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Pharmacokinetic and biodistribution studies of doxorubicin-loaded single-wall carbon nanohorns in mice

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Abstract

Pharmacokinetic and biodistribution studies of doxorubicin-loaded carbon nanohorns (DOX@oxSWCNHs/SA) in plasma and tissues were carried out. A high-performance liquid chromatographic method was developed and validated to determine the amount of doxorubicin. Compared with free DOX, the half-life (t 1/2) of DOX@oxSWCNHs/SA was increased from 5.44 ± 1.09 to 7.38 ± 0.98 h, area under plasma concentration–time curve (AUC0–∞) was increased from 0.63 ± 0.008 to 1.42 ± 0.12 μg/(ml h), and the clearance of DOX was declined from 634 ± 10.05 to 280 ± 24.06 ml/h. No DOX was detected in heart after intravenous injection with DOX@oxSWCNHs/SA, while higher concentrations of drug were found in other tissues. These results suggested that DOX@oxSWCNHs/SA had the potential to obtain a long retention time in blood, sustained drug release, and a low toxicity, especially low cardiotoxicity.

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References

  • Ajima K, Yudasaka M, Murakami T, Maigné A, Shiba K, Iijima S (2005) Carbon nanohorns as anticancer drug carriers. Mol Pharm 2(6):475–480

    Article  Google Scholar 

  • Alhareth K, Vauthier C, Bourasset F, Gueutin C, Ponchel G, Moussa F (2012a) Conformation of surface-decorating dextran chains affects the pharmacokinetics and biodistribution of doxorubicin-loaded nanoparticles. Eur J Pharm Biopharm 81(2):453–457

    Article  Google Scholar 

  • Alhareth K, Vauthier C, Gueutin C, Ponchel G, Moussa F (2012b) HPLC quantification of doxorubicin in plasma and tissues of rats treated with doxorubicin loaded poly (alkylcyanoacrylate) nanoparticles. J Chromatogr B 887:128–132

    Article  Google Scholar 

  • Al-Jamal KT, Nunes A, Methven L, Ali-Boucetta H, Li S, Toma FM, Herrero MA, Al-Jamal WT, ten Eikelder HM, Foster J (2012) Degree of chemical functionalization of carbon nanotubes determines tissue distribution and excretion profile. Angew Chem Int Edit 51(26):6389–6393

    Article  Google Scholar 

  • Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter 1. Annu Rev Pharmacol Toxicol 39(1):361–398

    Article  Google Scholar 

  • AssumpçãO JUCV, Campos ML, Nogueira Filho F, Antonio M, Pestana KC, Baldan HM, Formariz Pilon TP, de Oliveira AG, Peccinini RG (2013) Biocompatible microemulsion modifies the pharmacokinetic profile and cardiotoxicity of doxorubicin. J Pharm Sci 102(1):289–296

    Article  Google Scholar 

  • Barpe DR, Rosa DD, Froehlich PE (2010) Pharmacokinetic evaluation of doxorubicin plasma levels in normal and overweight patients with breast cancer and simulation of dose adjustment by different indexes of body mass. Eur J Pharm Sci 41(3):458–463

    Article  Google Scholar 

  • Bekyarova E, Kaneko K, Kasuya D, Murata K, Yudasaka M, Iijima S (2002) Oxidation and porosity evaluation of budlike single-wall carbon nanohorn aggregates. Langmuir 18(10):4138–4141

    Article  Google Scholar 

  • Bekyarova E, Kaneko K, Yudasaka M, Kasuya D, Iijima S, Huidobro A, Rodriguez-Reinoso F (2003) Controlled opening of single-wall carbon nanohorns by heat treatment in carbon dioxide. J Phys Chem B 107(19):4479–4484

    Article  Google Scholar 

  • Booser DJ, Hortobagyi GN (1994) Anthracycline antibiotics in cancer therapy. Drugs 47(2):223–258

    Article  Google Scholar 

  • Carvalho C, Santos RX, Cardoso S, Correia S, Oliveira PJ, Santos MS, Moreira PI (2009) Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem 16(25):3267–3285

    Article  Google Scholar 

  • Charrois GJ, Allen TM (2004) Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. BBA-Biomembranes 1663(1):167–177

    Article  Google Scholar 

  • Gabizon A, Isacson R, Rosengarten O, Tzemach D, Shmeeda H, Sapir R (2008) An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin. Cancer Chemother Pharmacol 61(4):695–702

    Article  Google Scholar 

  • Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ (2001) Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19(14):3312–3322

    Google Scholar 

  • Heldin C-H, Rubin K, Pietras K, Östman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 4(10):806–813

    Article  Google Scholar 

  • Horie M, Komaba LK, Fukui H, Kato H, Endoh S, Nakamura A, Miyauchi A, Maru J, Miyako E, Fujita K (2013) Evaluation of the biological influence of a stable carbon nanohorn dispersion. Carbon 54:155–167

    Article  Google Scholar 

  • Hu T, Le Q, Wu Z, Wu W (2007) Determination of doxorubicin in rabbit ocular tissues and pharmacokinetics after intravitreal injection of a single dose of doxorubicin-loaded poly-β-hydroxybutyrate microspheres. J Pharm Biomed Anal 43(1):263–269

    Article  Google Scholar 

  • Huang W, Zhang J, Dorn HC, Zhang C (2013) Assembly of bio-nanoparticles for double controlled drug release. PLoS One 8(9):e74679

