Öz
Recently, research has focused on the methods for administration of medications in an efficient and controlled manner while minimizing side effects. Hydrophilic polymeric hydrogels have wide application area as nanocarriers. The network structure created by cross-linking is suitable for encapsulating and carrying drugs. There are many approaches for developing suitable methods to produce nanoparticles with desirable properties such as size and stability. Thanks to advances in microfluidic systems, microsystems have also been found as a solution to produce complex drug carriers with controllable release profiles. However, the utilization of microfabrication techniques is limited due to the high cost and the necessity for special laboratories. In this study, a simple and inexpensive method for the production of antibiotic-loaded chitosan nanoparticles is proposed. Production was carried out with two different designs, a syringe-based flow focusing system (outer channel diameter 1 mm, inner channel diameter 120 µm) and a 2-inlet, 1-outlet port serpentine type microchannel with 250 µm width and 100 µm height microchannel designed with the help of computer numerical control (CNC). Sodium Triphosphate (TPP) was used as cross-linking agent for the production of chitosan particles and the effects of the concentrations and flow rates of the components on the particle formation was investigated. It has been observed that chitosan particles can be produced in a syringe-based flow focusing system, but it is not possible to control the size and, the resulting particles are not homogeneous. In the studies carried out with CNC microchannel, it was determined by SEM analysis that the obtained particles ranged in size from 39 to 771 nm, and it was seen that the CNC microchannel was more effective at low and equal flow rates (25 µl/min). It has been found that increasing the flow rate of chitosan greatly increases the particle size, similarly, the particle size increases in conditions where the chitosan concentration is higher. It was determined that Ampicillin loaded particles synthesized with CNC microchannel under optimum conditions exhibited high inhibition against Gram positive and Gram negative bacteria. These results show that the proposed approaches for the design of microsystems can be used in the formation of polymeric drug carriers without the need for specialized laboratories and expertise.
Anahtar Kelimeler
Antimicrobial Chitosan particle Drug delivery Microfabrication Microfluidic
Proje Numarası
19.F5119.0101.
Kaynakça
- 1. Khadka P., Ro J., Kim H., Kim I., Kim J.T., Kim H., Cho J.M. Yu G., Lee J., Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability, Asian J. Pharm. Sci., 9, 304–316, 2014.
- 2. Kalepu S., Nekkanti V., Insoluble drug delivery strategies: Review of recent advances and business prospects, Acta Pharm. Sin. B., 5, 442–453, 2015.
- 3. Zhang L., Chen Q., Ma Y., Sun J.., Microfluidic Methods for Fabrication and Engineering of Nanoparticle Drug Delivery Systems, ACS Appl. Bio Mater., 3, 107, 2020.
- 4. Agha, A., Waheed, W., Stiharu, I., Nerguizian, V., Destgeer, G., Abu-Nada, E., Alazzam, A., A review on microfluidic-assisted nanoparticle synthesis, and their applications using multiscale simulation methods. Discover Nano, 18 (1), 18, 2023.
- 5. Gimondi, S., Ferreira, H., Reis, R. L., Neves, N. M., Microfluidic Devices: A Tool for Nanoparticle Synthesis and Performance Evaluation. ACS Nano, 17 (15), 14205–14228, 2023.
- 6. Kumar K., Chawla R., Nanocarriers-mediated therapeutics as a promising approach for treatment and diagnosis of lung cancer, J. Drug Delivery Sci. Technol., 65, 102677, 2021.
- 7. Marquis M., Davy J., Cathala B., Fang A., Renard D., Microfluidics assisted generation of innovative polysaccharide hydrogel microparticles. Carbohydr. Polym., 116, 189, 2015.
- 8. Bazban-Shotorbani S., Dashtimoghadam E., Karkhaneh A., Hasani-Sadrabadi M.M., Jacob K.I., Microfluidic Directed Synthesis of Alginate Nanogels with Tunable Pore Size for Efficient Protein Delivery, Langmuir, 32, 4996, 2016.
- 9. Kim S., Oh J., Cha C., Enhancing the biocompatibility of microfluidics-assisted fabrication of cell-laden microgels with channel geometry, Colloids Surf B Biointerfaces, 147, 1, 2016.
