رهایش دارو در پوست و اثرات ضدقارچی نانوذرات سیلیسی حاوی اکونازول
محورهای موضوعی : قارچ شناسیمریم منتظری 1 , سامان احمد نصر الهی 2 , علیرضا فیض بخش 3 , مهدی رزاقی ابیانه 4
1 - دانشگاه آزاد اسلامی، واحد تهران مرکز، دانشکده علوم پایه، گروه شیمی، تهران، ایران
2 - دانشگاه علوم پزشکی تهران،بخش نانودرماتولوژی،مرکزآموزش وپژوهش بیماری‌های پوست وجذام،تهران، ایران
3 - دانشگاه آزاد اسلامی، واحد تهران مرکز، دانشکده علوم پایه، گروه شیمی، تهران، ایران
4 - انستیتو پاستور ایران
کلید واژه: دارورسانی هدفمند, فعالیت ضدقارچ, اکونازول, نانوذرات سیلیسی,
چکیده مقاله :
سابقه و هدف: نانوذرات سیلیکا (MCM41) از دسته مزوپورهای سیلیکا (MSNs) دارای منافذ بزرگ و چگالی نسبتاً پایین هستند. هدف ازاین پژوهش بارگذاری داروی اکونازول برروی نانوذرات MCM41-NH2 و MCM41 و بررسی رهایش اکونازول در پوست انسان (Ex-Vivo) و اثر ضدقارچی آن بود.مواد و روش‌ها: در ابتدا MCM41 تهیه شد، سپس با آمین ستیل تری متیل آمونیوم بروماید، نانوذرات MCM41-NH2ساخته شد و داروی اکونازول روی آن بارگذاری گردید. مورفولوژی نانوذرات با دستگاه SEM و بارگذاری دارو با دستگاه FT-IR تعیین و برای اندازه‌گیری رهایش از دستگاه فرنز سِل وUV-Vis استفاده شد. اثر ضد قارچ ECO/MSNs با روشهای چاهک پلیت برای قارچ آسپرژیلوس فیومگتس و با استفاده ازروش پورپلیت برروی کاندیدا آلبیکنس بررسی شد. در بررسی رهایش پوستی[p1][l2] کرم با نسبت 1 به 1 دارو/ نانوذرات تهیه و از دستگاه فرنز سِل استفاده شد.یافته ها:نانوذرات سیلیکا در ابعاد حدود 300 نانومتر شد و رها‌سازی دارو در پوست نشان داد، طی 8 ساعت اول رهایش80% و پس ازآن تا 24 ساعت رهایش دارو به صورت پیوسته ادامه دارد. بررسی اثر ضد قارچ به روش چاهک پلیت نشان دادECO/MCM41 دارای اثر‌هاله عدم رشد بزرگ تر و همچنین حداقل غلظت مهاری mg/ml(MIC)75 می‌باشد. اثرات ضدقارچی پس از 72 ساعت تایید گردید. همچنین حداقل غلظت مهاری ECO/MCM41 در متانول بیشتر بود.نتیجه‌گیری: به دلیل اثرات ضد قارچی نانوذرات سیلیسی حاوی اکونازول، استفاده از آن به عنوان داروی مناسب در کرم پیشنهاد می‌گردد.
