Comparison of Magnetically Responsive Trimethyl Chitosan and Chitosan Nanoparticles for Gemcitabine Delivery With in Vitro Studies

Year 2020, Volume: 4 Issue: 3, 249 - 257, 01.09.2020

Ayşe Ünal Güliz Ak Senay Hamarat Şanlıer

https://doi.org/10.30621/jbachs.2020.1074

Abstract

Purpose: Gemcitabine is nucleoside analogue and used for various carcinomas like non-small cell lung cancer. Nanoparticle-based therapeutic agents have been developed for use in cancer therapy. Trimethyl chitosan TMC is methylated derivative of chitosan. TMC can be preferable because of the limited solubility of chitosan. Magnetic nanoparticles can be concentrated at cancerous tissue which provide targeted cancer therapy. In this study, we tried to develop and compare magnetically targeted trimethyl chitosan and chitosan nanoparticles for gemcitabine delivery in lung cancer therapy. Methods: Chitosan was trimethylated using methyl iodide. Magnetic nanoparticles were synthesized using co-precipitation method. TMC and chitosan nanoparticles were prepared by cross-linking method with tripolyphosphate. Gemcitabine was loaded onto nanoparticles via adsorption technique. After that characterization studies were performed and in vitro drug release tests were carried out. In order to determine cytotoxicites against A549-luc-C8 and CRL5809 cell lines, MTT assays were performed. Results and conclusion: Trimethylation of chitosan was verified with FTIR analysis. Gemcitabine was loaded with 54.7 and 30.3% on magnetic TMC nanoparticles and chitosan nanoparticles, respectively. According to drug release experiments, both carrier system had controlled drug release profile. IC50 values of gemcitabine loaded magnetic TMC nanoparticles were lower than that of magnetic chitosan nanoparticles. In conclusion, it was suggested that trimethyl chitosan nanoparticles had greater potential than chitosan nanoparticles for further analysis as a magnetically targeted therapy agent for lung cancer.

Keywords

chitosan, trimethyl chitosan, gemcitabine, magnetic nanoparticle, drug delivery system, lung cancer

