Using Inorganic Nanoparticle-Based Drug Delivery Systems against Human Colon Cancer Cells: Effect of Particle Size on Anticancer Activity

Öz

Today’s nanoparticle technology enables the synthesis of nanoparticle-based drug delivery systems with desired size, shape, and materials especially for the applications of cancer nanomedicine. Thereby, understanding impact of particle sizes on anticancer activity will contribute to development of new drug delivery systems in cancer therapy. For this reason, in this study, two different sized nanoparticles (with ~55 and 314 nm) were used as drug delivery systems and the effects of their size on the cellular uptake, cytotoxicity and apoptosis were investigated against the human colon carcinoma Caco-2 and HCT-116 cells. The results demonstrated that small nanoparticles promoted fast nanoparticle accumulation in both cancer cells in comparison to large particles. Small nanoparticles exhibited higher cytotoxicity in cancer cells with lower half maximal inhibitory concentration (IC₅₀) values than large nanoparticles in 48 h. On the other hand, both nanoparticles showed similar IC₅₀ values after 72 h prolonged exposure. Moreover, it was found that small nanoparticles increased the number of apoptotic cells in 24 h, whereas large nanoparticles induced apoptosis when exposure time increased to 72 h. These observations show that small sized drug delivery systems could be more efficient for improving the anticancer effects of chemotherapeutic drugs against human colon carcinoma as compared to large sized drug delivery systems.

Anahtar Kelimeler

• Drug delivery systems,particle size,colon cancer,Caco-2 cells,HCT-116 cells

İnsan Kolon Kanseri Hücrelerine Karşı İnorganik Nanopartikül-Temelli İlaç Taşıyıcı Sistemlerin Kullanılması: Partikül Büyüklüğünün Antikanser Aktivitesine Etkisi

Öz

Günümüz nanopartikül teknolojisi, özellikle kanser nanotıp uygulamalarında kullanılmak üzere istenilen boyut, şekil ve malzemeye sahip nanopartikül-temelli ilaç taşıyıcı sistemlerinin sentezine olanak sağlamaktadır. Dolayısıyla, partikül boyutlarının antikanser aktivite üzerindeki etkisini anlamak, kanser tedavisinde yeni ilaç taşıyıcı sistemlerin geliştirilmesine katkıda bulunacaktır. Bu nedenle, bu çalışmada, ilaç taşıyıcı sistemler olarak iki farklı büyüklükteki inorganik temelli nanopartiküller (~ 55 ve 314 nm) kullanıldı ve boyutlarının hücresel birikim, sitotoksisite ve apoptoz üzerindeki etkileri insan kolon kanseri Caco-2 ve HCT-116 hücrelerine karşı araştırıldı. Elde edilen sonuçlar, büyük nanopartiküllerle karşılaştırıldığında küçük nanopartiküllerin her iki kanser hücresinde de hızlı nanopartikül birikimini desteklediğini gösterdi. Küçük nanopartiküller, büyük nanopartiküllere göre 48 saat içinde daha düşük yarı-maksimum inhibisyon konsantrasyonu (IC₅₀) değerleri ile kanser hücrelerinde daha yüksek sitotoksisite sergiledi. Öte yandan, her iki nanopartikül de 72 saate varan inkübasyon süreleri sonrası benzer IC₅₀ değerleri gösterdi. Ayrıca, küçük nanopartiküller 24 saatte apoptotik hücrelerin sayısını artırırken, büyük nanopartiküllerin 72 saatlik süre içerisinde apoptozu indüklediği belirlendi. Bu gözlemler, küçük boyutlu ilaç taşıma sistemlerinin, büyük boyutlu ilaç taşıma sistemleri ile karşılaştırıldığında, insan kolon kanseri hücrelerinde kemoterapötik ilaçların antikanser etkilerini artırmada daha verimli olduğunu göstermektedir.

