一氧化氮(nitric oxide, NO)由於其多重抗菌機制，使之具有廣譜抗菌能力，能對抗的病原菌類型非常廣泛，以細菌而言，能對抗革蘭氏陽性(gram-positive)菌與革蘭氏陰性(gram-negative)菌，同時還能避免耐藥性。由於一氧化氮之反應性極強造成其半衰期短暫，需以一氧化氮供體儲存並運輸之。本實驗欲開發一種具抗菌效果之一氧化氮傳輸系統，以一種以鐵離子作為中心金屬離子之金屬有機骨架(metal organic framework, MOF) MIL-88B經高溫碳化後生成之cMIL-88B作為藥物載體，裝載一氧化氮供體[Fe(μ-S-thioglycerol)(NO)2]2 (DNIC-TG)，並以聚合物PLGA((poly(lactic-co-glycolic acid))包裹之以形成微球DNIC:cMIL-88B@PLGA。由於cMIL-88B之構造為Fe3O4，為一磁性響應粒子，施加外加磁場作為外在物理性刺激，可以使之局部升溫，當溫度超過PLGA之玻璃轉化溫度(glass transition temperature, Tg) 42-46℃，PLGA即會呈現熔融狀態並有機會破裂，釋放出一氧化氮。以一氧化氮釋放實驗，探討此藥物遞送系統釋放一氧化氮之情形，並以體外抗菌實驗，驗證DNIC:cMIL-88B@PLGA對革蘭氏陽性菌S. aureus與革蘭氏陰性菌E. coli兩種致病菌的抗菌效果，再以小鼠皮膚上受E. coli感染之傷口作為感染傷口模型，以DNIC:cMIL-88B@PLGA治療傷口，達到抗菌及促進傷口組織修復之效果。另一方面，在嘗試開發治療肺部細菌感染之材料，則以MIL-88B作為藥物載體，裝載DNIC-TG後形成TG@MOF，初步以體外DNIC釋放實驗及體外抗菌實驗，評估其治療肺部細菌感染的潛力。

Nitric oxide (NO) has a broad-spectrum anti-bacterial ability due to its multiple anti-bacterial mechanisms, which means it can battle against a wide variety of bacteria. Moreover, NO can avoid drug resistance. NO donors are used to store and transport NO in order to solve the problem of high reactivity and short lifetime. In this study, we developed an anti-bacterial NO delivery system. A metal organic framework (MOF) with Fe as its metal ion, MIL-88B, was carbonized into cMIL-88B as the drug carrier to carry the NO donor [Fe(μ-S-thioglycerol)(NO)2]2 (DNIC-TG). The polymer PLGA (poly(lactic-co-glycolic acid)) was used to coat and form microspheres, DNIC:cMIL-88B@PLGA. Since cMIL-88B has the structure of Fe3O4, a magnetically responsive particle (MRP), we can apply an alternative magnetic field (AMF) as an external physical trigger. AMF can bring a local temperature increase to the microspheres, and when the temperature is above the glass transition temperature (Tg) of PLGA, 42-46℃, PLGA will melt and has a chance to break and release NO. The NO release experiment was done to investigate the performance of the system to release NO. And the in vitro test of bacterial viability was performed to demonstrate the anti-bacterial ability of cMIL-88B@PLGA and DNIC:cMIL-88B@PLGA against Gram-positive S. aureus and Gram-negative E. coli. Finally, the cutaneous E. coli-infected wound of mice was used as the model of in vivo test, and we treated the wound with DNIC:cMIL-88B@PLGA to achieve the bactericidal and wound healing effect. On the other hand, we tried to develop the material to treat pulmonary bacterial infections. We used MIL-88B to be the drug carrier to carry DNIC-TG, becoming TG@MOF. In vitro DNIC release experiment and in vitro antibacterial study was preliminary performed to evaluate the potential of TG@MOF to treat pulmonary bacterial infections.

目錄
摘要 i
Abstract ii
目錄 iii
List of Figures vi
List of Tables viii
一、緒論 1
1-1一氧化氮與其抗菌能力 1
1-1-1開發新型抗菌劑之背景 1
1-1-2一氧化氮之功能 2
1-1-3一氧化氮之抗菌能力 2
1-1-4一氧化氮供體 4
1-2 藥物遞送系統(drug delivery system, DDS) 5
1-2-1 DDS之物理性觸發 5
1-2-2以金屬有機骨架(metal organic framework, MOF)作為藥物載體 11
1-2-3 PLGA微球作為藥物遞送系統 11
1-3研究動機 14
二、實驗 16
2-1藥品 16
2-2儀器 17
2-3反應之環境條件 17
2-4小分子化合物之合成 18
2-4-1合成[Na-18-crown-6-ether][Fe(CO)3(NO)] 18
2-4-2合成[Fe(u-S-thioglycerol)(NO)2]2 (DNIC-TG) 18
2-5材料之合成 19
2-5-1合成MIL-88B 19
2-5-2合成cMIL-88B 19
2-5-3合成DNIC:cMIL-88B 19
2-5-4合成cMIL-88B@PLGA與DNIC:cMIL-88B@PLGA 20
2-5-5合成DNIC-TG@MIL-88B (TG@MOF) 20
2-6緩衝溶液配製 20
2-6-1配製磷酸鹽緩衝生理鹽水(Phosphate buffer saline, PBS, pH 7.4) 21
2-6-2磷酸緩衝溶液配製 21
2-6-3 pH 6.8 50 mM Phosphate buffer之配製 21
2-7測量TG@MOF之DNIC-TG的裝載率(loading content) 21
2-8在PBS下DNIC-TG從TG@MOF之釋放情形 21
2-9 DNIC:cMIL-88B@PLGA於AMF下的一氧化氮釋放 22
2-10抗菌實驗 22
2-10-1製備TSB與TSA培養基 22
2-10-2配製生物實驗用PBS 23
2-10-3細菌培養 23
2-10-4細菌繼代於TSA 23
2-10-5細菌繼代於TSB 23
2-10-6 S. aureus, E. coli, 及P. aeruginosa於PBS中的檢量線 24
2-10-7塗盤計數法 24
2-10-8 DNIC-TG對S. aureus, E. coli, 及P. aeruginosa的抗菌效果 24
2-10-9 AMF所使用菌液樣品製備 25
2-10-10 cMIL-88B@PLGA與DNIC:cMIL-88B@PLGA的AMF抗菌 25
2-10-11 DNIC-TG對S. aureus及E. coli的抗菌效果(與AMF抗菌做比較) 26
2-11動物實驗 26
2-11-1傷口之創建與處理 26
2-11-2傷口受細菌感染程度分析 26
2-11-3組織學分析 27
三、結果與討論 28
3-1材料之合成與鑑定 28
3-1-1 DNIC-TG之合成與鑑定 28
3-1-2 MIL-88B之合成與鑑定 29
3-1-3 cMIL-88B之合成與鑑定 31
3-1-4 DNIC:cMIL-88B之合成與鑑定 35
3-1-5 cMIL-88B@PLGA與DNIC:cMIL-88B@PLGA之合成與鑑定 36
3-1-6 TG@MOF之合成與鑑定 38
3-2在PBS下DNIC-TG從TG@MOF之釋放實驗 40
3-3 DNIC:cMIL-88B@PLGA於AMF下的一氧化氮釋放 41
3-3-1微球於AMF下之升溫曲線 41
3-3-2微球於AMF下之一氧化氮釋放 41
3-4抗菌實驗 42
3-4-1 S. aureus, E. coli, 及P. aeruginosa於PBS中的檢量線 43
3-4-2 DNIC-TG對S. aureus, E. coli, 及P. aeruginosa的抗菌效果 44
3-4-3 cMIL-88B@PLGA與DNIC:cMIL-88B@PLGA的AMF抗菌 45
3-4-4 DNIC-TG對S. aureus及E. coli的抗菌效果與DNIC:cMIL-88B@PLGA的AMF抗菌之比較 46
3-5動物實驗 49
3-5-1傷口受細菌感染程度分析 49
3-5-2組織學分析 50
四、結論 52
五、參考資料 53

(1) Rossolini, G. M.; Arena, F.; Pecile, P.; Pollini, S. Update on the antibiotic resistance crisis. Current opinion in pharmacology 2014, 18, 56-60.