Background & Objectives: Silica Nanoparticles (MCM41) are silica mesopores (MSNs), which have large pores and relatively low density. The purpose of this study was to load Econazole onto silica nanoparticles (MCM41-NH2 and MCM41) And release of econazole in human skin (Ex-Vivo) then the antifungal effect of loaded econazole on silica nanoparticles was investigated. Materials & Methods: In this study, MCM41 was prepared, then MCM41-NH2 nanoparticles were provided by using amine cetyltrimethylammonium bromide and finally, the drug econazole was loaded on it. The morphology of the nanoparticles was determined by SEM and drug loading by FT-IR. Francescell and UV-Vis were used to measure the release. The release cream from the skin containing 1/1 drug and nanoparticles was prepared. Finally, the anti-fungal effect of ECO/MSNs was investigated in three ways. Francescell device was also used to check skin release. Results: Silica nanoparticles were prepared about 300 nanometers Release of the drug into the skin showed that during the first 8 hours 80% release and then up to 24 hours of continuous drug release. Antifungal effect by disk diffusion method showed that ECO/MCM41 had a larger inhibitory effect and also minimal inhibition of fungal growth (MIC) 75 mg/ml. Antifungal tests showed that no fungus grew after 72 hours.the antifungal effect as well as ECO / MCM41 (MIC) was greater in methanol. Conclusion: The antifungal effect of the newest agar method was not suitable for this drug. Therefore, as a suitable drug in the cream, a drug loaded with methanol is recommended.
structural design and applications. Journal of Materials Chemistry. 2010 20(37):7924-37.
2. Alanio A, Sitterlé E, Liance M, Farrugia C, Foulet F, Botterel F, et al. Low prevalence of
resistance to azoles in Aspergillus fumigatus in a French cohort of patients treated for
haematological malignancies. Journal of antimicrobial chemotherapy. 2011 66(2):371-4.
3. Park H- , Lee I-S, Chun Y-J, Yun C-H, Johnston JB, de Montellano PRO, et al. Heterologous
expression and characterization of the sterol 14 -demethylase CYP51F1 from Candida
albicans. 2011 509(1):9-15.
4. Latgé J-P. The pathobiology of Aspergillus fumigatus. Trends in microbiology. 2001 9(8):
382-9.
5. Nierman WC, Pain A, Anderson MJ, Wortman JR, Kim HS, Arroyo J, et al. enomic
sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature.
2005 438(7071):1151.
6. Hornby JM, Nickerson KW. Enhanced production of farnesol by Candida albicans treated with
four azoles. Antimicrobial agents and chemotherapy. 2004 48(6):2305-7.
7. Sudbery PEJNRM. rowth of Candida albicans hyphae. 2011 9(10):737.
8. Dai T, de Arce VJB, Tegos P, Hamblin MR. Blue dye and red light, a dynamic combination
for prophylaxis and treatment of cutaneous Candida albicans infections in mice. Antimicrobial
agents and chemotherapy. 2011 55(12):5710-7.
9. Verma P, Pathak K. Nanosized ethanolic vesicles loaded with econazole nitrate for the
treatment of deep fungal infections through topical gel formulation. Nanomedicine:
Nanotechnology, Biology and Medicine. 2012 8(4):489-96.
10. Hardia A, Jamindar D, Mahajan A, Hardia A. FORMULATION AND IN VITRO AND SKIN
PERMEABILITY EVALUATION OF DEXAMETHASONE LOADED NIOSOMAL EL.
Asian Journal of Pharmaceutical Research and Development Vol. 2017 5(2):1-09.
11. Weinstein JN, Ralston E, Leserman LD, Klausner RD, Dragsten P, Henkart P, et al.
Self-quenching of carboxyfluorescein fluorescence: uses in studying liposome stability and
liposome-cell interaction. Liposome Technology Volume III: Targeted Drug Delivery and
Biological Interaction: CRC Press 2018. p. 183-204.
12. Ahmed TA. Preparation of transfersomes encapsulating sildenafil aimed for transdermal drug
delivery: Plackett–Burman design and characterization. Journal of liposome research. 2015 25
(1):1-10.
13. Sanna V, avini E, Cossu M, Rassu , iunchedi P. Solid lipid nanoparticles (SLN) as
carriers for the topical delivery of econazole nitrate: in‐vitro characterization, ex‐vivo and
in‐vivo studies. Journal of pharmacy and pharmacology. 2007 59(8):1057-64.
14. ratieri T, Krawczyk-Santos AP, da Rocha PB, elfuso M, Marreto RN, Taveira SF.
