近年來因抗生素在醫療上的濫用，使得越來越多細菌產生抗藥性的基因變異，目前已成為公共衛生安全的一大威脅。過去常以藥物敏感性試驗 (antibiotic susceptibility testing, AST) 來檢測菌株是否具抗藥性表現，但因耗時且易因人為判斷錯誤，因此需要開發出快速、高靈敏度的方法來檢測抗藥性細菌。本實驗以溶膠凝膠法 (sol-gel) 與界面活性劑製成中孔洞二氧化矽奈米粒子 (mesoporous silica nanoparticles, MSNP) ，此中孔洞奈米材料具有高表面積、顆粒均勻且可控制孔徑大小等優勢，可作為良好的反應物載體材料。本論文即利用β-內醯胺類抗生素-青黴素 (penicillin G) ，頭孢菌素類抗生素-頭孢他啶 (ceftazidime) 作為裝載藥物，當青黴素G 被 β-內醯胺酶 (β-lactamase) 水解而形成青黴噻唑酸 (penicilloic acid) 以及頭孢他啶與亞胺培南分別被β-lactamase水解，再利用質譜儀分析其質量的變化，藉此方法篩檢出具有抗藥性細菌之存在，本方法可計算β-內醯胺酶活性之最低偵測極限為2.5 x10-5 U/mL，並於兩小時內即可得到檢測結果，奈米粒子亦可同時裝載不同藥物與臨床細菌反應，並能觀察出該菌株對哪幾種抗生素具有抗性，可提供醫療人員抗生素藥物之選用參考，並預防抗生素藥物之濫用。

一、緒論 1
1、前言 1
2、測定β-內醯胺酶之方法 1
2.1、抗菌敏感性測試 3
2.1.1、 試片擴散法 4
2.1.2、 稀釋法 5
2.1.3、 E-test 6
2.2、碘測定法 7
2.3、酸性測定法 7
2.4、β-內醯胺類酶底物顯色基團測定法 8
2.5、伏安測定法 9
2.6、β-內醯胺類酶底物修飾螢光基團之螢光測定法 10
2.7、等溫滴定量熱測定法 13
2.8、質譜檢測法 14
3、細菌之抗藥性 18
4、抗生素之作用機制與β-內醯胺類抗生素 20
4.1、β-內醯胺類抗生素 22
4.2、青黴素類抗生素 23
4.3、頭孢菌素類抗生素 24
4.4、碳青黴烯類抗生素 25
5、抗藥性細菌之簡介 26
5.1、鮑氏不動桿菌 27
5.2、克雷伯氏肺炎菌 27
5.3、大腸桿菌 28
6、奈米材料簡介與發展 29
7、二氧化矽奈米材料的特性與應用 29
7.1、 二氧化矽奈米材料之製備 30
7.1.1、 水解反應 30
7.1.2、 縮合反應(Condensation) 31
7.1.3、 聚合反應(Polymerization) 31
7.2、 中孔洞二氧化矽奈米材料之簡介 32
8、研究動機 33
二、研究內容 35
1、藥品與儀器 35
1.1、藥品 35
1.2、儀器 36
2、實驗方法 37
3、實驗步驟 38
3.1、中孔洞二氧化矽奈米粒子之合成步驟 38
3.2、抗生素之藥物裝載 38
3.3、中孔洞二氧化矽奈米粒子之藥物裝載量計算 38
3.4、細菌樣品製備 39
3.5、以中孔洞二氧化矽奈米粒子檢測臨床細菌樣品 39
3.6、以β-內醯胺酶標準品水解抗生素 40
3.7、以MSNP/Pen G與β-內醯胺酶標準品反應 42
3.8、以中孔洞二氧化矽奈米粒子檢測牛奶真實樣品 42
3.9、以FTIR鑑定奈米粒子之官能基 43
三、結果與討論 45
1、中孔洞二氧化矽奈米粒子裝載青黴素G (MSNP/Pen G) 45
1.1、中孔洞二氧化矽奈米粒子裝載青黴素G之官能基鑑定 45
1.2、中孔洞二氧化矽奈米粒子之青黴素G裝載量測定 46
1.3、中孔洞二氧化矽奈米粒子裝載青黴素G與酵素反應之pH變化 47
1.4、以β-內醯胺酶（β-lactamases）標準品水解青黴素G之質譜分析 50
1.5、青黴素G與β-內醯胺酶標準品反應之偵測極限 51
1.6、以MSNP/Pen G與β-內醯胺酶標準品反應之質譜分析 53
1.7、以MSNP/Pen G/CAZ與β-內醯胺酶標準品反應之質譜分析 55
1.8、以青黴素G檢測臨床細菌之抗藥性 58
1.9、以MSNP/Pen G檢測臨床細菌樣品 59
1.10、以中孔洞二氧化矽奈米粒子裝載青黴素G檢測牛奶真實樣品 60
2、中孔洞二氧化矽奈米粒子裝載頭孢他啶 (MSNP/CAZ) 62
2.1、中孔洞二氧化矽奈米粒子裝載頭孢他啶之官能基鑑定 62
2.2、中孔洞二氧化矽奈米粒子之頭孢他啶裝載量測定 63