(2) Laxminarayan, R.; Duse, A.; Wattal, C.; Zaidi, A. K.; Wertheim, H. F.; Sumpradit, N.; Vlieghe, E.; Hara, G. L.; Gould, I. M.; Goossens, H. Antibiotic resistance—the need for global solutions. The Lancet infectious diseases 2013, 13 (12), 1057-1098. Roca, I.; Akova, M.; Baquero, F.; Carlet, J.; Cavaleri, M.; Coenen, S.; Cohen, J.; Findlay, D.; Gyssens, I.; Heure, O. The global threat of antimicrobial resistance: science for intervention. New microbes and new infections 2015, 6, 22-29.
(3) Gaurav, A.; Kothari, A.; Omar, B. J.; Pathania, R. Assessment of polymyxin B–doxycycline in combination against Pseudomonas aeruginosa in vitro and in a mouse model of acute pneumonia. Int. J. Antimicrob. Agents 2020, 56 (1), 106022.
(4) Wenzler, E.; Fraidenburg, D. R.; Scardina, T.; Danziger, L. H. Inhaled antibiotics for Gram-negative respiratory infections. Clin. Microbiol. Rev. 2016, 29 (3), 581-632.
(5) Ho, D.-K.; Nichols, B. L.; Edgar, K. J.; Murgia, X.; Loretz, B.; Lehr, C.-M. Challenges and strategies in drug delivery systems for treatment of pulmonary infections. Eur. J. Pharm. Biopharm. 2019, 144, 110-124.
(6) Rabea, E. I.; Badawy, M. E.-T.; Stevens, C. V.; Smagghe, G.; Steurbaut, W. Chitosan as antimicrobial agent: applications and mode of action. Biomacromolecules 2003, 4 (6), 1457-1465. Rai, M.; Yadav, A.; Gade, A. Silver nanoparticles as a new generation of antimicrobials. Biotechnol. Adv. 2009, 27 (1), 76-83. Jennings, M. C.; Minbiole, K. P.; Wuest, W. M. Quaternary ammonium compounds: an antimicrobial mainstay and platform for innovation to address bacterial resistance. ACS infectious diseases 2015, 1 (7), 288-303. Vincent, M.; Duval, R. E.; Hartemann, P.; Engels‐Deutsch, M. Contact killing and antimicrobial properties of copper. J. Appl. Microbiol. 2018, 124 (5), 1032-1046. Cheng, D.; He, M.; Li, W.; Wu, J.; Ran, J.; Cai, G.; Wang, X. Hydrothermal growing of cluster-like ZnO nanoparticles without crystal seeding on PET films via dopamine anchor. Appl. Surf. Sci. 2019, 467, 534-542.
(7) Furchgott, R. F.; Zawadzki, J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980, 288 (5789), 373-376. Rapoport, R. M.; Draznin, M. B.; Murad, F. Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation. Nature 1983, 306 (5939), 174-176. Ignarro, L. J.; Buga, G. M.; Wood, K. S.; Byrns, R. E.; Chaudhuri, G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proceedings of the National Academy of Sciences 1987, 84 (24), 9265-9269.
(8) Bolaños, J. P.; Almeida, A.; Stewart, V.; Peuchen, S.; Land, J. M.; Clark, J. B.; Heales, S. J. Nitric oxide‐mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J. Neurochem. 1997, 68 (6), 2227-2240.
(9) Carpenter, A. W.; Schoenfisch, M. H. Nitric oxide release: Part II. Therapeutic applications. Chem. Soc. Rev. 2012, 41 (10), 3742-3752.
(10) Seabra, A. B.; Justo, G. Z.; Haddad, P. S. State of the art, challenges and perspectives in the design of nitric oxide-releasing polymeric nanomaterials for biomedical applications. Biotechnol. Adv. 2015, 33 (6), 1370-1379.
(11) Hill, B. G.; Dranka, B. P.; Bailey, S. M.; Lancaster, J. R.; Darley-Usmar, V. M. What part of NO don't you understand? Some answers to the cardinal questions in nitric oxide biology. J. Biol. Chem. 2010, 285 (26), 19699-19704.
(12) Förstermann, U.; Sessa, W. C. Nitric oxide synthases: regulation and function. Eur. Heart J. 2012, 33 (7), 829-837.
(13) Friedman, A.; Blecher, K.; Sanchez, D.; Tuckman-Vernon, C.; Gialanella, P.; Friedman, J. M.; Martinez, L. R.; Nosanchuk, J. D. Susceptibility of Gram-positive and-negative bacteria to novel nitric oxide-releasing nanoparticle technology. Virulence 2011, 2 (3), 217-221.
(14) Efron, D. T.; Most, D.; Barbul, A. Role of nitric oxide in wound healing. Curr. Opin. Clin. Nutr. Metab. Care 2000, 3 (3), 197-204. Ramadass, S. K.; Nazir, L. S.; Thangam, R.; Perumal, R. K.; Manjubala, I.; Madhan, B.; Seetharaman, S. Type I collagen peptides and nitric oxide releasing electrospun silk fibroin scaffold: A multifunctional approach for the treatment of ischemic chronic wounds. Colloids Surf. B. Biointerfaces 2019, 175, 636-643. Zhang, Y.; Tang, K.; Chen, B.; Zhou, S.; Li, N.; Liu, C.; Yang, J.; Lin, R.; Zhang, T.; He, W. A polyethylenimine-based diazeniumdiolate nitric oxide donor accelerates wound healing. Biomaterials science 2019, 7 (4), 1607-1616.