- 10. Liu A.L., García A.J., Methods for Generating Hydrogel Particles for Protein Delivery, Ann. Biomed. Eng., 44, 1946–1958, 2016.
- 11. Porras-Gómez M., Vega-Baudrit J., Núñez-Corrales S., Ampicillin-Loaded Chitosan Nanoparticles for In Vitro Antimicrobial Screening on Escherichia coli. In: Chitin-Chitosan - Myriad Functionalities in Science and Technology, Ed:: Dongre, R.S, InTech, Londra, UK, 245-259, 2018.
- 12. van Bavel, N., Issler, T., Pang, L., Anikovskiy, M., Prenner, E. J., A Simple Method for Synthesis of Chitosan Nanoparticles with Ionic Gelation and Homogenization. Molecules, 28 (11), 4328, 2023.
- 13. Kravanja G., Primožič M., Knez Ž., Leitgeb M., Chitosan-based (Nano)materials for Novel Biomedical Applications. Molecules, 24, 2019.
- 14. Zhang, H., Yang, J., Sun, R., Han, S., Yang, Z., Teng, L., Microfluidics for nano-drug delivery systems: From fundamentals to industrialization. Acta Pharm. Sin. B., 13 (8), 3277–3299, 2023
- 15. Zamani, M. H., Khatibi, A., Tavana, B., Zahedi, P., Aghamohammadi, S., Characterization of drug-loaded alginate-chitosan polyelectrolyte nanoparticles synthesized by microfluidics. J. Polym. Res., 30 (2), 1–11, 2023.
- 16. Khayati, M., Manjili, H. K., Soleimani, M., Hosseinzadeh, S., Akrami, M., Haririan, I., Tafti, S. H. A., Microfluidic synthesis of zoledronic acid loaded chitosan nanoparticles used for osteogenic differentiation of mesenchymal cells. Int. J. Biol. Macromol., 234, 123056, 2023.
- 17. Pessoa A.C.S.N., Sipoli C.C., De La Torre L.G., Effects of diffusion and mixing pattern on microfluidic-assisted synthesis of chitosan/ATP nanoparticles, Lab Chip, 17, 2281–93, 2017.
- 18. Özdilek H., Mikrosistemlerde aljinat ve kitosan mikropartikül üretimi ve karakterizasyonu (Yüksek Lisans tezi), Gümüşhane Üniversitesi, Fen Bilim. Enstitüsü, Gümüşhane, 2020.
- 19. Kazan A., Hu X., Stahl A., Frerichs H., Smirnova I,. Yesil‐Celiktas O., An enzyme immobilized microreactor for continuous‐flow biocatalysis of ginsenoside Rb1, J. Chem. Technol. Biotechnol., 96 (12), 3349-3357, 2021.
- 20. Ghelich P., Salehi Z., Mohajerzedeh S., Jafarkhani M., Experimental and numerical study on a novel microfluidic method to fabricate curcumin loaded calcium alginate microfibres, Can. J. Chem. Eng., 96 (11):2342–51, 2018.
- 21. Zhang Y., Zhao Q., Yuan D., Liu H., Yun G., Lu H., Li M., Guo J., Li W., Tang S.Y., Modular off-chip emulsion generator enabled by a revolving needle, Lab Chip, 20, 4592-4599, 2020.
- 22. Brás E.J.S., Chu V., Aires-Barros M.R., Conde J.P., Fernandes P., A microfluidic platform for physical entrapment of yeast cells with continuous production of invertase, J. Chem. Technol. Biotechnol., 92 (2), 334–41, 2017.
- 23. Hossain M.M., Rahman T., Low Cost Micro Milling Machine for Prototyping Plastic Microfluidic Devices, Proceedings, 2:707,1-4 2018.
- 24. Balakrishnan H.K., Badar F., Doeven E.H., Novak J.I., Merenda A., Dumée L.F., Loy J., Guijt R.M., 3D Printing: An Alternative Microfabrication Approach with Unprecedented Opportunities in Design, Anal. Chem., 93, 350–366, 2021.
- 25. Sanka R., Lippai J., Samarasekera D., Nemsick S., Densmore D., 3DμF - Interactive Design Environment for Continuous Flow Microfluidic Devices, Sci. Rep., 9 (1), 1–10, 2019.