2.3、以β-內醯胺酶標準品水解頭孢他啶之質譜分析 64
2.4、頭孢他啶與β-內醯胺酶標準品反應之偵測極限 66
2.5、以MSNP/CAZ與β-內醯胺酶標準品反應之質譜分析 67
2.6、以頭孢他啶檢測臨床細菌之抗藥性 68
3、利用碳青黴烯類抗生素-亞胺培南檢測抗藥性細菌 70
3.1、β-lactamases標準品水解亞胺培南之分析 70
3.2、以亞胺培南檢測臨床細菌之抗藥性 73
四、結論 75
五、參考文獻 77
六、附錄 83

1. Elander, R. P., Industrial production of β-lactam antibiotics. Applied Microbiology and Biotechnology 2003, 61 (5), 385-392.
2. Kong, K.-F.; Schneper, L.; Mathee, K., Beta-lactam antibiotics: from antibiosis to resistance and bacteriology. APMIS 2010, 118 (1), 1-36.
3. Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L., Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Reviews Drug Discovery 2006, 6, 29.
4. WHO, Antimicrobial resistance: global report on surveillance 2014. 2014.
5. Ogawara, H., Antibiotic resistance in pathogenic and producing bacteria, with special reference to beta-lactam antibiotics. Microbiological reviews 1981, 45 (4), 591-619.
6. Wilke, M. S.; Lovering, A. L.; Strynadka, N. C. J., β-Lactam antibiotic resistance: a current structural perspective. Current Opinion in Microbiology 2005, 8 (5), 525-533.
7. Worthington, R. J.; Melander, C., Overcoming resistance to β-lactam antibiotics. The Journal of organic chemistry 2013, 78 (9), 4207-4213.
8. Kotra, L. P.; Mobashery, S., β-Lactam antibiotics, β-lactamases and bacterial resistance. Bulletin de l'Institut Pasteur 1998, 96 (3), 139-150.
9. Kiehlbauch, J. A.; Hannett, G. E.; Salfinger, M.; Archinal, W.; Monserrat, C.; Carlyn, C., Use of the National Committee for Clinical Laboratory Standards guidelines for disk diffusion susceptibility testing in New York state laboratories. J Clin Microbiol 2000, 38 (9), 3341-3348.
10. Sawai, T.; Takahashi, I.; Yamagishi, S., Iodometric assay method for beta-lactamase with various beta-lactam antibiotics as substrates. Antimicrobial agents and chemotherapy 1978, 13 (6), 910-913.