(15) Reynolds, M. M.; Witzeling, S. D.; Damodaran, V. B.; Medeiros, T. N.; Knodle, R. D.; Edwards, M. A.; Lookian, P. P.; Brown, M. A. Applications for nitric oxide in halting proliferation of tumor cells. Biochemical and biophysical research communications 2013, 431 (4), 647-651. Alimoradi, H.; Greish, K.; Barzegar-Fallah, A.; Alshaibani, L.; Pittalà, V. Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity. International journal of nanomedicine 2018, 13, 7771.
(16) Barraud, N.; J Kelso, M.; A Rice, S.; Kjelleberg, S. Nitric oxide: a key mediator of biofilm dispersal with applications in infectious diseases. Curr. Pharm. Des. 2015, 21 (1), 31-42. Quinn, J. F.; Whittaker, M. R.; Davis, T. P. Delivering nitric oxide with nanoparticles. Journal of Controlled Release 2015, 205, 190-205. Wo, Y.; Brisbois, E. J.; Bartlett, R. H.; Meyerhoff, M. E. Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO). Biomaterials science 2016, 4 (8), 1161-1183.
(17) De Groote, M. A.; Fang, F. C. NO inhibitions: antimicrobial properties of nitric oxide. Clin. Infect. Dis. 1995, 21 (Supplement_2), S162-S165.
(18) Hetrick, E. M.; Shin, J. H.; Stasko, N. A.; Johnson, C. B.; Wespe, D. A.; Holmuhamedov, E.; Schoenfisch, M. H. Bactericidal efficacy of nitric oxide-releasing silica nanoparticles. ACS nano 2008, 2 (2), 235-246.
(19) Wink, D. A.; Kasprzak, K. S.; Maragos, C. M.; Elespuru, R. K.; Misra, M.; Dunams, T. M.; Cebula, T. A.; Koch, W. H.; Andrews, A.; Allen, J. S. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 1991, 254 (5034), 1001-1003.
(20) Fang, F. C. Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. The Journal of clinical investigation 1997, 99 (12), 2818-2825. Ghaffari, A.; Miller, C.; McMullin, B.; Ghahary, A. Potential application of gaseous nitric oxide as a topical antimicrobial agent. Nitric Oxide 2006, 14 (1), 21-29. Schairer, D. O.; Chouake, J. S.; Nosanchuk, J. D.; Friedman, A. J. The potential of nitric oxide releasing therapies as antimicrobial agents. Virulence 2012, 3 (3), 271-279.
(21) Kiaee, G.; Mostafalu, P.; Samandari, M.; Sonkusale, S. A pH‐Mediated Electronic Wound Dressing for Controlled Drug Delivery. Advanced healthcare materials 2018, 7 (18), 1800396.
(22) Privett, B. J.; Broadnax, A. D.; Bauman, S. J.; Riccio, D. A.; Schoenfisch, M. H. Examination of bacterial resistance to exogenous nitric oxide. Nitric Oxide 2012, 26 (3), 169-173.
(23) Lee, J.; Kwak, D.; Kim, H.; Kim, J.; Hlaing, S. P.; Hasan, N.; Cao, J.; Yoo, J.-W. Nitric oxide-releasing s-nitrosoglutathione-conjugated poly (Lactic-Co-Glycolic Acid) nanoparticles for the treatment of MRSA-infected cutaneous wounds. Pharmaceutics 2020, 12 (7), 618.
(24) Miller, C.; McMullin, B.; Ghaffari, A.; Stenzler, A.; Pick, N.; Roscoe, D.; Ghahary, A.; Road, J.; Av-Gay, Y. Gaseous nitric oxide bactericidal activity retained during intermittent high-dose short duration exposure. Nitric Oxide 2009, 20 (1), 16-23.
(25) Miller, C. C.; Hergott, C. A.; Rohan, M.; Arsenault-Mehta, K.; Döring, G.; Mehta, S. Inhaled nitric oxide decreases the bacterial load in a rat model of Pseudomonas aeruginosa pneumonia. Journal of Cystic Fibrosis 2013, 12 (6), 817-820.
(26) Deppisch, C.; Herrmann, G.; Graepler-Mainka, U.; Wirtz, H.; Heyder, S.; Engel, C.; Marschal, M.; Miller, C. C.; Riethmüller, J. Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study. Infection 2016, 44 (4), 513-520.
(27) Chiarelli, L. R.; Degiacomi, G.; Egorova, A.; Makarov, V.; Pasca, M. R. Nitric oxide-releasing compounds for the treatment of lung infections. Drug Discovery Today 2021, 26 (2), 542-550.
(28) Howlin, R. P.; Cathie, K.; Hall-Stoodley, L.; Cornelius, V.; Duignan, C.; Allan, R. N.; Fernandez, B. O.; Barraud, N.; Bruce, K. D.; Jefferies, J. Low-dose nitric oxide as targeted anti-biofilm adjunctive therapy to treat chronic Pseudomonas aeruginosa infection in cystic fibrosis. Mol. Ther. 2017, 25 (9), 2104-2116.
(29) Gore, A.; Gauthier, A. G.; Lin, M.; Patel, V.; Thomas, D. D.; Ashby Jr, C. R.; Mantell, L. L. The nitric oxide donor,(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1, 2-diolate (DETA-NONOate/D-NO), increases survival by attenuating hyperoxia-compromised innate immunity in bacterial clearance in a mouse model of ventilator-associated pneumonia. Biochem. Pharmacol. 2020, 176, 113817.
(30) Rong, F.; Tang, Y.; Wang, T.; Feng, T.; Song, J.; Li, P.; Huang, W. Nitric oxide-releasing polymeric materials for antimicrobial applications: a review. Antioxidants 2019, 8 (11), 556.
(31) Rodeberg, D. A.; Chaet, M. S.; Bass, R. C.; Arkovitz, M. S.; Garcia, V. F. Nitric oxide: an overview. The American journal of surgery 1995, 170 (3), 292-303. Thomas, D. D. Breathing new life into nitric oxide signaling: a brief overview of the interplay between oxygen and nitric oxide. Redox biology 2015, 5, 225-233.
(32) Huang, Z.; Fu, J.; Zhang, Y. Nitric oxide donor-based cancer therapy: advances and prospects. J. Med. Chem. 2017, 60 (18), 7617-7635. Yang, L.; Feura, E. S.; Ahonen, M. J. R.; Schoenfisch, M. H. Nitric oxide–releasing macromolecular scaffolds for antibacterial applications. Advanced healthcare materials 2018, 7 (13), 1800155.