- 26. Aşık M.D., Kaplan M., Çetin B., Sağlam N., Synthesis of iron oxide core chitosan nanoparticles in a 3D printed microfluidic device, J. Nanopart. Res., 23 (3), 1-11, 2021.
- 27. Soheili S., Mandegar E., Moradikhah F., Doosti-Telgerd M., Javar H.A., Experimental and numerical studies on microfluidic preparation and engineering of chitosan nanoparticles, J. Drug Delivery Sci. Technol., 61, 102268, 2021.
- 28. Gokce, Y., Cengiz, B., Yildiz, N., Calimli, A., Aktas, Z., Ultrasonication of chitosan nanoparticle suspension: Influence on particle size. Colloids Surf. A: Physicochem. Eng. Asp., 462, 75–81,2014
- 29. Escareño N., Hassan N., Kogan M.J., Juárez J., Topete A., Daneri-Navarro A., Microfluidics-assisted conjugation of chitosan-coated polymeric nanoparticles with antibodies: Significance in drug release, uptake, and cytotoxicity in breast cancer cells, J. Colloid Interface Sci., 591, 440-50, 2021.
- 30. Pittermannová A., Pittermannová P., Ruberová Z., Ruberová R., Zadražil A.Z., Bremond N., Bibette J., Stěpánek F., Stěp S., Stěpánek S., Microfluidic fabrication of composite hydrogel microparticles in the size range of blood cells, RSC Adv., 6, 103532-40, 2016.
- 31. Nagarajan E., Shanmugasundaram P., Ravichandiran V., Vijayalakshmi A., Senthilnathan B., Masilamani K., Development and evaluation of chitosan based polymeric nanoparticles of an antiulcer drug Lansoprazole, J. Appl. Pharm. Sci., 5 (4), 20–5, 2015.
- 32. Bramosanti M., Chronopoulou L., Grillo F., Valletta A., Palocci C., Microfluidic-assisted nanoprecipitation of antiviral-loaded polymeric nanoparticles, Colloids Surf. A: Physicochem. Eng. Asp., 5, 532, 369–76, 2017.
- 33. Alqahtani F.Y., Aleanizy F.S., Tahir E. E., Alquadeib B.T., Alsarra I.A., Alanazi J.S., Abdelhady H.G., Preparation, characterization, and antibacterial activity of diclofenac-loaded chitosan nanoparticles, Saudi. Pharm. J., 1, 27 (1), 82–7, 2019.
- 34. Ma Z., Kim D., Adesogan A.T., Ko S., Galvao K., Jeong K.C., Chitosan Microparticles Exert Broad-Spectrum Antimicrobial Activity against Antibiotic-Resistant Micro-organisms without Increasing Resistance, ACS Appl. Mater. Interfaces, 8, 10700-9, 2016.
- 35. Sobhani Z., Samani S.M., Montaseri H., Khezri E., Nanoparticles of chitosan loaded ciprofloxacin: Fabrication and antimicrobial activity, Adv. Pharm. Bull., 7, 427-32, 2017.