11. Man, C.; Pang, X.; Xie, K.; Lu, Y.; Liu, S.; Yang, S.; Liu, Y.; Jiang, Y., Use of a gel iodometric method for the rapid determination of β–lactamase in milk. International Dairy Journal 2013, 33 (1), 44-48.
12. Rubin, F. A.; Smith, D. H., Characterization of R factor beta-lactamases by the acidimetric method. Antimicrobial agents and chemotherapy 1973, 3 (1), 68-73.
13. Anago, E.; Ayi-Fanou, L.; Akpovi, C. D.; Hounkpe, W. B.; Agassounon-Djikpo Tchibozo, M.; Bankole, H. S.; Sanni, A., Antibiotic resistance and genotype of beta-lactamase producing Escherichia coli in nosocomial infections in Cotonou, Benin. Annals of clinical microbiology and antimicrobials 2015, 14, 5-5.
14. Ghavami, A.; Labbé, G.; Brem, J.; Goodfellow, V. J.; Marrone, L.; Tanner, C. A.; King, D. T.; Lam, M.; Strynadka, N. C. J.; Pillai, D. R.; Siemann, S.; Spencer, J.; Schofield, C. J.; Dmitrienko, G. I., Assay for drug discovery: Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates. Analytical Biochemistry 2015, 486, 75-77.
15. Betelli, L.; Neuwirth, C.; Solanas, S.; Chantemesse, B.; Vienney, F.; Hartmann, A.; Rochelet, M., A voltammetric test for the rapid discrimination of β-lactamase-producing Enterobacteriaceae in blood cultures. Talanta 2018, 184, 210-218.
16. Li, L.; Li, Z.; Shi, W.; Li, X.; Ma, H., Sensitive and Selective Near-Infrared Fluorescent Off–On Probe and Its Application to Imaging Different Levels of β-Lactamase in Staphylococcus aureus. Analytical Chemistry 2014, 86 (12), 6115-6120.
17. Chen, Y.; Xianyu, Y.; Wu, J.; Zheng, W.; Rao, J.; Jiang, X., Point-of-Care Detection of β-Lactamase in Milk with a Universal Fluorogenic Probe. Analytical Chemistry 2016, 88 (11), 5605-5609.
18. Thai, H. B. D.; Yu, J. K.; Park, B. S.; Park, Y.-J.; Min, S.-J.; Ahn, D.-R., A fluorogenic substrate of beta-lactamases and its potential as a probe to detect the bacteria resistant to the third-generation oxyimino-cephalosporins. Biosensors and Bioelectronics 2016, 77, 1026-1031.
19. Mao, W.; Xia, L.; Wang, Y.; Xie, H., A Self-Immobilizing and Fluorogenic Probe for β-Lactamase Detection. Chemistry – An Asian Journal 2016, 11 (24), 3493-3497.
20. Zhang, Y.-J.; Wang, W.-M.; Oelschlaeger, P.; Chen, C.; Lei, J.-E.; Lv, M.; Yang, K.-W., Real-Time Monitoring of NDM-1 Activity in Live Bacterial Cells by Isothermal Titration Calorimetry: A New Approach To Measure Inhibition of Antibiotic-Resistant Bacteria. ACS Infectious Diseases 2018, 4 (12), 1671-1678.
21. Xu, Z.; Wang, H.-Y.; Huang, S.-X.; Wei, Y.-L.; Yao, S.-J.; Guo, Y.-L., Determination of β-Lactamase Residues in Milk Using Matrix-Assisted Laser Desorption/Ionization Fourier Transform Mass Spectrometry. Analytical Chemistry 2010, 82 (5), 2113-2118.
22. Li, L.; Guo, C.; Ai, L.; Dou, C.; Wang, G.; Sun, H., Research on degradation of penicillins in milk by β-lactamase using ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry. Journal of Dairy Science 2014, 97 (7), 4052-4061.
