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Cytotoxicity of doxrubicin loaded single-walled carbon nanotubes

Abstract

Carbon nanotube (CNTs) is a new alternative for efficient drug delivery and it has a great potential to change drug delivery system profile in pharmaceutical industry. One of the important advantage of CNTs is their needle-like, cylindrical shape. This shape provides a high surface area for multiple connections and adsorption onto for millions of therapeutic molecules. CNTs can be internalized by cells via endocytosis, passive diffusion and phagocytosis and release the drug with different effects like pH and temperature. The acidic nature of cancer cells and the susceptibility of CNTs to release the drug in the acidic environment have made it a promising area of research in cancer drug delivery. In this research, we investigated cell viability, cytotoxicity and drug delivery in breast cancer cell line by designing non-covalent single walled carbon nanotubes (SWNT)–doxorubicin (DOX) supramolecular complex that can be developed for cancer therapy. Applied high concentrations of DOX loaded SWNTs changed the actin structure of the cells and prevented the proliferation of the cells. It was showed that doxorubicin loaded SWNTs were more effective than free doxorubicin at relatively small concentrations. Once we applied same procedure for short and long (short: 1–1.3 µm; long: 2.5–4 µm) SWNTs and compared the results, more disrupted cell structure and reduction in cell proliferation were observed for long CNTs. DOX is bounded more to nanotubes in basic medium, less bound in acidic environment. Cancer cells were also examined for concentration at which they were effective by applying DOX and it was seen that 3.68 µM doxorubicin kills more than 55% of the cells.

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References

  1. Meyya M (2004) Carbon nanotubes: science and applications. CRC Press, Boca Raton, pp 16–20

    Google Scholar 

  2. Kannan B, Marko B (2005) Chemically functionalized carbon nanotubes. Small 1(2):180–192

    Article  CAS  Google Scholar 

  3. Rick A, Tracie B, Louise AB, Stacey F, Rachel AF, Ted G, Mia MG, Joan K, Chun Chieh L, Marji M, Kimberly M, Lisa AN, Dearell N, Anthony P, Cheri R, Ann GS, Scott S, Robert S, Dana W, Jiaquan X (2015) Breast cancer facts & figures. American Cancer Society, Atlanta, pp 1–6

    Google Scholar 

  4. Liming D, Mau AWH (2001) Controlled synthesis and modification of carbon nanotubes and C60: carbon nanostructures for advanced polymeric composite materials. Adv Mater 13:899–913

    Article  Google Scholar 

  5. Jin Z, Hongling Z, Quan Q, Yanlian Y, Qingwen L, Zhongfan L, Xinyong G (2003) Effect of chemical oxidation on structure of single-walled carbon nanotubes. J Phys Chem B 107(16):3712–3718

    Article  CAS  Google Scholar 

  6. Sun UL, Bong GC, Won HH (2013) Simple fabrication of exfoliated graphene/nafion hybrid as glucose bio-sensor electrodes. IFMBE Proc 40:54–56

    Google Scholar 

  7. Jing K, Nathan RF, Chongwu Z, Michael GC, Shu P, Kyeongjae C, Hongjie D (2000) Nanotube molecular wires as chemical sensors. Science 287:622–625

    Article  Google Scholar 

  8. Philip GC, Keith B, Masa I, Zettl A (2000) Extreme oxygen sensitivity of electronic properties of carbon nanotubes. Science 287:1801–1804

    Article  Google Scholar 

  9. Jing K, Hongjie D (2001) Full and modulated chemical gating of individual carbon nanotubes by organic amine compounds. J Phys Chem B 105:2890–2893

    Google Scholar 

  10. Nozomi N, Sarunya B, Xiaoming S, Kevin W, Hongjie D (2007) Noncovalent Functionalization of carbon nanotubes by fluorescein-polyethylene glycol: supramolecular conjugates with pH-dependent absorbance and fluorescence. J Am Chem Soc 129(9):2448–2449