Öz
Son zamanlarda araştırmalar, ilaçların yan etkilerini en aza indirirken etkili ve kontrollü bir şekilde uygulanmasına imkan veren yöntemlere odaklanmıştır. Hidrofilik polimerik yapıdaki hidrojeller, nanotaşıyıcı olarak yaygın bir kullanım alanına sahiptir. Çapraz bağlanma ile oluşturulan ağ yapısı ilaçların tutulmasına ve taşınmasına elverişlidir. Boyut ve kararlılık gibi istenen özelliklere sahip parçacıkların üretiminde uygun yöntemlerin geliştirilmesi için birçok yaklaşım vardır. Mikroakışkan sistemlerindeki ilerlemeler sayesinde mikrosistemler, salım profilleri kontrol edilebilen karmaşık ilaç taşıyıcılarını üretmek için de çözüm olarak görülmüştür. Ancak, mikrofabrikasyon tekniklerinin, yüksek maliyeti ve özel laboratuvarlar gerektirmesi nedeniyle kullanımı sınırlı kalmaktadır. Bu çalışmada, antibiyotik yüklü kitosan parçacıklarının üretimi için basit ve ucuz bir yöntem önerilmiştir. Şırınga tabanlı akış odaklama sistemi (dış kanal capı 1 mm iç kanal çapı 120 µm) ve bilgisayarlı sayısal kontrol (Computer numerical control, CNC) yardımıyla tasarlanan, 2 giriş, 1 çıkış portuna sahip ve 250 µm genişliğinde ve 100 µm derinliğinde serpantin tipi mikrokanal olmak üzer iki farklı tasarımın üretimi gerçekleştirilmiştir. Kitosan parçacıkların üretimi için çapraz bağlayıcı ajan olarak Sodyum Trifosfat (TPP) kullanılmış ve bileşenlerin konsantrasyonu ve akış hızlarının parçacık oluşumuna etkileri incelenmiştir. Kitosan parçacıkların, şırınga tabanlı akış odaklama sisteminde üretilebildiği, ancak boyutlarını kontrol etmenin mümkün olmadığı ve elde edilen parçacıkların homojen olmadığı görülmüştür. CNC mikrokanal ile yapılan çalışmalarda üretilen parçacıkların 39 ila 771 nm arasında değişen boyutlarda olduğu SEM analizleri ile tespit edilmiş ve CNC mikrokanalın, düşük ve eşit akış hızlarında (25 µl/dk) daha başarılı olduğu görülmüştür. Kitosan akış hızının arttırılmasının, parçacık boyutunu büyük ölçüde arttırdığı, benzer şekilde kitosan konsanstrasyonun daha yüksek olduğu koşullarda da parçacık boyutunun arttığı tespit edilmiştir. CNC mikrokanal ile optimum koşullarda üretilen, Ampisilin yüklü parçacıkların Gram pozitif ve Gram negatif bakteriler üzerinde inhibisyon gösterdiği belirlenmiştir. Bu sonuçlar, mikrosistemlerin tasarımı için önerilen yaklaşımların özel laboratuvar ve uzmanlık gerektirmeksizin, polimerik ilaç taşıyıcılarının üretiminde kullanılabileceğini göstermektedir.
Anahtar Kelimeler
Antimikrobiyal İlaç salım kitosan parçacık Mikroakışkan Mikrofabrikasyon
Destekleyen Kurum
Gümüşhane Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Dairesi Başkanlığı
Proje Numarası
19.F5119.0101.
Teşekkür
Bu çalışma Gümüşhane Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Dairesi Başkanlığı tarafından desteklenmiştir.
Kaynakça
- 1. Khadka P., Ro J., Kim H., Kim I., Kim J.T., Kim H., Cho J.M. Yu G., Lee J., Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability, Asian J. Pharm. Sci., 9, 304–316, 2014.
- 2. Kalepu S., Nekkanti V., Insoluble drug delivery strategies: Review of recent advances and business prospects, Acta Pharm. Sin. B., 5, 442–453, 2015.
- 3. Zhang L., Chen Q., Ma Y., Sun J.., Microfluidic Methods for Fabrication and Engineering of Nanoparticle Drug Delivery Systems, ACS Appl. Bio Mater., 3, 107, 2020.
- 4. Agha, A., Waheed, W., Stiharu, I., Nerguizian, V., Destgeer, G., Abu-Nada, E., Alazzam, A., A review on microfluidic-assisted nanoparticle synthesis, and their applications using multiscale simulation methods. Discover Nano, 18 (1), 18, 2023.
- 5. Gimondi, S., Ferreira, H., Reis, R. L., Neves, N. M., Microfluidic Devices: A Tool for Nanoparticle Synthesis and Performance Evaluation. ACS Nano, 17 (15), 14205–14228, 2023.
- 6. Kumar K., Chawla R., Nanocarriers-mediated therapeutics as a promising approach for treatment and diagnosis of lung cancer, J. Drug Delivery Sci. Technol., 65, 102677, 2021.
- 7. Marquis M., Davy J., Cathala B., Fang A., Renard D., Microfluidics assisted generation of innovative polysaccharide hydrogel microparticles. Carbohydr. Polym., 116, 189, 2015.