23. Espinosa, R. F.; Rumi, V.; Marchisio, M.; Cejas, D.; Radice, M.; Vay, C.; Barrios, R.; Gutkind, G.; Di Conza, J., Fast and easy detection of CMY-2 in Escherichia coli by direct MALDI-TOF mass spectrometry. Journal of Microbiological Methods 2018, 148, 22-28.
24. Park, J.-M.; Kim, J.-I.; Noh, J.-Y.; Kim, M.; Kang, M.-J.; Pyun, J.-C., Hypersensitive antibiotic susceptibility test based on a β-lactamase assay with a parylene-matrix chip. Enzyme and Microbial Technology 2017, 97, 90-96.
25. Fleurbaaij, F.; Heemskerk, A. A. M.; Russcher, A.; Klychnikov, O. I.; Deelder, A. M.; Mayboroda, O. A.; Kuijper, E. J.; van Leeuwen, H. C.; Hensbergen, P. J., Capillary-Electrophoresis Mass Spectrometry for the Detection of Carbapenemases in (Multi-)Drug-Resistant Gram-Negative Bacteria. Analytical Chemistry 2014, 86 (18), 9154-9161.
26. Balouiri, M.; Sadiki, M.; Ibnsouda, S. K., Methods for in vitro evaluating antimicrobial activity: A review. Journal of Pharmaceutical Analysis 2016, 6 (2), 71-79.
27. Espinel-Ingroff, A., Comparison of three commercial assays and a modified disk diffusion assay with two broth microdilution reference assays for testing zygomycetes, Aspergillus spp., Candida spp., and Cryptococcus neoformans with posaconazole and amphotericin B. J Clin Microbiol 2006, 44 (10), 3616.
28. European Committee for Antimicrobial Susceptibility Testing of the European Society of Clinical, M.; Infectious, D., Determination of minimum inhibitory concentrations (MICs) of antibacterial agents by broth dilution. Clinical Microbiology and Infection 2003, 9 (8), ix-xv.
29. Hoseinzadeh, E.; Makhdoumi, P.; Taha, P.; Hossini, H.; Pirsaheb, M.; Omid Rastegar, S.; Stelling, J., A review of available techniques for determination of nano-antimicrobials activity. Toxin Reviews 2017, 36 (1), 18-32.
30. Klare, I.; Fleige, C.; Geringer, U.; Witte, W.; Werner, G., Performance of three chromogenic VRE screening agars, two Etest® vancomycin protocols, and different microdilution methods in detecting vanB genotype Enterococcus faecium with varying vancomycin MICs. Diagnostic Microbiology and Infectious Disease 2012, 74 (2), 171-176.
31. Shannon, K.; Phillips, I., β-Lactamase detection by three simple methods: Intralactam, nitrocefin and acidimetric. Journal of Antimicrobial Chemotherapy 1980, 6 (5), 617-621.
32. Bidya, S.; Suman, R. S., Comparative Study of Three β-Lactamase Test Methods in Staphylococcus aureus Isolated from Two Nepalese Hospitals. Open Journal of Clinical Diagnostics 2014, Vol.04No.01, 6.
33. O'Callaghan, C. H.; Morris, A.; Kirby, S. M.; Shingler, A. H., Novel method for detection of beta-lactamases by using a chromogenic cephalosporin substrate. Antimicrobial agents and chemotherapy 1972, 1 (4), 283-288.
34. 黃偉恩, 利用螢光中孔洞二氧化矽奈米粒子快速篩檢抗藥性細菌及測定β-內醯胺酶之活性. 2018.
35. Rochelet, M.; Solanas, S.; Betelli, L.; Neuwirth, C.; Vienney, F.; Hartmann, A., Amperometric detection of extended-spectrum β-lactamase activity: application to the characterization of resistant E. coli strains. Analyst 2015, 140 (10), 3551-3556.
36. Erdem, S. S.; Khan, S.; Palanisami, A.; Hasan, T., Rapid, low-cost fluorescent assay of β-lactamase-derived antibiotic resistance and related antibiotic susceptibility. Journal of biomedical optics 2014, 19 (10), 105007-105007.
