Aljinat/Kitosan Nanopartiküllere Pemetrekset Adsorpsiyonu ve Kontrollü İlaç Salımı

Yıl 2021, Cilt: 14 Sayı: 3, 1066 - 1076, 18.12.2021

Ayça Erek , Safiye Kübra Aktaş , Yağmur Özdemir , Güliz Ak

https://doi.org/10.18185/erzifbed.1000206

Öz

Pemetrekset (PEM) küçük hücre dışı akciğer kanseri tedavisi için kullanılmaktadır. Bununla birlikte, pemetreksetin hızlı eliminasyon, düşük biyoyararlanım, zayıf tümör hücresi seçiciliği ve penetrasyon gibi sorunları vardır. Pemetreksetin akciğer kanseri hücrelerinde etkisini artırmak ve yan etkilerini en aza indirmek için ilaç taşıyıcı sistem kullanımına ihtiyaç vardır. Bu çalışmadaki amaç, biyobozunur ve non-toksik yapıdaki aljinat/kitosan nanopartiküllerine (ACNP) pemetrekset adsopsiyonunu gerçekleştirerek, pemetreksetin vücut içinde etkin bir şekilde taşınımını ve istenilen bölgede salımını sağlamaktır. Çalışmada iyonotropik jelasyon yöntemi kullanılarak aljinat/kitosan nanopartikülleri sentezlenip adsorpsiyon metodu ile pemetrekset taşıyıcı sisteme yüklendi. İlaç yükleme verimi % 57,80 olarak hesaplandı ve karakterizasyon testleri yapıldı. Pemetrekset yüklü aljinat/kitosan nanopartiküller (PACNP) ve serbest pemetrekset çözeltisi kullanılarak pH 5,5 ve 7,4 ortamlarında ilaç salım çalışmaları gerçekleştirildi. Elde edilen sonuçlar birbiriyle karşılaştırıldı. İlaç salım profili 25 saat boyunca izlendi ve nanopartiküllerden pH 7,4’te gözlenen %7’lik salım miktarının pH 5,5’ta %11’e yükseldiği belirlendi. Geliştirilen bu nanopartikül sistemi, pemetreksetin kontrollü salımı için daha ileri çalışmalarda in vitro ve in vivo olarak araştırılma potansiyeline sahiptir.

Anahtar Kelimeler

Aljinat/kitosan nanopartiküller, pemetrekset, adsorpsiyon, akciğer kanseri, pasif hedefleme

Alginate/Chitosan Nanoparticles for Adsorption and Controlled Release of Pemetrexed

Öz

Pemetrexed (PEM) is used for treatment of non-small cell lung cancer. However, PEM has disadvantages like fast elimination, low bioavailability, poor tumor cell selectivity, and penetration. Thus, there is a need for using pemetrexed delivery system to increase the anticancer effect of drug in lung cancer cells and to minimize its side effects. The purpose of this study is development of alginate/chitosan nanoparticles (ACNP) that have biodegradable and non-toxic structure for effective delivery of PEM for lung cancer therapy. In the present study, ACNP were prepared using the ionic gelation method, and pemetrexed was loaded via the adsorption method. Drug adsorption efficiency was calculated to be 57.80% and characterization studies were performed. In vitro drug release tests were carried out at pH levels of 5.5 and 7.4 with pemetrexed-loaded alginate/chitosan nanoparticles (PACNP) and free pemetrexed, and both the results were subsequently compared. Up to 11% release yield was observed at pH 5.5, and the yield reached up to 7% in pH 7.4 in the 25 hours. This nanoparticle system could be investigated in vitro and in vivo in further studies for controlled release of pemetrexed.