(33) Stasko, N. A.; Schoenfisch, M. H. Dendrimers as a scaffold for nitric oxide release. Journal of the American Chemical Society 2006, 128 (25), 8265-8271. Grommersch, B. M.; Pant, J.; Hopkins, S. P.; Goudie, M. J.; Handa, H. Biotemplated synthesis and characterization of mesoporous nitric oxide-releasing diatomaceous earth silica particles. ACS applied materials & interfaces 2018, 10 (3), 2291-2301.
(34) Riccio, D. A.; Dobmeier, K. P.; Hetrick, E. M.; Privett, B. J.; Paul, H. S.; Schoenfisch, M. H. Nitric oxide-releasing S-nitrosothiol-modified xerogels. Biomaterials 2009, 30 (27), 4494-4502.
(35) Drago, R. S.; Paulik, F. The reaction of nitrogen (II) oxide with diethylamine. Journal of the American Chemical society 1960, 82 (1), 96-98. Drago, R. S.; Karstetter, B. R. The reaction of nitrogen (II) oxide with various primary and secondary amines. Journal of the American Chemical Society 1961, 83 (8), 1819-1822.
(36) Park, J.; Kim, J.; Singha, K.; Han, D.-K.; Park, H.; Kim, W. J. Nitric oxide integrated polyethylenimine-based tri-block copolymer for efficient antibacterial activity. Biomaterials 2013, 34 (34), 8766-8775.
(37) Ragsdale, R. O.; Karstetter, B. R.; Drago, R. S. Decomposition of the adducts of diethylamine and isopropylamine with nitrogen (II) oxide. Inorg. Chem. 1965, 4 (3), 420-422. Lowe, A.; Deng, W.; Smith Jr, D. W.; Balkus Jr, K. J. Acrylonitrile-based nitric oxide releasing melt-spun fibers for enhanced wound healing. Macromolecules 2012, 45 (15), 5894-5900.
(38) Liu, S.; Cai, X.; Xue, W.; Ma, D.; Zhang, W. Chitosan derivatives co-delivering nitric oxide and methicillin for the effective therapy to the methicillin-resistant S. aureus infection. Carbohydr. Polym. 2020, 234, 115928. DOI: https://doi.org/10.1016/j.carbpol.2020.115928.
(39) Jones, H. O.; Tasker, H. S. CCXI.—The action of mercaptans on acid chlorides. Part I. Oxalyl chloride; the mono-and dithio-oxalates. Journal of the Chemical Society, Transactions 1909, 95, 1904-1909.
(40) Swift, H. Decomposition of S-nitrosothiols by mercury (II) and silver salts. Journal of the Chemical Society, Perkin Transactions 2 1997, (10), 1933-1935. Stotz, W.; Brown, L. A. S.; Jain, L. Elevated Temperature Enhances Release of Nitric Oxide from S-Nitroso-glutathione (GSNO) 351. Pediatr. Res. 1998, 43 (4), 62-62. Williams, D. L. H. The Chemistry of S-Nitrosothiols. Acc. Chem. Res. 1999, 32 (10), 869-876. DOI: 10.1021/ar9800439. Veleeparampil, M. M.; Aravind, U. K.; Aravindakumar, C. Decomposition of S-nitrosothiols induced by UV and sunlight. Advances in Physical Chemistry 2009, 2009. Moran, E. E.; Timerghazin, Q. K.; Kwong, E.; English, A. M. Kinetics and mechanism of S-nitrosothiol acid-catalyzed hydrolysis: sulfur activation promotes facile NO+ release. The Journal of Physical Chemistry B 2011, 115 (12), 3112-3126. Smith, B. C.; Marletta, M. A. Mechanisms of S-nitrosothiol formation and selectivity in nitric oxide signaling. Curr. Opin. Chem. Biol. 2012, 16 (5-6), 498-506.
(41) Konorev, E. A.; Tarpey, M. M.; Joseph, J.; Baker, J. E.; Kalyanaraman, B. S-nitrosoglutathione improves functional recovery in the isolated rat heart after cardioplegic ischemic arrest-evidence for a cardioprotective effect of nitric oxide. Journal of Pharmacology and Experimental Therapeutics 1995, 274 (1), 200-206.
(42) Ignarro, L. J.; Lippton, H.; Edwards, J. C.; Baricos, W. H.; Hyman, A. L.; Kadowitz, P. J.; Gruetter, C. A. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. Journal of Pharmacology and Experimental Therapeutics 1981, 218 (3), 739-749.
(43) Pant, J.; Gao, J.; Goudie, M. J.; Hopkins, S. P.; Locklin, J.; Handa, H. A multi-defense strategy: Enhancing bactericidal activity of a medical grade polymer with a nitric oxide donor and surface-immobilized quaternary ammonium compound. Acta Biomater. 2017, 58, 421-431.
(44) Lewandowska, H.; Męczyńska, S.; Sochanowicz, B.; Sadło, J.; Kruszewski, M. Crucial role of lysosomal iron in the formation of dinitrosyl iron complexes in vivo. JBIC Journal of Biological Inorganic Chemistry 2007, 12 (3), 345-352.
(45) Kleschyov, A. L.; Hubert, G.; Munzel, T.; Stoclet, J.-C.; Bucher, B. Low molecular mass dinitrosyl nonheme-iron complexes up-regulate noradrenaline release in the rat tail artery. BMC Pharmacol. 2002, 2 (1), 1-5.
(46) Cha, W.; Meyerhoff, M. E. Catalytic generation of nitric oxide from S-nitrosothiols using immobilized organoselenium species. Biomaterials 2007, 28 (1), 19-27. Molina, M. M.; Seabra, A. B.; de Oliveira, M. G.; Itri, R.; Haddad, P. S. Nitric oxide donor superparamagnetic iron oxide nanoparticles. Materials Science and Engineering: C 2013, 33 (2), 746-751.
(47) Tai, L.-A.; Wang, Y.-C.; Yang, C.-S. Heat-activated sustaining nitric oxide release from zwitterionic diazeniumdiolate loaded in thermo-sensitive liposomes. Nitric Oxide 2010, 23 (1), 60-64. Zhang, K.; Xu, H.; Jia, X.; Chen, Y.; Ma, M.; Sun, L.; Chen, H. Ultrasound-triggered nitric oxide release platform based on energy transformation for targeted inhibition of pancreatic tumor. ACS nano 2016, 10 (12), 10816-10828. Wang, Y.; Huang, X.; Tang, Y.; Zou, J.; Wang, P.; Zhang, Y.; Si, W.; Huang, W.; Dong, X. A light-induced nitric oxide controllable release nano-platform based on diketopyrrolopyrrole derivatives for pH-responsive photodynamic/photothermal synergistic cancer therapy. Chemical science 2018, 9 (42), 8103-8109.