    Article  CAS  Google Scholar 

  11. Ke L, Hao L, Wei G, Mu C, Yun Z, Jiajun L, Liang X, Daocheng W (2015) Mulberry-like dual-drug complicated nanocarriers assembled with apogossypolone amphiphilic starch micelles and doxorubicin hyaluronic acid nanoparticles for tumor combination and targeted therapy. Biomaterials 39:131–144

    Article  CAS  Google Scholar 

  12. Fuyin Z, Shige W, Mingwu S, Meifang Z, Xiangyang S (2013) Antitumor efficacy of doxorubicin-loaded electrospun nano-hydroxyapatite-poly(lactic-co-glycolic acid) composite nanofibers. Polym Chem 4(4):933–941

    Article  Google Scholar 

  13. Robert JM, James HD, Kalyanasundaram V, Karen C, James R, George S, Lucille L, Merry T, Stephen S, Victor H, Kim M, Stephen F, Steven A, Paul C, Chul A, Lawrence W, Uday G, Jonathan H (1997) High-dose infusional doxorubicin and cyclophosphamide: a feasibility study of tandem high-dose chemotherapy cycles without stem cell support. Clin Cancer Res 3:2337–2345

    Google Scholar 

  14. Suming C, Caiqiao X, Huihui L, Qiongqiong W, Jian H, Qing H, Abraham B, Zongxiu N (2015) Mass spectrometry imaging reveals the sub-organ distribution of carbon nanomaterials. Nat Nanotechnol 10:176–182

    Article  CAS  Google Scholar 

  15. Zhaung L, Xiaoming S, Nozomi N-R, Hongjie D (2007) Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery. ACS Nano 1(1):50–56

    Article  CAS  Google Scholar 

  16. Safarova K, Dvorak A, Kubinek R, Vujtek M, Rek A (2007) Usage of AFM, SEM and TEM for the research of carbon nanotubes. Mod Res Educ Top Microsc 513–519

  17. Zhuang L, Xiaoming S, Nakayama-Ratchford N, Dai H (2007) Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery. ACS Nano 1(1):50–56

    Article  CAS  Google Scholar 

  18. Türker Şener L, Albeni̇z G, Di̇nç B, Albeni̇z I (2017) iCELLigence real time cell analysis system for examining the cytotoxicity of drugs to cancer cell lines. Exp Ther Med 14(3):1866–1870

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bektaş M, Hacıosmanoğlu E, Özerman Edis B, Varol B, Nurten R, Bermek E (2011) On diphtheria toxin fragment A release into the cytosol—Cytochalasin D effect and involvement of actin filaments and eukaryotic elongation factor 2. Int J Biochem Cell Biol 43:1365–1372

    Article  PubMed  CAS  Google Scholar 

  20. Claudia M, Markus A, Eva R, Eleonore F (2013) Suitability of cell-based label-free detection for cytotoxicity screening of carbon nanotubes. BioMed Res Int 564804:13

    Google Scholar 

  21. Pilco-Ferreto N, Pilco-Ferreto N (2016) Influence of doxorubicin on apoptosis and oxidative stress in breast cancer cell lines. Int J Oncol 49:753–762

    Article  PubMed  CAS  Google Scholar 

  22. Sinha BK, Mimnaugh EG, Rajagopalan S, Myers CE (1989) Adriamycin activation and oxygen free radical formation in human breast tumor cells: protective role of glutathione peroxidase in adriamycin resistance. Cancer Res 49:3844–3848

    PubMed  CAS  Google Scholar 

  23. Zongbin L, Yeonju L, Joon HJ, Yin L, Xin H, Kenji Y, Mauro F, Ledu Z, Lidong Q (2015) Microfluidic cytometric analysis of cancer cell transportability and invasiveness. Sci Rep 5:14272

    Article  CAS  Google Scholar 

  24. Nahid MD, Fatemeh A, Mohammad-Reza R, Mohsen A, Ali-Akbar G, Rassoul D (2014) Doxorubicin loaded folate-targeted carbon nanotubes: preparation, cellular internalization, in vitro cytotoxicity and disposition kinetic study in the isolated perfused rat liver. Mater Sci Eng C 39:47–55