SLN-and NLC-encapsulating antifungal agents: skin drug delivery and their unexplored
potential for treating onychomycosis. Current pharmaceutical design. 2017 23(43):6684-95.
15. Vallet-Regi M, Ramila A, Del Real R, Pérez-Pariente J. A new property of MCM-41: drug
delivery system. Chemistry of Materials. 2001 13(2):308-11.
16. Shah RM, Eldridge DS, Palombo EA, Harding IHJEJoP, Biopharmaceutics.
Microwave-assisted microemulsion technique for production of miconazole nitrate-and
econazole nitrate-loaded solid lipid nanoparticles. 2017 117:141-50.
17. Manzano M, Aina V, Arean C, Balas F, Cauda V, Colilla M, et al. Studies on MCM-41
mesoporous silica for drug delivery: effect of particle morphology and amine functionalization.
Chemical Engineering Journal. 2008 137(1):30-7.
18. Brezoiu A-M, Deaconu M, Nicu I, Vasile E, Mitran R-A, Matei C, et al. Heteroatom modified
MCM-41-silica carriers for Lomefloxacin delivery systems. Microporous and Mesoporous
Materials. 2019 275:214-22.
19. Horcajada P, Ramila A, Perez-Pariente J, Vallet-Regı M. Influence of pore size of MCM-41
matrices on drug delivery rate. Microporous and Mesoporous Materials. 2004 68(1):105-9.
20. Vallet‐Regí M, Balas F, Arcos D. Mesoporous materials for drug delivery. Angewandte
Chemie International Edition. 2007 46(40):7548-58.
21. Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug
delivery. Nature reviews Drug discovery. 2004 3(2):115.
22. u W, Yu Q, Yu C, Sun S. In vivo activity of fluconazole/tetracycline combinations in
alleria mellonella with resistant Candida albicans infection. Journal of global antimicrobial
resistance. 2018 13:74-80.
23. Naglik JR, Rodgers CA, Shirlaw PJ, Dobbie JL, Fernandes-Naglik LL, reenspan D, et al.
Differential expression of Candida albicans secreted aspartyl proteinase and phospholipase B
genes in humans correlates with active oral and vaginal infections. The Journal of infectious
diseases. 2003 188(3):469-79.
24. Firooz A, Nafisi S, Maibach HIJIjop. Novel drug delivery strategies for improving econazole
antifungal action. 2015 495(1):599-607.
25. Ambrogi V, Perioli L, Pagano C, Marmottini F, Moretti M, Mizzi F, et al. Econazole
nitrate‐loaded MCM‐41 for an antifungal topical powder formulation. Journal of
pharmaceutical sciences. 2010 99(11):4738-45.
26. Montazeri M, Razzaghi-Abyaneh M, Nasrollahi S, Maibach H, Nafisi S. Enhanced topical
econazole antifungal efficacy by amine-functionalized silica nanoparticles. Bulletin of
Materials Science. 2020 43(1):13.
27. Barry A, Pfaller M, Rennie R, Fuchs P, Brown S. Precision and accuracy of fluconazole
susceptibility testing by broth microdilution, Etest, and disk diffusion methods. Antimicrobial
agents and chemotherapy. 2002 46(6):1781-4.
28. Arjomandzadegan M, Emami N, Habibi , Farazi AA, Kahbazi M, Sarmadian H, et al.
Antimycobacterial activity assessment of three ethnobotanical plants against Mycobacterium
Tuberculosis: An In Vitro study. International journal of mycobacteriology. 2016 5(5):108.
29. Dubey A, Sharma A, Verma S. Ferulic acid surface modified silica polymer nanocomposites
(SMS/FA) for antioxidant and antifungal activities. Materials Today: Proceedings. 2020.
30. Kamaly N, Xiao , Valencia PM, Radovic-Moreno AF, Farokhzad OC. Targeted polymeric
therapeutic nanoparticles: design, development and clinical translation. Chemical Society
Reviews. 2012 41(7):2971-3010.