(48) Yang, F.; Li, M.; Liu, Y.; Wang, T.; Feng, Z.; Cui, H.; Gu, N. Glucose and magnetic-responsive approach toward in situ nitric oxide bubbles controlled generation for hyperglycemia theranostics. Journal of Controlled Release 2016, 228, 87-95.
(49) Ghalei, S.; Hopkins, S.; Douglass, M.; Garren, M.; Mondal, A.; Handa, H. Nitric oxide releasing halloysite nanotubes for biomedical applications. Journal of Colloid and Interface Science 2021, 590, 277-289.
(50) Singh, N.; Patel, K.; Sahoo, S. K.; Kumar, R. Human nitric oxide biomarker as potential NO donor in conjunction with superparamagnetic iron oxide@ gold core shell nanoparticles for cancer therapeutics. Colloids Surf. B. Biointerfaces 2018, 163, 246-256.
(51) Gao, Q.; Zhang, X.; Yin, W.; Ma, D.; Xie, C.; Zheng, L.; Dong, X.; Mei, L.; Yu, J.; Wang, C. Functionalized MoS2 nanovehicle with near‐infrared laser‐mediated nitric oxide release and photothermal activities for advanced bacteria‐infected wound therapy. Small 2018, 14 (45), 1802290.
(52) Feng, T.; Wan, J.; Li, P.; Ran, H.; Chen, H.; Wang, Z.; Zhang, L. A novel NIR-controlled NO release of sodium nitroprusside-doped Prussian blue nanoparticle for synergistic tumor treatment. Biomaterials 2019, 214, 119213.
(53) Liu, T.; Zhang, P.; Huang, X.; Chi, X.; Li, Z.; Zhang, Z.; Guo, D.-S.; Yang, X. Magnetic core-shell S-nitrosothiols nanoparticles as tumor dual-targeting theranostic platform. Colloids Surf. B. Biointerfaces 2019, 181, 400-407.
(54) Zhang, C.; Li, Q.; Zhao, Y.; Liu, H.; Song, S.; Zhao, Y.; Lin, Q.; Chang, Y. Near-infrared light-mediated and nitric oxide-supplied nanospheres for enhanced synergistic thermo-chemotherapy. Journal of Materials Chemistry B 2019, 7 (4), 548-555.
(55) Yu, Y.-T.; Shi, S.-W.; Wang, Y.; Zhang, Q.-L.; Gao, S.-H.; Yang, S.-P.; Liu, J.-G. A ruthenium nitrosyl-functionalized magnetic nanoplatform with near-infrared light-controlled nitric oxide delivery and photothermal effect for enhanced antitumor and antibacterial therapy. ACS applied materials & interfaces 2019, 12 (1), 312-321.
(56) Yin, H.; Guan, X.; Lin, H.; Pu, Y.; Fang, Y.; Yue, W.; Zhou, B.; Wang, Q.; Chen, Y.; Xu, H. Nanomedicine‐enabled photonic thermogaseous cancer therapy. Advanced Science 2020, 7 (2), 1901954.
(57) Lu, B.; Hu, E.; Xie, R.; Yu, K.; Lu, F.; Bao, R.; Wang, C.; Lan, G.; Dai, F. Magnetically Guided Nanoworms for Precise Delivery to Enhance In Situ Production of Nitric Oxide to Combat Focal Bacterial Infection In Vivo. ACS Applied Materials & Interfaces 2021.
(58) Jin, Z.; Wen, Y.; Hu, Y.; Chen, W.; Zheng, X.; Guo, W.; Wang, T.; Qian, Z.; Su, B.-L.; He, Q. MRI-guided and ultrasound-triggered release of NO by advanced nanomedicine. Nanoscale 2017, 9 (10), 3637-3645.
(59) Kang, Y.; Kim, J.; Park, J.; Lee, Y. M.; Saravanakumar, G.; Park, K. M.; Choi, W.; Kim, K.; Lee, E.; Kim, C. Tumor vasodilation by N-Heterocyclic carbene-based nitric oxide delivery triggered by high-intensity focused ultrasound and enhanced drug homing to tumor sites for anti-cancer therapy. Biomaterials 2019, 217, 119297.
(60) An, J.; Hu, Y.-G.; Li, C.; Hou, X.-L.; Cheng, K.; Zhang, B.; Zhang, R.-Y.; Li, D.-Y.; Liu, S.-J.; Liu, B. A pH/ultrasound dual-response biomimetic nanoplatform for nitric oxide gas-sonodynamic combined therapy and repeated ultrasound for relieving hypoxia. Biomaterials 2020, 230, 119636.
(61) Zheng, Y.; Liu, Y.; Wei, F.; Xiao, H.; Mou, J.; Wu, H.; Yang, S. Functionalized g-C3N4 nanosheets for potential use in magnetic resonance imaging-guided sonodynamic and nitric oxide combination therapy. Acta Biomater. 2021, 121, 592-604.
(62) Xu, Y.; Liu, J.; Liu, Z.; Chen, G.; Li, X.; Ren, H. Damaging Tumor Vessels with an Ultrasound-Triggered NO Release Nanosystem to Enhance Drug Accumulation and T Cells Infiltration. International Journal of Nanomedicine 2021, 16, 2597.
(63) Wang, J.; Wang, L.; Pan, J.; Zhao, J.; Tang, J.; Jiang, D.; Hu, P.; Jia, W.; Shi, J. Magneto‐Based Synergetic Therapy for Implant‐Associated Infections via Biofilm Disruption and Innate Immunity Regulation. Advanced Science 2021, 8 (6), 2004010.
(64) Zhao, J.; Hu, Y.; wei Lin, S.; Resch-Genger, U.; Zhang, R.; Wen, J.; Kong, X.; Qin, A.; Ou, J. Enhanced luminescence intensity of near-infrared-sensitized upconversion nanoparticles via Ca 2+ doping for a nitric oxide release platform. Journal of Materials Chemistry B 2020, 8 (30), 6481-6489.
(65) Kao, P.-T.; Lee, I.-J.; Liau, I.; Yeh, C.-S. Controllable NO release from Cu 1.6 S nanoparticle decomposition of S-nitrosoglutathiones following photothermal disintegration of polymersomes to elicit cerebral vasodilatory activity. Chemical science 2017, 8 (1), 291-297.
(66) Yu, S.; Li, G.; Liu, R.; Ma, D.; Xue, W. Dendritic Fe3O4@ poly (dopamine)@ PAMAM nanocomposite as controllable NO‐releasing material: a synergistic photothermal and NO antibacterial study. Adv. Funct. Mater. 2018, 28 (20), 1707440.