    Article  CAS  Google Scholar 

  25. Shixian L, Zhaohui T, Mingqiang L, Jian L, Wantong S, Huaiyu L, Yubin H, Yuanyuan Z, Xuesi C (2014) Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer. Biomaterials 35:6118–6129

    Article  CAS  Google Scholar 

  26. Heister E, Neves V, Tîlmaciu C, Lipert K, Beltrán VS, Coley HM, Silva SRP, McFadden J (2009) Triple functionalisation of single-walled carbon nanotubes with doxorubicin, a monoclonal antibody, and a fluorescent marker for targeted cancer therapy. Carbon 47:2152–2160

    Article  CAS  Google Scholar 

  27. Dan K, Christa M, Rebecca J, Charles PU, Simon JO, Elyce M, Catherine E, Angel E, Scott G (2015) Application of xCELLigence RTCA biosensor technology for revealing the profile and window of drug responsiveness in real time. Biosensors 5(2):199–222

    Article  CAS  Google Scholar 

  28. Donaldson et al (2010) Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Part Fibre Toxicol 7(5):1–7

    Google Scholar 

  29. Kostarelos K (2008) The long and short of nanotube toxicity. Nat Biotechnol 28(7):774–776

    Article  CAS  Google Scholar 

  30. Alan C, Maria D, Eva H, Fiona L, Hung B, Gordon C (2007) Probing the interaction of single-walled carbon nanotubes within cell culture medium as a precursor to toxicity testing. Carbon 45(1):34–40

    Article  CAS  Google Scholar 

  31. Alan C, Eva H, Maria D, Fiona L, Hung B, Gordon C (2007) Spectroscopic analysis confirms the interactions between single walled carbon nanotubes and various dyes commonly used to assess cytotoxicity. Carbon 45(7):1425–1432

    Article  CAS  Google Scholar 

  32. Robert HH, Marc M, Agnes K (2006) Toxicology of carbon nanomaterials: status, trends, and perspectives on the special issue. Carbon 44(6):1028–1033

    Article  CAS  Google Scholar 

  33. Nancy MR, Alfred OI (2005) Challenges for assessing carbon nanomaterial toxicity to the skin. Carbon 44:1070–1078

    Google Scholar 

  34. Worle-Knirsch JM, Pulskamp K, Krug HF (2006) Oops they did it again! Carbon nanotubes hoax scientists in viability assays. Nano Lett 6(6):1261–1268

    Article  PubMed  CAS  Google Scholar 

  35. Pilco-Ferreto N, Calaf GM (2016) Influence of doxorubicin on apoptosis and oxidative stress in breast cancer cell lines. Int J Oncol 49(2):753–762

    Article  PubMed  CAS  Google Scholar 

  36. Pichot CS, Hartig SM, Xia L, Arvanitis C, Monisvais D, Lee FY, Frost JA, Corey SJ (2009) Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Br J Cancer 101(1):38–47

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Chan KWY, Jiang L, Cheng M, Wijnen JP, Liu G, Huang P, Zijl PCM (2016) CEST-MRI detects metabolite levels altered by breast cancer cell aggressivenes and chemotherapy response. NMR Biomed 29:806–816

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Cheng M, Riwan A, Jiang L, Bhujwalla ZM, Glunde K (2017) Molecular effects of doxorubicin on choline metabolism in breast cancer. Neoplasia 19:617–627

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Correspondence to Ayhan Ünlü.

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Ayhan Ünlü, Mehdi Partovi Meran, Bircan Dinç, Nilgün Karatepe, Muhammet Bektaş, and Seniha Güner declare that they have no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Ünlü, A., Meran, M., Dinc, B. et al. Cytotoxicity of doxrubicin loaded single-walled carbon nanotubes. Mol Biol Rep 45, 523–531 (2018). https://doi.org/10.1007/s11033-018-4189-5

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  • DOI: https://doi.org/10.1007/s11033-018-4189-5

Keywords

  • Single-walled carbon nanotubes
  • Doxorubicin
  • Nanotechnology
  • Cytotoxicity
  • MDA-MB-231