Anahtar Kelimeler

Alginate/chitosan nanoparticle, pemetrexed, adsorption, lung cancer, passive targeting

Kaynakça

• Affram, K. O., Smith, T., Ofori, E., Krishnan, S., Underwood, P., Trevino, J. G., and Agyare, E., 2020. “Cytotoxic Effects of Gemcitabine-Loaded Solid Lipid Nanoparticles in Pancreatic Cancer Cells “, Journal of Drug Delivery Science and Technology, 55, 101374.
• Ak, G., Aksu, D., Çapkın, E., Sarı, Ö., Kımız Geboloğlu, I., and Şanlıer, Ş. H. 2020. “ Delivery of Pemetrexed by Magnetic Nanoparticles: Design, Characterization, in Vitro and in vivo Assessment“, Preparative Biochemistry and Biotechnology, 50(3), 215–225.
• Ak G., 2021. “Covalently Coupling Doxorubicin to Polymeric Nanoparticles as Potential Inhaler Therapy: in vitro Studies“, Pharmaceutical Development and Technology, 26(8), 890–898.
• Arias, J. L., Gallardo, V., and Ruiz, M. A. 2012. “Multifunctional Anticancer Nanomedicine Based on a Magnetically Responsive Cyanoacrylate Polymer“, In Methods in Enzymology, 508, 61–88.
• Bakhtiary, Z., Barar, J., Aghanejad, A., Saei, A. A., Nemati, E., Ezzati Nazhad Dolatabadi, J., and Omidi, Y., 2017. “Microparticles Containing Erlotinib-Loaded Solid Lipid Nanoparticles for Treatment of Non-Small Cell Lung Cancer”, Drug Development and Industrial Pharmacy, 43(8), 1244–1253.
• Chen, J., Huang, L., Lai, H., Lu, C., Fang, M., Zhang, Q. and Luo, X., 2014. “ Methotrexate-Loaded Pegylated Chitosan Nanoparticles: Synthesis, Characterization, and in vitro and in vivo Antitumoral Activity “ , Molecular Pharmaceutics, 11(7):2213-2223.
• Chattopadhyay, S., Moran, R. G., and Goldman, I. D. 2007. “ Pemetrexed: Biochemical And Cellular Pharmacology, Mechanisms, and Clinical Applications“, Molecular Cancer Therapeutics, 6(2), 404–417.
• Chiarelli, P., Kievit, F., Zhang, M., & Ellenbogen, R., 2015. "Bionanotechnology and the Future of Glioma", Surgical Neurology International, 6(2), S45–S58.
• Daemi, H., and Barikani, M. 2012. “Synthesis and Characterization of Calcium Alginate Nanoparticles, Sodium Homopolymannuronate Salt and its Calcium Nanoparticles“ Scientia Iranica, 19(6), 2023–2028.
• Damadoğlu, E. 2007 “Küçük Hücreli Dışı Akciğer Kanserinde Tanı ve Tedavi Gecikmeleri ve Bu Gecikmelerin Patolojik Tümör Evresine Etkisi “,Yayımlanmamış Uzmanlık Tezi, T.C. Sağlık Bakanlığı Süreyyapaşa Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve Araştırma Hastanesi,İstanbul, 1-5.
• Farshi Azhar, F., and Olad, A. 2014. “A Study on Sustained Release Formulations for Oral Delivery Of 5-Fluorouracil Based on Alginate-Chitosan/Montmorillonite Nanocomposite Systems. Applied Clay Science“, 101, 288–296.
• Gazori, T., Khoshayand, M. R., Azizi, E., Yazdizade, P., Nomani, A., and Haririan, I. 2009. “Evaluation Of Alginate/Chitosan Nanoparticles as Antisense Delivery Vector: Formulation, Optimization and in vitro Characterization“, Carbohydrate Polymers, 77(3), 599–606.