- 8. Bazban-Shotorbani S., Dashtimoghadam E., Karkhaneh A., Hasani-Sadrabadi M.M., Jacob K.I., Microfluidic Directed Synthesis of Alginate Nanogels with Tunable Pore Size for Efficient Protein Delivery, Langmuir, 32, 4996, 2016.
- 9. Kim S., Oh J., Cha C., Enhancing the biocompatibility of microfluidics-assisted fabrication of cell-laden microgels with channel geometry, Colloids Surf B Biointerfaces, 147, 1, 2016.
- 10. Liu A.L., García A.J., Methods for Generating Hydrogel Particles for Protein Delivery, Ann. Biomed. Eng., 44, 1946–1958, 2016.
- 11. Porras-Gómez M., Vega-Baudrit J., Núñez-Corrales S., Ampicillin-Loaded Chitosan Nanoparticles for In Vitro Antimicrobial Screening on Escherichia coli. In: Chitin-Chitosan - Myriad Functionalities in Science and Technology, Ed:: Dongre, R.S, InTech, Londra, UK, 245-259, 2018.
- 12. van Bavel, N., Issler, T., Pang, L., Anikovskiy, M., Prenner, E. J., A Simple Method for Synthesis of Chitosan Nanoparticles with Ionic Gelation and Homogenization. Molecules, 28 (11), 4328, 2023.
- 13. Kravanja G., Primožič M., Knez Ž., Leitgeb M., Chitosan-based (Nano)materials for Novel Biomedical Applications. Molecules, 24, 2019.
- 14. Zhang, H., Yang, J., Sun, R., Han, S., Yang, Z., Teng, L., Microfluidics for nano-drug delivery systems: From fundamentals to industrialization. Acta Pharm. Sin. B., 13 (8), 3277–3299, 2023
- 15. Zamani, M. H., Khatibi, A., Tavana, B., Zahedi, P., Aghamohammadi, S., Characterization of drug-loaded alginate-chitosan polyelectrolyte nanoparticles synthesized by microfluidics. J. Polym. Res., 30 (2), 1–11, 2023.
- 16. Khayati, M., Manjili, H. K., Soleimani, M., Hosseinzadeh, S., Akrami, M., Haririan, I., Tafti, S. H. A., Microfluidic synthesis of zoledronic acid loaded chitosan nanoparticles used for osteogenic differentiation of mesenchymal cells. Int. J. Biol. Macromol., 234, 123056, 2023.
- 17. Pessoa A.C.S.N., Sipoli C.C., De La Torre L.G., Effects of diffusion and mixing pattern on microfluidic-assisted synthesis of chitosan/ATP nanoparticles, Lab Chip, 17, 2281–93, 2017.
- 18. Özdilek H., Mikrosistemlerde aljinat ve kitosan mikropartikül üretimi ve karakterizasyonu (Yüksek Lisans tezi), Gümüşhane Üniversitesi, Fen Bilim. Enstitüsü, Gümüşhane, 2020.
- 19. Kazan A., Hu X., Stahl A., Frerichs H., Smirnova I,. Yesil‐Celiktas O., An enzyme immobilized microreactor for continuous‐flow biocatalysis of ginsenoside Rb1, J. Chem. Technol. Biotechnol., 96 (12), 3349-3357, 2021.
- 20. Ghelich P., Salehi Z., Mohajerzedeh S., Jafarkhani M., Experimental and numerical study on a novel microfluidic method to fabricate curcumin loaded calcium alginate microfibres, Can. J. Chem. Eng., 96 (11):2342–51, 2018.
- 21. Zhang Y., Zhao Q., Yuan D., Liu H., Yun G., Lu H., Li M., Guo J., Li W., Tang S.Y., Modular off-chip emulsion generator enabled by a revolving needle, Lab Chip, 20, 4592-4599, 2020.
- 22. Brás E.J.S., Chu V., Aires-Barros M.R., Conde J.P., Fernandes P., A microfluidic platform for physical entrapment of yeast cells with continuous production of invertase, J. Chem. Technol. Biotechnol., 92 (2), 334–41, 2017.
- 23. Hossain M.M., Rahman T., Low Cost Micro Milling Machine for Prototyping Plastic Microfluidic Devices, Proceedings, 2:707,1-4 2018.
