 1996, 8, 1682-1701.
[6] Huo, Q.; Margolese, D. I.; Ciesla, U.; Feng, P.; Gier, T. E.; Sieger, P.; Leon, R.; Petroff, P. M.; Schuth, F.; Stucky, G. D. Nature 1994, 368, 317-321.
[7] Rath, D.; Rana, S.; Parida, K. M. RSC Advances 2014, 4, 57111-57124.
[8] Soler-Illia, G. J. d. A. A.; Sanchez, C.; Lebeau, B.; Patarin, J. Chem. Rev. 2002, 102, 4093-4138.
[9] Ward, M. D.; Horner, M. J. CrystEngComm 2004, 6, 401-407.
[10] Lindman, B.; Wennerström, H., Micelles. 1980, In Micelles, Springer Berlin Heidelberg
[11] Israelachvili, J. N.; Mitchell, D. J.; Ninham, B. W. J. Chem. Soc., Faraday Trans. 2 1976, 72, 1525-1568.
[12] Beck, J. S.; Vartuli, J. C.; Roth, W. J.; Leonowicz, M. E.; Kresge, C. T.; Schmitt, K. D.; Chu, C. T. W.; Olson, D. H.; Sheppard, E. W. J. Am. Chem. Soc. 1992, 114, 10834-10843.
[13] Chen, C.-Y.; Li, H.-X.; Davis, M. E. Microporous Mater. 1993, 2, 17-26.
[14] Chen, C.-Y.; Burkett, S. L.; Li, H.-X.; Davis, M. E. Microporous Mater. 1993, 2, 27-34.
[15] Firouzi, A.; Atef, F.; Oertli, A. G.; Stucky, G. D.; Chmelka, B. F. J. Am. Chem. Soc. 1997, 119, 3596-3610.
[16] Huo, Q.; Margolese, D. I.; Ciesla, U.; Demuth, D. G.; Feng, P.; Gier, T. E.; Sieger, P.; Firouzi, A.; Chmelka, B. F. Chem. Mater. 1994, 6, 1176-1191.
[17] Hoffmann, F.; Cornelius, M.; Morell, J.; Fröba, M. Angew. Chem. Int. Ed. 2006, 45, 3216-3251.
[18] Monnier, A.; Schüth, F.; Huo, Q.; Kumar, D.; Margolese, D.; Maxwell, R. S.; Stucky, G. D.; Krishnamurty, M.; Petroff, P.; Firouzi, A.; Janicke, M.; Chmelka, B. F. Science 1993, 261, 1299-1303.
[19] Li, J. A.; Liu, J.; Wang, D. H.; Guo, R. S.; Li, X. L.; Qi, W. Langmuir 2010, 26, 12267-12272.
[20] Lin, Y. S.; Wu, S. H.; Tseng, C. T.; Hung, Y.; Chang, C.; Mou, C. Y. Chemical Communications 2009, 3542-3544.
[21] Yang, W. L.; Li, B. S. Journal of Materials Chemistry B 2013, 1, 2525-2532.
[22] Yang, W. L.; Li, B. S. Nanoscale 2014, 6, 2292-2298.
[23] Chen, D. Y.; Jiang, M. Accounts of Chemical Research 2005, 38, 494-502.
[24] Hao, N.; Wang, H. T.; Webley, P. A.; Zhao, D. Y. Microporous and Mesoporous Mater. 2010, 132, 543-551.
[25] Mandal, M.; Kruk, M. Chemistry of Materials 2012, 24, 123-132.
[26] Qi, G. G.; Wang, Y. B.; Estevez, L.; Switzer, A. K.; Duan, X. N.; Yang, X. F.; Giannelis, E. P. Chemistry of Materials 2010, 22, 2693-2695.
[27] Chen, J. F.; Ding, H. M.; Wang, J. X.; Shao, L. Biomaterials 2004, 25, 723-727.
[28] Lai, N. C.; Lin, C. H.; Ku, P. H.; Chang, L. L.; Liao, K. W.; Lin, W. T.; Yang, C. M. Nano Research 2014, 7, 1439-1448.
[29] Yang, C. M.; Lin, C. Y.; Sakamoto, Y.; Huang, W. C.; Chang, L. L. Chem. Commun. 2008, 5969-5971.
[30] Kékicheff, P.; Cabane, B. J. Phys. France 1987, 48, 1571-1583.
[31] Alpérine, S.; Hendrikx, Y.; Charvolin, J. J. Physique Lett. 1985, 46, 27-31.
[32] Yang, C.-M.; Lin, C.-Y.; Sakamoto, Y.; Huang, W.-C.; Chang, L.-L. Chemical Communications 2008, 5969-5971.