• Hamarat Sanlıer, S., Yasa, M., Cihnioglu, A. O., Abdulhayoglu, M., Yılmaz, H., and Ak, G. 2016. “Development of Gemcitabine-Adsorbed Magnetic Gelatin Nanoparticles for Targeted Drug Delivery in Lung Cancer“, Artificial Cells, Nanomedicine and Biotechnology, 44(3), 943–949.
• Ji, M., Sun, X., Guo, X., Zhu, W., Wu, J., Chen, L., Wang J., Chen M., Cheng C., and Zhang, Q. (2019). “Green Synthesis, Characterization and in vitro Release of Cinnamaldehyde/Sodium Alginate/Chitosan Nanoparticles“, Food Hydrocolloids, 90, 515–522.
• Kaya, M., Cakmak, Y. S., Baran, T., Asan-Ozusaglam, M., Mentes, A., and Tozak, K. O. 2014. “New Chitin, Chitosan, and O-Carboxymethyl Chitosan Sources from Resting Eggs of Daphnia Longispina (Crustacea); with Physicochemical Characterization, and Antimicrobial and Antioxidant Activities“, Biotechnology and Bioprocess Engineering, 19(1), 58–69.
• Kocaefe, Ç. 2007. “Nanotıp: Yaşam Bilimlerinde Nanotaknoloji Uygulamaları“ Hacettepe Tıp Dergisi 2007;, 38(1), 33–38.
• Kumari, S. D. C., Tharani, C. B., Narayanan, N., and Kumar, C. S. 2013. “Formulation and Characterization of Methotrexate Loaded Sodium Alginate Chitosan Nanoparticles“, Indian Journal of Research in Pharmacy and Biotechnology, 1(6), 915–921.
• Küçüktürkmen, B., Devrim, B., Saka, O. M., Yilmaz, Ş., Arsoy, T., and Bozkir, A. 2017. “Co-Delivery of Pemetrexed and Mir-21 Antisense Oligonucleotide by Lipid-Polymer Hybrid Nanoparticles and Effects on Glioblastoma Cells“, Drug Development and Industrial Pharmacy, 43(1), 12–21.
• Li, P., Dai, Y., Zhang, J., Wang, A., and Wei, Q. 2015. “Chitosan-Alginate Nanoparticles as a Novel Drug Delivery System for Nifedipine“, International Journal of Biomedical Science, 4(3), 221–228.
• Lizardi-Mendoza, J., Argüelles Monal, W. M., and Goycoolea Valencia, F. M. 2016. “Chemical Characteristics and Functional Properties of Chitosan“, Chitosan in the Preservation of Agricultural Commodities, 351-366.
• Paques, J. P., Van Der Linden, E., Van Rijn, C. J. M., and Sagis, L. M. C. 2014. “ Preparation methods of alginate nanoparticles“, Advances in Colloid and Interface Science, 209, 163–171.
• Rollins, K. D., and Lindley, C. 2005. “Pemetrexed: A Multitargeted Antifolate“, Clinical Therapeutics, 27(9), 1343–1382.
• Singh, R., and Lillard, J. W. 2009. “Nanoparticle-Based Targeted Drug Delivery“, Experimental and Molecular Pathology, 86, 215–223.
• Soni, K., Mujtaba, A., and Kohli, K. 2017. “Lipid Drug Conjugate Nanoparticle as a Potential Nanocarrier for the Oral Delivery of Pemetrexed Diacid: Formulation Design, Characterization, ex vivo, and in vivo Assessment“, International Journal of Biological Macromolecules, 103, 139–151.
• Sozzi, G. 2001. “Molecular Biology of Lung Cancer“, European Journal of Cancer, 37(7), 63–73.
• Zappa, C., & Mousa, S. A. 2016. “Non-Small Cell Lung Cancer: Current Treatment and Future Advances“, Translational Lung Cancer Research, 5(3), 288–300.
• Zhang, X. F., Liu, Z. G., Shen, W., and Gurunathan, S. 2016. “Silver Nanoparticles: Synthesis, Characterization, Properties, Applications, and Therapeutic Approaches“, International Journal of Molecular Sciences, 17(9), 1–34.