- 24. Balakrishnan H.K., Badar F., Doeven E.H., Novak J.I., Merenda A., Dumée L.F., Loy J., Guijt R.M., 3D Printing: An Alternative Microfabrication Approach with Unprecedented Opportunities in Design, Anal. Chem., 93, 350–366, 2021.
- 25. Sanka R., Lippai J., Samarasekera D., Nemsick S., Densmore D., 3DμF - Interactive Design Environment for Continuous Flow Microfluidic Devices, Sci. Rep., 9 (1), 1–10, 2019.
- 26. Aşık M.D., Kaplan M., Çetin B., Sağlam N., Synthesis of iron oxide core chitosan nanoparticles in a 3D printed microfluidic device, J. Nanopart. Res., 23 (3), 1-11, 2021.
- 27. Soheili S., Mandegar E., Moradikhah F., Doosti-Telgerd M., Javar H.A., Experimental and numerical studies on microfluidic preparation and engineering of chitosan nanoparticles, J. Drug Delivery Sci. Technol., 61, 102268, 2021.
- 28. Gokce, Y., Cengiz, B., Yildiz, N., Calimli, A., Aktas, Z., Ultrasonication of chitosan nanoparticle suspension: Influence on particle size. Colloids Surf. A: Physicochem. Eng. Asp., 462, 75–81,2014
- 29. Escareño N., Hassan N., Kogan M.J., Juárez J., Topete A., Daneri-Navarro A., Microfluidics-assisted conjugation of chitosan-coated polymeric nanoparticles with antibodies: Significance in drug release, uptake, and cytotoxicity in breast cancer cells, J. Colloid Interface Sci., 591, 440-50, 2021.
- 30. Pittermannová A., Pittermannová P., Ruberová Z., Ruberová R., Zadražil A.Z., Bremond N., Bibette J., Stěpánek F., Stěp S., Stěpánek S., Microfluidic fabrication of composite hydrogel microparticles in the size range of blood cells, RSC Adv., 6, 103532-40, 2016.
- 31. Nagarajan E., Shanmugasundaram P., Ravichandiran V., Vijayalakshmi A., Senthilnathan B., Masilamani K., Development and evaluation of chitosan based polymeric nanoparticles of an antiulcer drug Lansoprazole, J. Appl. Pharm. Sci., 5 (4), 20–5, 2015.
- 32. Bramosanti M., Chronopoulou L., Grillo F., Valletta A., Palocci C., Microfluidic-assisted nanoprecipitation of antiviral-loaded polymeric nanoparticles, Colloids Surf. A: Physicochem. Eng. Asp., 5, 532, 369–76, 2017.
- 33. Alqahtani F.Y., Aleanizy F.S., Tahir E. E., Alquadeib B.T., Alsarra I.A., Alanazi J.S., Abdelhady H.G., Preparation, characterization, and antibacterial activity of diclofenac-loaded chitosan nanoparticles, Saudi. Pharm. J., 1, 27 (1), 82–7, 2019.
- 34. Ma Z., Kim D., Adesogan A.T., Ko S., Galvao K., Jeong K.C., Chitosan Microparticles Exert Broad-Spectrum Antimicrobial Activity against Antibiotic-Resistant Micro-organisms without Increasing Resistance, ACS Appl. Mater. Interfaces, 8, 10700-9, 2016.
- 35. Sobhani Z., Samani S.M., Montaseri H., Khezri E., Nanoparticles of chitosan loaded ciprofloxacin: Fabrication and antimicrobial activity, Adv. Pharm. Bull., 7, 427-32, 2017.
Ayrıntılar
| Birincil Dil | Türkçe |
|---|---|
| Konular | Mühendislik |
| Bölüm | Makaleler |
| Yazarlar | |
| Proje Numarası | 19.F5119.0101. |
| Erken Görünüm Tarihi | 17 Mayıs 2024 |
| Yayımlanma Tarihi | 20 Mayıs 2024 |
| Gönderilme Tarihi | 24 Mayıs 2023 |
| Kabul Tarihi | 26 Kasım 2023 |
| Yayımlandığı Sayı | Yıl 2024 Cilt: 39 Sayı: 4 |