[33] Johnston, A. P. R.; Such, G. K.; Ng, S. L.; Caruso, F. Current Opinion in Colloid & Interface Science 2011, 16, 171-181.
[34] Allen, T. M.; Cullis, P. R. Science 2004, 303, 1818-1822.
[35] Kamaly, N.; Xiao, Z. Y.; Valencia, P. M.; Radovic-Moreno, A. F.; Farokhzad, O. C. Chemical Society Reviews 2012, 41, 2971-3010.
[36] Torchilin, V. P. Nat Rev Drug Discov 2005, 4, 145-160.
[37] Gregoriadis, G. New England Journal of Medicine 1976, 295, 704-710.
[38] Al-Abd, A. M.; Lee, S. H.; Kim, S. H.; Cha, J. H.; Park, T. G.; Lee, S. J.; Kuh, H. J. Journal of Controlled Release 2009, 137, 130-135.
[39] Murakami, Y.; Yokoyama, M.; Okano, T.; Nishida, H.; Tomizawa, Y.; Endo, M.; Kurosawa, H. Journal of Biomedical Materials Research Part A 2007, 80A, 421-427.
[40] Ponta, A.; Bae, Y. Pharmaceutical Research 2010, 27, 2330-2342.
[41] Yokoyama, M.; Okano, T.; Sakurai, Y.; Suwa, S.; Kataoka, K. Journal of Controlled Release 1996, 39, 351-356.
[42] Soppimath, K. S.; Aminabhavi, T. M.; Kulkarni, A. R.; Rudzinski, W. E. Journal of Controlled Release 2001, 70, 1-20.
[43] Müller, R. H.; Mäder, K.; Gohla, S. European Journal of Pharmaceutics and Biopharmaceutics 2000, 50, 161-177.
[44] Cartiera, M. S.; Johnson, K. M.; Rajendran, V.; Caplan, M. J.; Saltzman, W. M. Biomaterials 2009, 30, 2790-2798.
[45] Kocbek, P.; Obermajer, N.; Cegnar, M.; Kos, J.; Kristl, J. Journal of Controlled Release 2007, 120, 18-26.
[46] Lai, C.-H.; Lai, N.-C.; Chuang, Y.-J.; Chou, F.-I.; Yang, C.-M.; Lin, C.-C. Nanoscale 2013, 5, 9412-9418.
[47] Lin, Y. S.; Abadeer, N.; Hurley, K. R.; Haynes, C. L. Journal of the American Chemical Society 2011, 133, 20444-20457.
[48] Meng, H.; Xue, M.; Xia, T.; Ji, Z. X.; Tarn, D. Y.; Zink, J. I.; Nel, A. E. Acs Nano 2011, 5, 4131-4144.
[49] Vivero-Escoto, J. L.; Slowing, I. I.; Trewyn, B. G.; Lin, V. S. Y. Small 2010, 6, 1952-1967.
[50] Wang, L. S.; Wu, L. C.; Lu, S. Y.; Chang, L. L.; Teng, I. T.; Yang, C. M.; Ho, J. A. A. Acs Nano 2010, 4, 4371-4379.
[51] Knezevic, N. Z.; Trewyn, B. G.; Lin, V. S. Y. Chemistry-a European Journal 2011, 17, 3338-3342.
[52] Solomon, R.; Gabizon, A. A. Clinical Lymphoma and Myeloma 2008, 8, 21-32.
[53] Fader, A. N.; Rose, P. G. International Journal of Gynecological Cancer 2009, 19, 1281-1283.
[54] Brinker, C. J.; Carnes, E. C.; Ashley, C. E., Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery and methods of using same. Google Patents: 2014.
[55] Cauda, V.; Engelke, H.; Sauer, A.; Arcizet, D.; Brauchle, C.; Radler, J.; Bein, T. Nano Lett 2010, 10, 2484-92.
[56] Liu, J. W.; Jiang, X. M.; Ashley, C.; Brinker, C. J. Journal of the American Chemical Society 2009, 131, 7567-+.
[57] Liu, J. W.; Stace-Naughton, A.; Jiang, X. M.; Brinker, C. J. Journal of the American Chemical Society 2009, 131, 1354-+.
[58] Meng, H.; Wang, M. Y.; Liu, H. Y.; Liu, X. S.; Situ, A.; Wu, B.; Ji, Z. X.; Chang, C. H.; Nel, A. E. Acs Nano 2015, 9, 3540-3557.
[59] Canton, I.; Battaglia, G. Chemical Society Reviews 2012, 41, 2718-2739.
[60] Conner, S. D.; Schmid, S. L. Nature 2003, 422, 37-44.