37. Peng, L.; Xiao, L.; Ding, Y.; Xiang, Y.; Tong, A., A simple design of fluorescent probes for indirect detection of β-lactamase based on AIE and ESIPT processes. Journal of Materials Chemistry B 2018, 6 (23), 3922-3926.
38. Wang, W.-J.; Wang, Q.; Zhang, Y.; Lu, R.; Zhang, Y.-L.; Yang, K.-W.; Lei, J.-E.; He, Y., Characterization of β-lactamase activity using isothermal titration calorimetry. Biochimica et Biophysica Acta (BBA) - General Subjects 2017, 1861 (8), 2031-2038.
39. Merola, G.; Martini, E.; Tomassetti, M.; Campanella, L., Simple and suitable immunosensor for β-lactam antibiotics analysis in real matrixes: Milk, serum, urine. Journal of Pharmaceutical and Biomedical Analysis 2015, 106, 186-196.
40. Junza, A.; Montané, A.; Barbosa, J.; Minguillón, C.; Barrón, D., High resolution mass spectrometry in the identification of transformation products and metabolites from β-lactam antibiotics in thermally treated milk. Journal of Chromatography A 2014, 1368, 89-99.
41. Hooff, G. P.; van Kampen, J. J. A.; Meesters, R. J. W.; van Belkum, A.; Goessens, W. H. F.; Luider, T. M., Characterization of β-Lactamase Enzyme Activity in Bacterial Lysates using MALDI-Mass Spectrometry. Journal of Proteome Research 2012, 11 (1), 79-84.
42. Boucher, H. W.; Talbot, G. H.; Bradley, J. S.; Edwards, J. E.; Gilbert, D.; Rice, L. B.; Scheld, M.; Spellberg, B.; Bartlett, J., Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America. Clinical Infectious Diseases 2009, 48 (1), 1-12.
43. Sparbier, K.; Schubert, S.; Weller, U.; Boogen, C.; Kostrzewa, M., Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry-Based Functional Assay for Rapid Detection of Resistance against β-Lactam Antibiotics. J Clin Microbiol 2012, 50 (3), 927.
44. van Duin, D.; Paterson, D. L., Multidrug-Resistant Bacteria in the Community: Trends and Lessons Learned. Infectious disease clinics of North America 2016, 30 (2), 377-390.
45. 衛生福利部疾病管制署, 國內多重抗藥性細菌之基因型變異現況及臨床相關資料之蒐集與流行病學研究. 2016.
46. 衛生福利部疾病管制署, 2016 年台灣肺炎鏈球菌抗藥性監測報告. 2016.
47. Page, M. I. T., W. Y. ; Ahmed, N., Comparison of the mechanisms of reactions of β-lactams and β-sultams, including their reactions with some serine enzymes. JOURNAL OF PHYSICAL ORGANIC CHEMISTRY 2006, 19(8-9), 446-451.
48. Moscow J, M. C., Cowan KH., General Mechanisms of Drug Resistance. Holland-Frei Cancer Medicine. 6th edition. 2013.
49. Fleming, A., On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to Their Use in the Isolation of B. influenzae. British journal of experimental pathology 1979, 60 (1), 3-13.
50. Bbosa, G.; Mwebaza, N.; Odda, J.; B Kyegombe, D.; Ntale, M., Antibiotics/antibacterial drug use, their marketing and promotion during the post-antibiotic golden age and their role in emergence of bacterial resistance. 2014; Vol. 6, p 410-425.
51. Hu, Y.-F.; Hou, C. J.-Y.; Kuo, C.-F.; Wang, N.-Y.; Wu, A. Y.-J.; Leung, C.-H.; Liu, C.-P.; Yeh, H.-I., Emergence of carbapenem-resistant Acinetobacter baumannii ST787 in clinical isolates from blood in a tertiary teaching hospital in Northern Taiwan. Journal of Microbiology, Immunology and Infection 2017, 50 (5), 640-645.