References

• 1. Polnok A, Borchard G, Verhoef JC, Sarisuta N, Junginger HE. Influence of methylation process on the degree of quaternization of N-trimethyl chitosan chloride. Eur J Pharm Biopharm 2004;57:77–83. [CrossRef]
• 2. Verheul RJ, Amidi M, Van der Wal S, van Riet E, Jiskoot W, Hennink WE. Synthesis, characterization and in vitro biological properties of O-methyl free N, N, N-trimethylated chitosan. Biomaterials 2008;29:3642–3649. [CrossRef]
• 3. Sandri G, Bonferoni MC, Rossi S, et al. Nanoparticles based on N-trimethylchitosan: Evaluation of absorption properties using in vitro (Caco-2 cells) and ex vivo (excised rat jejunum) models. Eur J Pharm Biopharm 2007;65:68–77. [CrossRef]
• 4. Kulkarni AD, Patel HM, Surana SJ, Vanjari YH, Belgamwar VS, Pardeshi CV. N, N, N-Trimethyl chitosan: An advanced polymer with myriad of opportunities in nanomedicine. Carbohydrate Polymers 2016;157:875–902. https://doi.org/10.1016/j.carbpol.2016.10.041
• 5. Alvarellos ML, Lamba J, Sangkuhl K, et al. PharmGKB summary; Gemcitabine Pathway. Pharmacogenet Genomics 2014;24:564–574. [CrossRef]
• 6. Doğaç Yİ, Teke M. Immobılızatıon of bovıne catalase onto magnetıc nanopartıcles. Prep Biochem Biotechnol 2013;43:750–765. [CrossRef]
• 7. Amidi M, Romeijn SG, Borchard G, Junginger HE, Hennink WE, Jiskoot W. Preparation and characterization of protein-loaded N-trimethyl chitosan nanoparticles as nasal delivery system. J Control Release 2006;111:107–116. [CrossRef]
• 8. Mourya VK, Inamdar NN. Trimethyl chitosan and its applications in drug delivery. J Mater Sci Mater Med 2008;20:1057–1079. [CrossRef]
• 9. Chen F, Zhang ZR, Yuan F, Qin X, Wang M, Huang Y. In vitro and in vivo study of N-trimethyl chitosan nanoparticles for oral protein delivery. Int J Pharm 2008;349:226–233. [CrossRef]
• 10. Bulmer C, Margaritis A, Xenocostas A. Production and characterization of novel chitosan nanoparticles for controlled release of rHuErythropoietin. Biochem Eng J 2012;68:61–69. [CrossRef]
• 11. Garg NK, Dwivedi P, Campbell C, Tyagi RK. Site specific/targeted delivery of gemcitabine through anisamide anchored chitosan/ poly ethylene glycol nanoparticles: An understanding of lung cancer therapeutic intervention. Eur J Pharm Sci 2012;47:1006–1014. [CrossRef]
• 12. Derakhshandeh K, Fathi S. Role of chitosan nanoparticles in the oral absorption of Gemcitabine. Int J Pharm 2012;437:172–177. [CrossRef]
• 13. Hamarat Şanlıer Ş, Ak G, Yılmaz H, et al. Development of ultrasoundtriggered and magnetic-targeted nanobubble system for dual-drug delivery. J Pharm Sci 2019;108:1272–1283. [CrossRef]
• 14. Ak G, Yılmaz H, Hamarat Sanlıer S. Preparation of magnetically responsive albumin nanospheres and in vitro drug release studies. Artif Cells Nanomed Biotechnol 2014;42:18–26. [CrossRef]
• 15. Selvi Gunel N, Ozel B, Kipcak S, et al. Synthesis of methotrexate loaded chitosan nanoparticles and in vitro evaluation of the potential in treatment of prostate cancer. Anticancer Agents Med Chem 2016;16:1038–1042. [CrossRef]
• 16. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol 2006;17:v7–v12. [CrossRef]
• 17. Banerjee S, Zhang Y, Ali S, et al. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res 2005;65:9064–9072. [CrossRef]
• 18. Nitsch E, Mina S, Brammer I, et al. Synergistic cytotoxic activity of treosulfan and gemcitabine in pancreatic cancer cell lines. Anticancer Res 2014;34:1779–1784. http://ar.iiarjournals.org/ content/34/4/1779.long
• 19. Boonyo W, Junginger HE, Waranuch N, Polnok A, Pitaksuteepong T. Preparation and characterization of particles from chitosan with different molecular weights and their trimethyl chitosan derivatives for nasal immunization. J Miner Met Mater Eng 2008;18:59–65. https://www.researchgate.net/publication/237688697_Preparation_ and_Characterization_of_Particles_from_Chitosan_with_Different_ Molecular_Weights_and_Their_Trimethyl_Chitosan_Derivatives_for_ Nasal_Immunization
• 20. Mourya VK, Inamdar NN. Chitosan-modifications and applications: Opportunities galore. React Funct Polym 2008;68:1013–1051. [CrossRef]
• 21. Rampino A, Borgogna M, Blasi P, Bellich B, Cesàroa A. Chitosan nanoparticles: Preparation, size evolution and stability. Int J Pharm 2013;455:219–228. [CrossRef]
• 22. Zhao H, Saatchi K, Hafeli UO. Preparation of biodegradable magnetic microspheres with poly (lactic acid)-coated magnetite J Magn Magn Mater 2009;321:1356–1363. [CrossRef]
• 23. Xu J, Xu B, Shou D, Xia X, Hu Y. Preparation and evaluation of vancomycin-loaded n-trimethyl chitosan nanoparticles. Polymers 2015;7:1850–1870. [CrossRef]
• 24. Zheng Y, Cai Z, Song X, Chen Q, Bi Y, Li Y, Hou S. Preparation and characterization of folate conjugated N-trimethyl chitosan nanoparticles as protein carrier targeting folate receptor: in vitro studies. J Drug Target 2009;17:294–303. [CrossRef]
• 25. Arias JL, Reddy LH, Couvreur P. Fe3O4/chitosan nanocomposite for magnetic drug targeting to cancer. J Mater Chem B 2012;22:7622. [CrossRef]
• 26. Ak G, Yilmaz H, Güneş A, Hamarat Sanlier S. In vitro and in vivo evaluation of folate receptor-targeted a novel magnetic drug delivery system for ovarian cancer therapy. Artif Cells Nanomed Biotechnol 2018;46:926–937. [CrossRef]
• 27. Xu Y, Du Y. Effect of molecular structure of chitosan on protein delivery properties of chitosan nanoparticles. Int J Pharm 2013;250:215–226. [CrossRef]
• 28. Arya G, Vandana M, Acharya S, Sahoo SK. Enhanced antiproliferative activity of Herceptin (HER2)-conjugated gemcitabine-loaded chitosan nanoparticle in pancreatic cancer therapy. Nanomedicine 2011;7:859–870. [CrossRef]
• 29. Lin J, Wang S, Su ZF, Yuan Y. Synergistic effects of sorafenib in combination with gemcitabine or pemetrexed in lung cancer cell lines with K-ras mutations. Contemp Oncol (Pozn) 2016;20:33–38. [CrossRef]