[61] Petros, R. A.; DeSimone, J. M. Nat Rev Drug Discov 2010, 9, 615-627.
[62] Stockhofe, K.; Postema, J. M.; Schieferstein, H.; Ross, T. L. Pharmaceuticals 2014, 7, 392-418.
[63] Maeda, H.; Nakamura, H.; Fang, J. Advanced Drug Delivery Reviews 2013, 65, 71-79.
[64] Adiseshaiah, P. P.; Hall, J. B.; McNeil, S. E. Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology 2010, 2, 99-112.
[65] Benezra, M.; Penate-Medina, O.; Zanzonico, P. B.; Schaer, D.; Ow, H.; Burns, A.; DeStanchina, E.; Longo, V.; Herz, E.; Iyer, S.; Wolchok, J.; Larson, S. M.;
Wiesner, U.; Bradbury, M. S. Journal of Clinical Investigation 2011, 121, 2768-2780.
[66] Lynch, I.; Salvati, A.; Dawson, K. A. Nature Nanotechnology 2009, 4, 546-547.
[67] Nel, A. E.; Madler, L.; Velegol, D.; Xia, T.; Hoek, E. M. V.; Somasundaran, P.; Klaessig, F.; Castranova, V.; Thompson, M. Nature Materials 2009, 8, 543-557.
[68] Lin, Y. S.; Hurley, K. R.; Haynes, C. L. Journal of Physical Chemistry Letters 2012, 3, 364-374.
[69] Mamaeva, V.; Sahlgren, C.; Lindén, M. Advanced Drug Delivery Reviews 2013, 65, 689-702.
[70] Yu, T.; Greish, K.; McGill, L. D.; Ray, A.; Ghandehari, H. Acs Nano 2012, 6, 2289-2301.
[71] Zhao, Y.; Sun, X.; Zhang, G.; Trewyn, B. G.; Slowing, I. I.; Lin, V. S. Y. ACS Nano 2011, 5, 1366-1375.
[72] Lin, Y.-S.; Haynes, C. L. Journal of the American Chemical Society 2010, 132, 4834-4842.
[73] Tarn, D.; Ashley, C. E.; Xue, M.; Carnes, E. C.; Zink, J. I.; Brinker, C.J. Accounts of Chemical Research 2013, 46, 792-801.
[74] Slowing, II; Wu, C. W.; Vivero-Escoto, J. L.; Lin, V. S. Y. Small 2009, 5, 57-62.
[75] Nash, T.; Allison, A. C.; Haringto.Js. Nature 1966, 210, 259-&.
[76] Murashov, V.; Harper, M.; Demchuk, E. Journal of Occupational and Environmental Hygiene 2006, 3, 718-723.
[77] Slowing, I.; Trewyn, B. G.; Lin, V. S. Y. Journal of the American Chemical Society 2006, 128, 14792-14793.
[78] Bhattacharjee, S.; de Haan, L. H. J.; Evers, N. M.; Jiang, X.; Marcelis, A. T. M.; Zuilhof, H.; Rietjens, I.; Alink, G. M. Particle and Fibre Toxicology 2010, 7, 12.
[79] Li, L.-L.; Yin, Q.; Cheng, J.; Lu, Y. Advanced Healthcare Materials 2012, 1, 567-572.
[80] He, Q.; Shi, J.; Zhu, M.; Chen, Y.; Chen, F. Microporous and Mesoporous Mater. 2010, 131, 314-320.
[81] Yamada, H.; Urata, C.; Aoyama, Y.; Osada, S.; Yamauchi, Y.; Kuroda, K. Chemistry of Materials 2012, 24, 1462-1471.
[82] Cauda, V.; Schlossbauer, A.; Bein, T. Microporous and Mesoporous Mater. 2010, 132, 60-71.
[83] Wallace, D. C. Faseb Journal 2008, 22, 1.
[84] Fleury, C.; Mignotte, B.; Vayssiere, J. L. Biochimie 2002, 84, 131-141.
[85] Halliwell, B. British journal of experimental pathology 1989, 70, 737-757.
[86] Warburg, O. Science 1956, 123, 309-314.
[87] Hoye, A. T.; Davoren, J. E.; Wipf, P.; Fink, M. P.; Kagan, V. E. Accounts of Chemical Research 2008, 41, 87-97.
[88] Marrache, S.; Tundup, S.; Harn, D. A.; Dhar, S. Acs Nano 2013, 7, 7392-7402.
[89] Zhou, J.; Zhao, W. Y.; Ma, X.; Ju, R. J.; Li, X. Y.; Li, N.; Sun, M. G.; Shi, J. F.; Zhang, C. X.; Lu, W. L. Biomaterials 2013, 34, 3626-3638.