52. Liu, C.-P.; Shih, S.-C.; Wang, N.-Y.; Wu, A. Y.; Sun, F.-J.; Chow, S.-F.; Chen, T.-L.; Yan, T.-R., Risk factors of mortality in patients with carbapenem-resistant Acinetobacter baumannii bacteremia. Journal of Microbiology, Immunology and Infection 2016, 49 (6), 934-940.
53. Lin, Y.-T.; Cheng, Y.-H.; Juan, C.-H.; Wu, P.-F.; Huang, Y.-W.; Chou, S.-H.; Yang, T.-C.; Wang, F.-D., High mortality among patients infected with hypervirulent antimicrobial-resistant capsular type K1 Klebsiella pneumoniae strains in Taiwan. International Journal of Antimicrobial Agents 2018, 52 (2), 251-257.
54. Huang, Y.-T.; Jiang, J.-Y.; Hsu, M.-S.; Hsu, H.-S.; Liao, C.-H.; Hsueh, P.-R., The prevalence of rectal carriage of Klebsiella pneumoniae amongst diabetic patients and their clinical relevance in Taiwan: A five-year prospective study. Journal of Microbiology, Immunology and Infection 2018, 51 (4), 510-518.
55. Jean, S.-S.; Lee, W.-S.; Bai, K.-J.; Yu, K.-W.; Hsu, C.-W.; Yu, K.-W.; Liao, C.-H.; Chang, F.-Y.; Ko, W.-C.; Wu, J.-J.; Chen, Y.-H.; Chen, Y.-S.; Liu, J.-W.; Lu, M.-C.; Liu, C.-Y.; Chen, R.-J.; Hsueh, P.-R., Carbapenem susceptibility among Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates obtained from patients in intensive care units in Taiwan in 2005, 2007, and 2009. Diagnostic Microbiology and Infectious Disease 2015, 81 (4), 290-295.
56. Lin, K.-Y.; Lauderdale, T.-L.; Wang, J.-T.; Chang, S.-C., Carbapenem-resistant Pseudomonas aeruginosa in Taiwan: Prevalence, risk factors, and impact on outcome of infections. Journal of Microbiology, Immunology and Infection 2016, 49 (1), 52-59.
57. Nissinen, T.; Näkki, S.; Latikka, M.; Heinonen, M.; Liimatainen, T.; Xu, W.; Ras, R. H. A.; Gröhn, O.; Riikonen, J.; Lehto, V.-P., Facile synthesis of biocompatible superparamagnetic mesoporous nanoparticles for imageable drug delivery. Microporous and Mesoporous Materials 2014, 195, 2-8.
58. Näkki, S.; Wang, J. T. W.; Wu, J.; Fan, L.; Rantanen, J.; Nissinen, T.; Kettunen, M. I.; Backholm, M.; Ras, R. H. A.; Al-Jamal, K. T.; Lehto, V.-P.; Xu, W., Designed inorganic porous nanovector with controlled release and MRI features for safe administration of doxorubicin. International Journal of Pharmaceutics 2019, 554, 327-336.
59. Näkki, S.; Rytkönen, J.; Nissinen, T.; Florea, C.; Riikonen, J.; Ek, P.; Zhang, H.; Santos, H. A.; Närvänen, A.; Xu, W.; Lehto, V.-P., Improved stability and biocompatibility of nanostructured silicon drug carrier for intravenous administration. Acta Biomaterialia 2015, 13, 207-215.
60. Nakamura, T.; Sugihara, F.; Matsushita, H.; Yoshioka, Y.; Mizukami, S.; Kikuchi, K., Mesoporous silica nanoparticles for 19F magnetic resonance imaging, fluorescence imaging, and drug delivery. Chemical Science 2015, 6 (3), 1986-1990.