31. Canu , Sanna VA, avini E, Cossu M, Rassu , iunchedi P. Ex vivo cutaneous penetration
of econazole nitrate from SLN incorporated in hydrophilic gels. 2006.
32. Wang Y, heng Y, hang L, Wang Q, hang D. Stability of nanosuspensions in drug delivery.
Journal of controlled release. 2013 172(3):1126-41.
33. Wu L, hang J, Watanabe W. Physical and chemical stability of drug nanoparticles. Advanced
drug delivery reviews. 2011 63(6):456-69.
34. arcia-Bennett AE. Synthesis, toxicology and potential of ordered mesoporous materials in
nanomedicine. Nanomedicine. 2011 6(5):867-77.
35. Hoffmann F, Cornelius M, Morell J, Fröba M. Periodic mesoporous organosilicas (PMOs):
past, present, and future. Journal of nanoscience and nanotechnology. 2006 6(2):265-88.
36. Tang F, Li L, Chen D. Mesoporous silica nanoparticles: synthesis, biocompatibility and drug
delivery. Advanced Materials. 2012 24(12):1504-34.
37. Wan Y, hao D. On the controllable soft-templating approach to mesoporous silicates.
Chemical reviews. 2007 107(7):2821-60.
38. Berlier , astaldi L, Sapino S, Miletto I, Bottinelli E, Chirio D, et al. MCM-41 as a useful
vector for rutin topical formulations: synthesis, characterization and testing. International
journal of pharmaceutics. 2013 457(1):177-86.
39. Laghaei M, Sadeghi M, halei B, Dinari M. The effect of various types of post-synthetic
modifications on the structure and properties of MCM-41 mesoporous silica. Progress in
Organic Coatings. 2016 90:163-70.
40. Szalewski DA, Hinrichs VS, inniel DK, Barletta R . The pathogenicity of Aspergillus
fumigatus, drug resistance, and nanoparticle delivery. Canadian journal of microbiology.
2018 64(7):439-53.
41. Shimokawa O, Niimi M, Kikuchi K, Saito M, Kajiwara H, Yoshida S-i. Relationship between
MIC and minimum sterol 14 -demethylation-inhibitory concentration as a factor in evaluating
activities of azoles against various fungal species. Journal of clinical microbiology. 2005 43
(11):5547-9.
_||_
structural design and applications. Journal of Materials Chemistry. 2010 20(37):7924-37.
2. Alanio A, Sitterlé E, Liance M, Farrugia C, Foulet F, Botterel F, et al. Low prevalence of
resistance to azoles in Aspergillus fumigatus in a French cohort of patients treated for
haematological malignancies. Journal of antimicrobial chemotherapy. 2011 66(2):371-4.
3. Park H- , Lee I-S, Chun Y-J, Yun C-H, Johnston JB, de Montellano PRO, et al. Heterologous
expression and characterization of the sterol 14 -demethylase CYP51F1 from Candida
albicans. 2011 509(1):9-15.
4. Latgé J-P. The pathobiology of Aspergillus fumigatus. Trends in microbiology. 2001 9(8):
382-9.
5. Nierman WC, Pain A, Anderson MJ, Wortman JR, Kim HS, Arroyo J, et al. enomic
sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature.
2005 438(7071):1151.
6. Hornby JM, Nickerson KW. Enhanced production of farnesol by Candida albicans treated with
four azoles. Antimicrobial agents and chemotherapy. 2004 48(6):2305-7.
7. Sudbery PEJNRM. rowth of Candida albicans hyphae. 2011 9(10):737.
8. Dai T, de Arce VJB, Tegos P, Hamblin MR. Blue dye and red light, a dynamic combination
for prophylaxis and treatment of cutaneous Candida albicans infections in mice. Antimicrobial
agents and chemotherapy. 2011 55(12):5710-7.