Anahtar Kelimeler

• İlaç taşıma sistemleri,partikül boyutu,kolon kanseri,Caco-2 hücreleri,HCT-116 hücreleri

Kaynakça

1. [1] Müller R. H, Jacobs C. and Kayser O., “Nanosuspensions as particulate drug formulations in therapy: Rationale for development and what we can expect for the future”, Adv Drug Deliv Rev., 47: 3–19, (2001)[2] Jaracz S., Chen J., Kuznetsova L. V. and Ojima I., “Recent advances in tumor-targeting anticancer drug conjugates”, Bioorg. Med. Chem., 13: 5043–5054, (2005) [3] Müller R. H. and Peters K., “Nanosuspensions for the formulation of poorly soluble drugs: I. Preparation by a size-reduction technique”, Int J Pharm., 160: 229–237, (1998)[4] Rizzo L. Y., Theek B., Storm G., Kiessling F. and Lammers T., “Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications”, Curr. Opin. Biotechnol., 24: 1159–1166, (2013)[5] Shapira A., Livney Y. D., Broxterman H. J. and Assaraf Y. G., “Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance”, Drug Resist Updat., 14: 150–163, (2011)[6] Sun C., Lee J. S. and Zhang M., “Magnetic nanoparticles in MR imaging and drug delivery”, Adv Drug Deliv Rev., 60: 1252–1265, (2008)[7] Park J. H., von Maltzahn G., Ruoslahti E., Bhatia S. N. and Sailor M. J., “Micellar hybrid nanoparticles for simultaneous magneto-fluorescent imaging and drug delivery”, Angew Chem Int Ed Engl., 47: 7284−7288, (2008)[8] Sykes E. A., Chen J., Zheng G. and Chan W. C., “Investigating the Impact of Nanoparticle Size on Active and Passive Tumor Targeting Efficiency”, ACS Nano., 8: 5696−706, (2014)[9] Danhier F., Feron O. and Préat V., “To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery”, J. Control. Release, 148: 135–146, (2010)[10] Laurent S., Forge D., Port M., Roch A., Robic C., Elst L. V. and Muller R. N., “Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications”, Chem. Rev., 108: 2064–2110, (2008)[11] Uchiyama K., Nagayasu A., Yamagiwa Y., Nishida T., Harashima H. and Kiwada H., “Effects of the size and fluidity of liposomes on their accumulation in tumors: A presumption of their interaction with tumors”, Int. J. Pharm., 121: 195–203, (1995)[12] Nagayasu A., Shimooka T., Kinouchi Y., Uchiyama K., Takeichi Y. and Kiwada H., “Effects of fluidity and vesicle size on antitumor activity and myelosuppressive activity of liposomes loaded with daunorubicin”, Biol Pharm Bull., 17: 935–939, (1994)[13] Nagayasu A., Uchiyama K. and Kiwada H., “The size of liposomes: a factor which affects their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs”, Adv Drug Deliv Rev., 40: 75–87, (1999)[14] Gao J. H., Gu H. W. and Xu B., “Multifunctional magnetic nanoparticles: design, synthesis, and biomedical applications”, Acc. Chem. Res., 42: 1097−1107, (2009)[15] Lee J. E., Lee N., Kim H., Kim J., Choi S. H., Kim J. H., Kim T., Song I. C., Park S. P., Moon W. K. and Hyeon T., “Uniform mesoporous dye-doped silica nanoparticles decorated with multiple magnetite nanocrystals for simultaneous enhanced magnetic resonance imaging, fluorescence imaging, and drug delivery”, J. Am. Chem. Soc., 132: 552−557, (2010)[16] Daglioglu C. and Okutucu B., “Synthesis and characterization of AICAR and DOX conjugated multifunctional nanoparticles as a platform for synergistic inhibition of cancer cell growth”, Bioconjug. Chem., 27: 1098−1111, (2016) [17] Daglioglu C., “Enhancing tumor cell response to multidrug resistance with pH-sensitive quercetin and doxorubicin conjugated multifunctional nanoparticles”, Colloids Surf. B Biointerfaces, 156: 175–185, (2017)[18] Daglioglu C., “Environmentally responsive dual-targeting nanoparticles: improving drug accumulation in cancer cells as a way of preventing anticancer drug efflux”, J. Pharma. Sci., 107: 934-941, (2018)[19] Russell-Jones G., McTavish K., McEwan J., Rice J. and Nowotnik D., “Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumors”, J. Inorg. Biochem., 98: 1625–1633, (2004)[20] Daglioglu C. and Okutucu B., “Therapeutic effects of AICAR and DOX conjugated multifunctional nanoparticles in sensitization and elimination of cancer cells via survivin targeting”, Pharm. Res., 34: 175−84, (2017)[21] Daglioglu C., “İlaç Taşıma Sistemleri olarak Nanopartiküller kullanılarak Pasif ve Aktif Tümör Hedeflemelerinin Karşılaştırmalı İncelenmesi”, Akademik Platform Mühendislik ve Fen Bilimleri Dergisi, 6: 01-07, (2018)