61. Taylor, K. M. L.; Kim, J. S.; Rieter, W. J.; An, H.; Lin, W.; Lin, W., Mesoporous Silica Nanospheres as Highly Efficient MRI Contrast Agents. Journal of the American Chemical Society 2008, 130 (7), 2154-2155.
62. Hu, H.; Arena, F.; Gianolio, E.; Boffa, C.; Di Gregorio, E.; Stefania, R.; Orio, L.; Baroni, S.; Aime, S., Mesoporous silica nanoparticles functionalized with fluorescent and MRI reporters for the visualization of murine tumors overexpressing αvβ3 receptors. Nanoscale 2016, 8 (13), 7094-7104.
63. Jaque, D.; Martínez Maestro, L.; del Rosal, B.; Haro-Gonzalez, P.; Benayas, A.; Plaza, J. L.; Martín Rodríguez, E.; García Solé, J., Nanoparticles for photothermal therapies. Nanoscale 2014, 6 (16), 9494-9530.
64. Zhang, C.; Fu, Y.-Y.; Zhang, X.; Yu, C.; Zhao, Y.; Sun, S.-K., BSA-directed synthesis of CuS nanoparticles as a biocompatible photothermal agent for tumor ablation in vivo. Dalton Transactions 2015, 44 (29), 13112-13118.
65. Stöber, W.; Fink, A.; Bohn, E., Controlled growth of monodisperse silica spheres in the micron size range. Journal of Colloid and Interface Science 1968, 26 (1), 62-69.
66. Bharti, C.; Nagaich, U.; Pal, A. K.; Gulati, N., Mesoporous silica nanoparticles in target drug delivery system: A review. International journal of pharmaceutical investigation 2015, 5 (3), 124-133.
67. Lin, Y.-S.; Abadeer, N.; Haynes, C. L., Stability of small mesoporous silica nanoparticles in biological media. Chemical Communications 2011, 47 (1), 532-534.
68. Narayan, R.; Nayak, U. Y.; Raichur, A. M.; Garg, S., Mesoporous Silica Nanoparticles: A Comprehensive Review on Synthesis and Recent Advances. Pharmaceutics 2018, 10 (3), 118.
69. Wu, S.-H.; Mou, C.-Y.; Lin, H.-P., Synthesis of mesoporous silica nanoparticles. Chemical Society Reviews 2013, 42 (9), 3862-3875.
70. Iler, R. K., The Chemistry of Silica. Solubility, Polymerization, Colloid and Surface Properties, and Biochemistry. Von R. K. Iler. John Wiley and Sons, Chichester 1979. XXIV, 886 S., geb. £ 39.50. Angewandte Chemie 1980, 92 (4), 328-328.
71. Yue, Q.; Zhang, Y.; Jiang, Y.; Li, J.; Zhang, H.; Yu, C.; Elzatahry, A. A.; Alghamdi, A.; Deng, Y.; Zhao, D., Nanoengineering of Core–Shell Magnetic Mesoporous Microspheres with Tunable Surface Roughness. Journal of the American Chemical Society 2017, 139 (13), 4954-4961.
72. Jafari, S.; Derakhshankhah, H.; Alaei, L.; Fattahi, A.; Varnamkhasti, B. S.; Saboury, A. A., Mesoporous silica nanoparticles for therapeutic/diagnostic applications. Biomedicine & Pharmacotherapy 2019, 109, 1100-1111.
73. Farjadian, F.; Roointan, A.; Mohammadi-Samani, S.; Hosseini, M., Mesoporous silica nanoparticles: Synthesis, pharmaceutical applications, biodistribution, and biosafety assessment. Chemical Engineering Journal 2019, 359, 684-705.
74. Sparbier, K.; Schubert, S.; Weller, U.; Boogen, C.; Kostrzewa, M., Matrix-assisted laser desorption ionization-time of flight mass spectrometry-based functional assay for rapid detection of resistance against β-lactam antibiotics. J Clin Microbiol 2012, 50 (3), 927-937.