9. Verma P, Pathak K. Nanosized ethanolic vesicles loaded with econazole nitrate for the
treatment of deep fungal infections through topical gel formulation. Nanomedicine:
Nanotechnology, Biology and Medicine. 2012 8(4):489-96.
10. Hardia A, Jamindar D, Mahajan A, Hardia A. FORMULATION AND IN VITRO AND SKIN
PERMEABILITY EVALUATION OF DEXAMETHASONE LOADED NIOSOMAL EL.
Asian Journal of Pharmaceutical Research and Development Vol. 2017 5(2):1-09.
11. Weinstein JN, Ralston E, Leserman LD, Klausner RD, Dragsten P, Henkart P, et al.
Self-quenching of carboxyfluorescein fluorescence: uses in studying liposome stability and
liposome-cell interaction. Liposome Technology Volume III: Targeted Drug Delivery and
Biological Interaction: CRC Press 2018. p. 183-204.
12. Ahmed TA. Preparation of transfersomes encapsulating sildenafil aimed for transdermal drug
delivery: Plackett–Burman design and characterization. Journal of liposome research. 2015 25
(1):1-10.
13. Sanna V, avini E, Cossu M, Rassu , iunchedi P. Solid lipid nanoparticles (SLN) as
carriers for the topical delivery of econazole nitrate: in‐vitro characterization, ex‐vivo and
in‐vivo studies. Journal of pharmacy and pharmacology. 2007 59(8):1057-64.
14. ratieri T, Krawczyk-Santos AP, da Rocha PB, elfuso M, Marreto RN, Taveira SF.
SLN-and NLC-encapsulating antifungal agents: skin drug delivery and their unexplored
potential for treating onychomycosis. Current pharmaceutical design. 2017 23(43):6684-95.
15. Vallet-Regi M, Ramila A, Del Real R, Pérez-Pariente J. A new property of MCM-41: drug
delivery system. Chemistry of Materials. 2001 13(2):308-11.
16. Shah RM, Eldridge DS, Palombo EA, Harding IHJEJoP, Biopharmaceutics.
Microwave-assisted microemulsion technique for production of miconazole nitrate-and
econazole nitrate-loaded solid lipid nanoparticles. 2017 117:141-50.
17. Manzano M, Aina V, Arean C, Balas F, Cauda V, Colilla M, et al. Studies on MCM-41
mesoporous silica for drug delivery: effect of particle morphology and amine functionalization.
Chemical Engineering Journal. 2008 137(1):30-7.
18. Brezoiu A-M, Deaconu M, Nicu I, Vasile E, Mitran R-A, Matei C, et al. Heteroatom modified
MCM-41-silica carriers for Lomefloxacin delivery systems. Microporous and Mesoporous
Materials. 2019 275:214-22.
19. Horcajada P, Ramila A, Perez-Pariente J, Vallet-Regı M. Influence of pore size of MCM-41
matrices on drug delivery rate. Microporous and Mesoporous Materials. 2004 68(1):105-9.
20. Vallet‐Regí M, Balas F, Arcos D. Mesoporous materials for drug delivery. Angewandte
Chemie International Edition. 2007 46(40):7548-58.
21. Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug
delivery. Nature reviews Drug discovery. 2004 3(2):115.
22. u W, Yu Q, Yu C, Sun S. In vivo activity of fluconazole/tetracycline combinations in
alleria mellonella with resistant Candida albicans infection. Journal of global antimicrobial
resistance. 2018 13:74-80.
23. Naglik JR, Rodgers CA, Shirlaw PJ, Dobbie JL, Fernandes-Naglik LL, reenspan D, et al.
Differential expression of Candida albicans secreted aspartyl proteinase and phospholipase B
genes in humans correlates with active oral and vaginal infections. The Journal of infectious
diseases. 2003 188(3):469-79.
24. Firooz A, Nafisi S, Maibach HIJIjop. Novel drug delivery strategies for improving econazole
antifungal action. 2015 495(1):599-607.