[90] Millard, M.; Pathania, D.; Shabaik, Y.; Taheri, L.; Deng, J. X.; Neamati, N. Plos One 2010, 5, 18.
[91] Smith, R. A. J.; Porteous, C. M.; Gane, A. M.; Murphy, M. P. Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 5407-5412.
[92] Gao, Y.; Chen, Y.; Ji, X.; He, X.; Yin, Q.; Zhang, Z.; Shi, J.; Li, Y. Acs Nano 2011, 5, 9788-9798.
[93] Wang, T. T.; Zhang, L. Y.; Su, Z. M.; Wang, C. G.; Liao, Y.; Fu, Q. Acs Applied Materials & Interfaces 2011, 3, 2479-2486.
[94] Zhao, Y.; Lin, L. N.; Lu, Y.; Chen, S. F.; Dong, L. A.; Yu, S. H. Advanced Materials 2010, 22, 5255-5259.
[95] Ross, M. F.; Prime, T. A.; Abakumova, I.; James, A. M.; Porteous, C. M.; Smith, R. A. J.; Murphy, M. P. Biochemical Journal 2008, 411, 633-645.
[96] Nam, Y.; Lee, D.; Cho, E.-B. Materials Letters 2013, 110, 176-179.
[97] Kokubo, T.; Takadama, H. Biomaterials 2006, 27, 2907-2915.
[98] Mullin, J. B.; Riley, J. P. Analytica Chimica Acta 1955, 12, 162-176.
[99] Lin, Y. S.; Abadeer, N.; Haynes, C. L. Chem Commun (Camb) 2011, 47, 532-4.
[100] Gupta, A. K.; Gupta, M. Biomaterials 2005, 26, 1565-1573.
[101] Chung, T. H.; Wu, S. H.; Yao, M.; Lu, C. W.; Lin, Y. S.; Hung, Y.; Mou, C. Y.; Chen, Y. C.; Huang, D. M. Biomaterials 2007, 28, 2959-66.
[102] Oh, W.-K.; Kim, S.; Choi, M.; Kim, C.; Jeong, Y. S.; Cho, B.-R.; Hahn, J.-S.; Jang, J. ACS Nano 2010, 4, 5301-5313.
[103] Ruizendaal, L.; Bhattacharjee, S.; Pournazari, K.; Rosso-Vasic, M.; de Haan, L. H. J.; Alink, G. M.; Marcelis, A. T. M.; Zuilhof, H. Nanotoxicology 2009, 3, 339-347.
[104] Feng, Z.; Li, Y.; Niu, D.; Li, L.; Zhao, W.; Chen, H.; Li, L.; Gao, J.; Ruan, M.; Shi, J. Chemical Communications 2008, 2629-2631.
[105] Li, J.; Liu, J.; Wang, D.; Guo, R.; Li, X.; Qi, W. Langmuir 2010, 26, 12267-12272.
[106] Cebrián, V.; Yagüe, C.; Arruebo, M.; Martín-Saavedra, F.; Santamaría, J.; Vilaboa, N. Journal of Nanoparticle Research 2011, 13, 4097-4108.
[107] Lin, Y. S.; Abadeer, N.; Hurley, K. R.; Haynes, C. L. J Am Chem Soc 2011, 133, 20444-57.
[108] He, Q.; Shi, J. Journal of Materials Chemistry 2011, 21, 5845-5855.
[109] Izquierdo-Barba, I.; Colilla, M.; Manzano, M.; Vallet-Regí, M. Microporous and Mesoporous Mater. 2010, 132, 442-452.
[110] Hao, N.; Liu, H.; Li, L.; Chen, D.; Li, L.; Tang, F. Journal of Nanoscience and Nanotechnology 2012, 12, 6346-6354.
[111] Zhai, W.; He, C.; Wu, L.; Zhou, Y.; Chen, H.; Chang, J.; Zhang, H. J Biomed Mater Res B Appl Biomater 2012, 100, 1397-403.
[112] Izak-Nau, E.; Voetz, M.; Eiden, S.; Duschl, A.; Puntes, V. F. Particle and Fibre Toxicology 2013, 10, 12.
[113] Juang, L. C.; Wang, C. C.; Lee, C. K. Chemosphere 2006, 64, 1920-1928.
[114] Alahmadi, S. M.; Mohamad, S.; Maah, M. J. International Journal of Molecular Sciences 2012, 13, 13726-13736.
[115] Knapp, D. R., Handbook of analytical derivatization reactions. John Wiley & Sons: 1979.
[116] Nounou, M. M.; El-Khordagui, L. K.; Khalafallah, N. A.; Khalil, S. A.Acta Pharmaceutica (Zagreb) 2006, 56, 311-324.