(67) Su, C.-H.; Li, W.-P.; Tsao, L.-C.; Wang, L.-C.; Hsu, Y.-P.; Wang, W.-J.; Liao, M.-C.; Lee, C.-L.; Yeh, C.-S. Enhancing microcirculation on multitriggering manner facilitates angiogenesis and collagen deposition on wound healing by photoreleased NO from hemin-derivatized colloids. ACS nano 2019, 13 (4), 4290-4301.
(68) Li, J.; Jiang, R.; Wang, Q.; Li, X.; Hu, X.; Yuan, Y.; Lu, X.; Wang, W.; Huang, W.; Fan, Q. Semiconducting polymer nanotheranostics for NIR-II/Photoacoustic imaging-guided photothermal initiated nitric oxide/photothermal therapy. Biomaterials 2019, 217, 119304.
(69) Ding, Y.; Du, C.; Qian, J.; Dong, C.-M. NIR-responsive polypeptide nanocomposite generates NO gas, mild photothermia, and chemotherapy to reverse multidrug-resistant cancer. Nano Lett. 2019, 19 (7), 4362-4370.
(70) Jin, R.; Xie, J.; Yang, X.; Tian, Y.; Yuan, P.; Bai, Y.; Liu, S.; Cai, B.; Chen, X. A tumor-targeted nanoplatform with stimuli-responsive cascaded activities for multiple model tumor therapy. Biomaterials science 2020, 8 (7), 1865-1874.
(71) Lee, I.-J.; Kao, P.-T.; Hung, S.-A.; Wang, Z.-W.; Lin, H.-J.; Chang, W.-T.; Yeh, C.-S.; Liau, I. Light triggering goldsomes enable local NO-generation and alleviate pathological vasoconstriction. Nanomed. Nanotechnol. Biol. Med. 2020, 30, 102282.
(72) Yang, Q.; Yin, H.; Xu, T.; Zhu, D.; Yin, J.; Chen, Y.; Yu, X.; Gao, J.; Zhang, C.; Chen, Y. Engineering 2D Mesoporous Silica@ MXene‐Integrated 3D‐Printing Scaffolds for Combinatory Osteosarcoma Therapy and NO‐Augmented Bone Regeneration. Small 2020, 16 (14), 1906814.
(73) Fan, W.; Bu, W.; Zhang, Z.; Shen, B.; Zhang, H.; He, Q.; Ni, D.; Cui, Z.; Zhao, K.; Bu, J. X‐ray radiation‐controlled NO‐release for on‐demand depth‐independent hypoxic radiosensitization. Angew. Chem. Int. Ed. 2015, 54 (47), 14026-14030.
(74) Dou, Y.; Liu, Y.; Zhao, F.; Guo, Y.; Li, X.; Wu, M.; Chang, J.; Yu, C. Radiation-responsive scintillating nanotheranostics for reduced hypoxic radioresistance under ROS/NO-mediated tumor microenvironment regulation. Theranostics 2018, 8 (21), 5870.
(75) Gao, S.; Zhang, W.; Wang, R.; Hopkins, S. P.; Spagnoli, J. C.; Racin, M.; Bai, L.; Li, L.; Jiang, W.; Yang, X. Nanoparticles encapsulating nitrosylated maytansine to enhance radiation therapy. ACS nano 2020, 14 (2), 1468-1481.
(76) Xue, Z.; Jiang, M.; Liu, H.; Zeng, S.; Hao, J. Low dose soft X-ray-controlled deep-tissue long-lasting NO release of persistent luminescence nanoplatform for gas-sensitized anticancer therapy. Biomaterials 2020, 263, 120384.
(77) Zhang, F.; Liu, S.; Zhang, N.; Kuang, Y.; Li, W.; Gai, S.; He, F.; Gulzar, A.; Yang, P. X-ray-triggered NO-released Bi–SNO nanoparticles: all-in-one nano-radiosensitizer with photothermal/gas therapy for enhanced radiotherapy. Nanoscale 2020, 12 (37), 19293-19307.
(78) Sun, T.; Dasgupta, A.; Zhao, Z.; Nurunnabi, M.; Mitragotri, S. Physical triggering strategies for drug delivery. Adv. Drug Del. Rev. 2020, 158, 36-62. DOI: https://doi.org/10.1016/j.addr.2020.06.010.
(79) Xiao, Y.; Guo, X.; Huang, H.; Yang, Q.; Huang, A.; Zhong, C. Synthesis of MIL-88B(Fe)/Matrimid mixed-matrix membranes with high hydrogen permselectivity. RSC Advances 2015, 5 (10), 7253-7259, 10.1039/C4RA13727B. DOI: 10.1039/C4RA13727B.
(80) Wu, M. X.; Yang, Y. W. Metal–organic framework (MOF)‐based drug/cargo delivery and cancer therapy. Adv. Mater. 2017, 29 (23), 1606134.
(81) Murray, L. J.; Dincă, M.; Long, J. R. Hydrogen storage in metal–organic frameworks. Chem. Soc. Rev. 2009, 38 (5), 1294-1314. Chughtai, A. H.; Ahmad, N.; Younus, H. A.; Laypkov, A.; Verpoort, F. Metal–organic frameworks: versatile heterogeneous catalysts for efficient catalytic organic transformations. Chem. Soc. Rev. 2015, 44 (19), 6804-6849. Li, J.-R.; Ma, Y.; McCarthy, M. C.; Sculley, J.; Yu, J.; Jeong, H.-K.; Balbuena, P. B.; Zhou, H.-C. Carbon dioxide capture-related gas adsorption and separation in metal-organic frameworks. Coord. Chem. Rev. 2011, 255 (15-16), 1791-1823.
(82) Zhou, H.-C.; Long, J. R.; Yaghi, O. M. Introduction to metal–organic frameworks. Chem. Rev. 2012, 112 (2), 673-674.
(83) Giménez-Marqués, M.; Hidalgo, T.; Serre, C.; Horcajada, P. Nanostructured metal–organic frameworks and their bio-related applications. Coord. Chem. Rev. 2016, 307, 342-360.
(84) Huxford, R. C.; Della Rocca, J.; Lin, W. Metal–organic frameworks as potential drug carriers. Curr. Opin. Chem. Biol. 2010, 14 (2), 262-268. Horcajada, P.; Gref, R.; Baati, T.; Allan, P. K.; Maurin, G.; Couvreur, P.; Ferey, G.; Morris, R. E.; Serre, C. Metal–organic frameworks in biomedicine. Chem. Rev. 2012, 112 (2), 1232-1268.
(85) Horcajada, P.; Serre, C.; Vallet‐Regí, M.; Sebban, M.; Taulelle, F.; Férey, G. Metal–organic frameworks as efficient materials for drug delivery. Angew. Chem. 2006, 118 (36), 6120-6124.