25. Ambrogi V, Perioli L, Pagano C, Marmottini F, Moretti M, Mizzi F, et al. Econazole
nitrate‐loaded MCM‐41 for an antifungal topical powder formulation. Journal of
pharmaceutical sciences. 2010 99(11):4738-45.
26. Montazeri M, Razzaghi-Abyaneh M, Nasrollahi S, Maibach H, Nafisi S. Enhanced topical
econazole antifungal efficacy by amine-functionalized silica nanoparticles. Bulletin of
Materials Science. 2020 43(1):13.
27. Barry A, Pfaller M, Rennie R, Fuchs P, Brown S. Precision and accuracy of fluconazole
susceptibility testing by broth microdilution, Etest, and disk diffusion methods. Antimicrobial
agents and chemotherapy. 2002 46(6):1781-4.
28. Arjomandzadegan M, Emami N, Habibi , Farazi AA, Kahbazi M, Sarmadian H, et al.
Antimycobacterial activity assessment of three ethnobotanical plants against Mycobacterium
Tuberculosis: An In Vitro study. International journal of mycobacteriology. 2016 5(5):108.
29. Dubey A, Sharma A, Verma S. Ferulic acid surface modified silica polymer nanocomposites
(SMS/FA) for antioxidant and antifungal activities. Materials Today: Proceedings. 2020.
30. Kamaly N, Xiao , Valencia PM, Radovic-Moreno AF, Farokhzad OC. Targeted polymeric
therapeutic nanoparticles: design, development and clinical translation. Chemical Society
Reviews. 2012 41(7):2971-3010.
31. Canu , Sanna VA, avini E, Cossu M, Rassu , iunchedi P. Ex vivo cutaneous penetration
of econazole nitrate from SLN incorporated in hydrophilic gels. 2006.
32. Wang Y, heng Y, hang L, Wang Q, hang D. Stability of nanosuspensions in drug delivery.
Journal of controlled release. 2013 172(3):1126-41.
33. Wu L, hang J, Watanabe W. Physical and chemical stability of drug nanoparticles. Advanced
drug delivery reviews. 2011 63(6):456-69.
34. arcia-Bennett AE. Synthesis, toxicology and potential of ordered mesoporous materials in
nanomedicine. Nanomedicine. 2011 6(5):867-77.
35. Hoffmann F, Cornelius M, Morell J, Fröba M. Periodic mesoporous organosilicas (PMOs):
past, present, and future. Journal of nanoscience and nanotechnology. 2006 6(2):265-88.
36. Tang F, Li L, Chen D. Mesoporous silica nanoparticles: synthesis, biocompatibility and drug
delivery. Advanced Materials. 2012 24(12):1504-34.
37. Wan Y, hao D. On the controllable soft-templating approach to mesoporous silicates.
Chemical reviews. 2007 107(7):2821-60.
38. Berlier , astaldi L, Sapino S, Miletto I, Bottinelli E, Chirio D, et al. MCM-41 as a useful
vector for rutin topical formulations: synthesis, characterization and testing. International
journal of pharmaceutics. 2013 457(1):177-86.
39. Laghaei M, Sadeghi M, halei B, Dinari M. The effect of various types of post-synthetic
modifications on the structure and properties of MCM-41 mesoporous silica. Progress in
Organic Coatings. 2016 90:163-70.
40. Szalewski DA, Hinrichs VS, inniel DK, Barletta R . The pathogenicity of Aspergillus
fumigatus, drug resistance, and nanoparticle delivery. Canadian journal of microbiology.
2018 64(7):439-53.
41. Shimokawa O, Niimi M, Kikuchi K, Saito M, Kajiwara H, Yoshida S-i. Relationship between
MIC and minimum sterol 14 -demethylation-inhibitory concentration as a factor in evaluating
activities of azoles against various fungal species. Journal of clinical microbiology. 2005 43
(11):5547-9.