(86) Park, J.; Jiang, Q.; Feng, D.; Mao, L.; Zhou, H.-C. Size-controlled synthesis of porphyrinic metal–organic framework and functionalization for targeted photodynamic therapy. Journal of the American Chemical Society 2016, 138 (10), 3518-3525.
(87) Wang, L.; Zhang, J.-W.; Li, C.; Sun, J.-L.; Wang, G.-M.; Chen, Y.-Z. Novel CoNi-metal–organic framework crystal-derived CoNi@C: synthesis and effective cascade catalysis. Dalton Transactions 2020, 49 (30), 10567-10573, 10.1039/D0DT01558J. DOI: 10.1039/D0DT01558J. Chen, Y.-Z.; Zhang, R.; Jiao, L.; Jiang, H.-L. Metal–organic framework-derived porous materials for catalysis. Coord. Chem. Rev. 2018, 362, 1-23.
(88) Serre, C.; Mellot-Draznieks, C.; Surblé, S.; Audebrand, N.; Filinchuk, Y.; Férey, G. Role of Solvent-Host Interactions That Lead to Very Large Swelling of Hybrid Frameworks. Science 2007, 315 (5820), 1828-1831. DOI: 10.1126/science.1137975.
(89) Mukherjee, P. K.; Harwansh, R. K.; Bhattacharyya, S. Chapter 10 - Bioavailability of Herbal Products: Approach Toward Improved Pharmacokinetics. In Evidence-Based Validation of Herbal Medicine, Mukherjee, P. K. Ed.; Elsevier, 2015; pp 217-245.
(90) Berkland, C.; King, M.; Cox, A.; Kim, K. K.; Pack, D. W. Precise control of PLG microsphere size provides enhanced control of drug release rate. Journal of controlled release 2002, 82 (1), 137-147.
(91) Naha, P. C.; Kanchan, V.; Manna, P. K.; Panda, A. K. Improved bioavailability of orally delivered insulin using Eudragit-L30D coated PLGA microparticles. Journal of Microencapsulation 2008, 25 (4), 248-256. DOI: 10.1080/02652040801903843. Burgess, D. J.; Hickey, A. J. Microspheres: design and manufacturing. In Injectable dispersed systems, CRC Press, 2005; pp 337-386.
(92) Giri, T. K.; Choudhary, C.; Alexander, A.; Badwaik, H.; Tripathi, D. K. Prospects of pharmaceuticals and biopharmaceuticals loaded microparticles prepared by double emulsion technique for controlled delivery. Saudi Pharmaceutical Journal 2013, 21 (2), 125-141.
(93) Han, S.; Zhang, X.; Li, M. Progress in research and application of PLGA embolic microspheres. Front. Biosci. 2016, 21, 931-940.
(94) Koerner, J.; Horvath, D.; Groettrup, M. Harnessing Dendritic Cells for Poly (D,L-lactide-co-glycolide) Microspheres (PLGA MS)-Mediated Anti-tumor Therapy. Front. Immunol. 2019, 10, 707-707. DOI: 10.3389/fimmu.2019.00707 PubMed.
(95) Bodmer, D.; Kissel, T.; Traechslin, E. Factors influencing the release of peptides and proteins from biodegradable parenteral depot systems. Journal of Controlled Release 1992, 21 (1), 129-137. DOI: https://doi.org/10.1016/0168-3659(92)90014-I.
(96) Jiang, W.; Gupta, R. K.; Deshpande, M. C.; Schwendeman, S. P. Biodegradable poly (lactic-co-glycolic acid) microparticles for injectable delivery of vaccine antigens. Adv. Drug Del. Rev. 2005, 57 (3), 391-410.
(97) Jeh, H.; Lu, S.; George, S. Encapsulation of PROLI/NO in biodegradable microparticles. Journal of microencapsulation 2004, 21 (1), 3-13.
(98) Gomes, A. J.; Barbougli, P. A.; Espreafico, E. M.; Tfouni, E. trans-[Ru (NO)(NH3) 4 (py)](BF4) 3· H2O encapsulated in PLGA microparticles for delivery of nitric oxide to B16-F10 cells: Cytotoxicity and phototoxicity. J. Inorg. Biochem. 2008, 102 (4), 757-766.
(99) Major, T. C.; Brant, D. O.; Reynolds, M. M.; Bartlett, R. H.; Meyerhoff, M. E.; Handa, H.; Annich, G. M. The attenuation of platelet and monocyte activation in a rabbit model of extracorporeal circulation by a nitric oxide releasing polymer. Biomaterials 2010, 31 (10), 2736-2745.
(100) Yoo, J.-W.; Choe, E.-S.; Ahn, S.-M.; Lee, C. H. Pharmacological activity and protein phosphorylation caused by nitric oxide-releasing microparticles. Biomaterials 2010, 31 (3), 552-558.
(101) Yoo, J. W.; Lee, J. S.; Lee, C. H. Characterization of nitric oxide‐releasing microparticles for the mucosal delivery. Journal of Biomedical Materials Research Part A: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials 2010, 92 (4), 1233-1243.
(102) Cai, W.; Wu, J.; Xi, C.; Meyerhoff, M. E. Diazeniumdiolate-doped poly (lactic-co-glycolic acid)-based nitric oxide releasing films as antibiofilm coatings. Biomaterials 2012, 33 (32), 7933-7944.
(103) Verma, R. K.; Singh, A. K.; Mohan, M.; Agrawal, A. K.; Verma, P. R.; Gupta, A.; Misra, A. Inhalable microparticles containing nitric oxide donors: saying NO to intracellular Mycobacterium tuberculosis. Mol. Pharm. 2012, 9 (11), 3183-3189.
(104) Soni, S. D.; Song, W.; West, J. L.; Khera, M. Nitric Oxide‐Releasing Polymeric Microspheres Improve Diabetes‐Related Erectile Dysfunction. The journal of sexual medicine 2013, 10 (8), 1915-1925.
(105) Handa, H.; Brisbois, E. J.; Major, T. C.; Refahiyat, L.; Amoako, K. A.; Annich, G. M.; Bartlett, R. H.; Meyerhoff, M. E. In vitro and in vivo study of sustained nitric oxide release coating using diazeniumdiolate-doped poly (vinyl chloride) matrix with poly (lactide-co-glycolide) additive. Journal of Materials Chemistry B 2013, 1 (29), 3578-3587.
(106) Gomes, A. J.; Espreafico, E. M.; Tfouni, E. trans-[Ru (NO) Cl (cyclam)](PF6) 2 and [Ru (NO)(Hedta)] Incorporated in PLGA Nanoparticles for the Delivery of Nitric Oxide to B16–F10 Cells: Cytotoxicity and Phototoxicity. Mol. Pharm. 2013, 10 (10), 3544-3554.
(107) Verma, R. K.; Agrawal, A. K.; Singh, A. K.; Mohan, M.; Gupta, A.; Gupta, P.; Gupta, U. D.; Misra, A. Inhalable microparticles of nitric oxide donors induce phagosome maturation and kill Mycobacterium tuberculosis. Tuberculosis 2013, 93 (4), 412-417.
(108) Chung, M. F.; Liu, H. Y.; Lin, K. J.; Chia, W. T.; Sung, H. W. A pH‐responsive carrier system that generates NO bubbles to trigger drug release and reverse P‐glycoprotein‐mediated multidrug resistance. Angew. Chem. Int. Ed. 2015, 54 (34), 9890-9893.
(109) Nurhasni, H.; Cao, J.; Choi, M.; Kim, I.; Lee, B. L.; Jung, Y.; Yoo, J.-W. Nitric oxide-releasing poly (lactic-co-glycolic acid)-polyethylenimine nanoparticles for prolonged nitric oxide release, antibacterial efficacy, and in vivo wound healing activity. International journal of nanomedicine 2015, 10, 3065.
(110) Lautner, G.; Meyerhoff, M. E.; Schwendeman, S. P. Biodegradable poly (lactic-co-glycolic acid) microspheres loaded with S-nitroso-N-acetyl-D-penicillamine for controlled nitric oxide delivery. Journal of Controlled Release 2016, 225, 133-139.
(111) Regmi, S.; Cao, J.; Pathak, S.; Gupta, B.; Poudel, B. K.; Tung, P. T.; Yook, S.; Park, J.-B.; Yong, C. S.; Kim, J. O. A three-dimensional assemblage of gingiva-derived mesenchymal stem cells and NO-releasing microspheres for improved differentiation. International journal of pharmaceutics 2017, 520 (1-2), 163-172.
(112) Lin, Y. J.; Chen, C. C.; Chi, N. W.; Nguyen, T.; Lu, H. Y.; Nguyen, D.; Lai, P. L.; Sung, H. W. In Situ Self‐Assembling Micellar Depots that Can Actively Trap and Passively Release NO with Long‐Lasting Activity to Reverse Osteoporosis. Adv. Mater. 2018, 30 (22), 1705605.
(113) Hlaing, S. P.; Kim, J.; Lee, J.; Hasan, N.; Cao, J.; Naeem, M.; Lee, E. H.; Shin, J. H.; Jung, Y.; Lee, B.-L. S-Nitrosoglutathione loaded poly (lactic-co-glycolic acid) microparticles for prolonged nitric oxide release and enhanced healing of methicillin-resistant Staphylococcus aureus-infected wounds. Eur. J. Pharm. Biopharm. 2018, 132, 94-102.
(114) Hasan, N.; Cao, J.; Lee, J.; Naeem, M.; Hlaing, S. P.; Kim, J.; Jung, Y.; Lee, B.-L.; Yoo, J.-W. PEI/NONOates-doped PLGA nanoparticles for eradicating methicillin-resistant Staphylococcus aureus biofilm in diabetic wounds via binding to the biofilm matrix. Materials Science and Engineering: C 2019, 103, 109741.
(115) Cao, J.; Su, M.; Hasan, N.; Lee, J.; Kwak, D.; Kim, D. Y.; Kim, K.; Lee, E. H.; Jung, J. H.; Yoo, J.-W. Nitric Oxide-Releasing Thermoresponsive Pluronic F127/Alginate Hydrogel for Enhanced Antibacterial Activity and Accelerated Healing of Infected Wounds. Pharmaceutics 2020, 12 (10), 926.
(116) Lin, Y. J.; Chen, C. C.; Nguyen, D.; Su, H. R.; Lin, K. J.; Chen, H. L.; Hu, Y. J.; Lai, P. L.; Sung, H. W. Biomimetic Engineering of a Scavenger‐Free Nitric Oxide‐Generating/Delivering System to Enhance Radiation Therapy. Small 2020, 16 (23), 2000655.
(117) Uchida, T.; Yoshida, K.; Ninomiya, A.; Goto, S. Optimization of preparative conditions for polylactide (PLA) microspheres containing ovalbumin. Chemical and pharmaceutical bulletin 1995, 43 (9), 1569-1573. Mi, F.-L.; Lin, Y.-M.; Wu, Y.-B.; Shyu, S.-S.; Tsai, Y.-H. Chitin/PLGA blend microspheres as a biodegradable drug-delivery system: phase-separation, degradation and release behavior. Biomaterials 2002, 23 (15), 3257-3267. Furlan, M.; Kluge, J.; Mazzotti, M.; Lattuada, M. Preparation of biocompatible magnetite–PLGA composite nanoparticles using supercritical fluid extraction of emulsions. The Journal of Supercritical Fluids 2010, 54 (3), 348-356. Shiga, K.; Muramatsu, N.; Kondo, T. Preparation of poly (D, L‐lactide) and copoly (lactide‐glycolide) microspheres of uniform size. Journal of pharmacy and pharmacology 1996, 48 (9), 891-895.
(118) Lai, M. K.; Tsiang, R. C. C. Microencapsulation of acetaminophen into poly(L-lactide) by three different emulsion solvent-evaporation methods. Journal of Microencapsulation 2005, 22 (3), 261-274. DOI: 10.1080/02652040500100261.
(119) Vysloužil, J.; Doležel, P.; Kejdušová, M.; Mašková, E.; Mašek, J.; Lukáč, R.; Košťál, V.; Vetchý, D.; Dvořáčková, K. Influence of different formulations and process parameters during the preparation of drug-loaded PLGA microspheres evaluated by multivariate data analysis. Acta Pharmaceutica 2014, 64 (4), 403-417. DOI: doi:10.2478/acph-2014-0032.
(120) Liang, Z.; Ni, R.; Zhou, J.; Mao, S. Recent advances in controlled pulmonary drug delivery. Drug Discovery Today 2015, 20 (3), 380-389.
(121) Chung, C.-W.; Liao, B.-W.; Huang, S.-W.; Chiou, S.-J.; Chang, C.-H.; Lin, S.-J.; Chen, B.-H.; Liu, W.-L.; Hu, S.-H.; Chuang, Y.-C. Magnetic Responsive Release of Nitric Oxide from an MOF-Derived Fe3O4@ PLGA Microsphere for the Treatment of Bacteria-Infected Cutaneous Wound. ACS Applied Materials & Interfaces 2022.
(122) Andrews, J. M. Determination of minimum inhibitory concentrations. J. Antimicrob. Chemother. 2001, 48 (suppl_1), 5-16. DOI: 10.1093/jac/48.suppl_1.5 (acccessed 6/13/2022).