    Article  Google Scholar 

  • Iijima S, Yudasaka M, Yamada R, Bandow S, Suenaga K, Kokai F, Takahashi K (1999) Nano-aggregates of single-walled graphitic carbon nano-horns. Chem Phys Lett 309(3):165–170

    Article  Google Scholar 

  • Iwamoto T (2013) Clinical application of drug delivery systems in cancer chemotherapy: review of the efficacy and side effects of approved drugs. Biol Pharm Bull 36(5):715–718

    Article  Google Scholar 

  • Jain D (2000) Cardiotoxicity of doxorubicin and other anthracycline derivatives. J Nucl Cardiol 7(1):53–62

    Article  Google Scholar 

  • Kümmerle A, Krueger T, Dusmet M, Vallet C, Pan Y, Ris H, Decosterd LA (2003) A validated assay for measuring doxorubicin in biological fluids and tissues in an isolated lung perfusion model: matrix effect and heparin interference strongly influence doxorubicin measurements. J Pharm Biomed 33(3):475–494

    Article  Google Scholar 

  • Laginha KM, Verwoert S, Charrois GJ, Allen TM (2005) Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer tumors. Clin Cancer Res 11(19):6944–6949

    Article  Google Scholar 

  • Li N, Zhao Q, Shu C, Ma X, Li R, Shen H, Zhong W (2015) Targeted killing of cancer cells in vivo and in vitro with IGF-IR antibody-directed carbon nanohorns based drug delivery. Int J Pharm 478(2):644–654

    Article  Google Scholar 

  • Lin J, Shigdar S, Fang DZ, Xiang D, Wei MQ, Danks A, Kong L, Li L, Qiao L, Duan W (2014) Improved efficacy and reduced toxicity of doxorubicin encapsulated in sulfatide-containing nanoliposome in a glioma model. PLoS One 9(7):1–13

    Google Scholar 

  • Liu Z, Davis C, Cai W, He L, Chen X, Dai H (2008) Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. Proc Natl Acad Sci USA 105(5):1410–1415

    Article  Google Scholar 

  • Liu Z, Fan AC, Rakhra K, Sherlock S, Goodwin A, Chen X, Yang Q, Felsher DW, Dai H (2009) Supramolecular stacking of doxorubicin on carbon nanotubes for in vivo cancer therapy. Angew Chem Int Edit 48(41):7668–7672

    Article  Google Scholar 

  • Liu H, Xu H, Wang Y, He Z, Li S (2012) Effect of intratumoral injection on the biodistribution and therapeutic potential of novel chemophor EL-modified single-walled nanotube loading doxorubicin. Drug Dev Ind Pharm 38(9):1031–1038

    Article  Google Scholar 

  • Ma X, Shu C, Guo J, Pang L, Su L, Fu D, Zhong W (2014) Targeted cancer therapy based on single-wall carbon nanohorns with doxorubicin in vitro and in vivo. J Nanopart Res 16(7):1–14

    Article  Google Scholar 

  • Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65(1):271–284

    Article  Google Scholar 

  • Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12 Part 1):6387–6392

    Google Scholar 

  • Miyawaki J, Yudasaka M, Azami T, Kubo Y, Iijima S (2008) Toxicity of single-walled carbon nanohorns. ACS Nano 2(2):213–226

    Article  Google Scholar 

  • Miyawaki J, Matsumura S, Yuge R, Murakami T, Sato S, Tomida A, Tsuruo T, Ichihashi T, Fujinami T, Irie H (2009) Biodistribution and ultrastructural localization of single-walled carbon nanohorns determined in vivo with embedded Gd2O3 labels. ACS Nano 3(6):1399–1406

    Article  Google Scholar 

  • Murakami T, Sawada H, Tamura G, Yudasaka M, Iijima S, Tsuchida K (2008) Water-dispersed single-wall carbon nanohorns as drug carriers for local cancer chemotherapy. Nanomedicine 3(4):453–463

    Article  Google Scholar 

  • Murata K, Kaneko K, Steele W, Kokai F, Takahashi K, Kasuya D, Yudasaka M, Iijima S (2001) Porosity evaluation of intrinsic intraparticle nanopores of single wall carbon nanohorn. Nano Lett 1(4):197–199

    Article  Google Scholar 

  • Nakamura M, Tahara Y, Ikehara Y, Murakami T, Tsuchida K, Iijima S, Waga I, Yudasaka M (2011) Single-walled carbon nanohorns as drug carriers: adsorption of prednisolone and anti-inflammatory effects on arthritis. Nanotechnology 22(46):465102

    Article  Google Scholar 

  • Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL (2012) Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 52(6):1213–1225

    Article  Google Scholar 

  • Ogura M (2001) Adriamycin (doxorubicin). Gan to kagaku ryoho Cancer Chemother 28(10):1331–1338

    Google Scholar 

  • Patel NR, Pattni BS, Abouzeid AH, Torchilin VP (2013) Nanopreparations to overcome multidrug resistance in cancer. Adv Drug Deliv Rev 65(13):1748–1762

    Article  Google Scholar 

  • Sharma R, Tobin P, Clarke SJ (2005) Management of chemotherapy-induced nausea, vomiting, oral mucositis, and diarrhoea. Lancet Oncol 6(2):93–102

    Article  Google Scholar 

  • Tahara Y, Miyawaki J, Zhang M, Yang M, Waga I, Iijima S, Irie H, Yudasaka M (2011) Histological assessments for toxicity and functionalization-dependent biodistribution of carbon nanohorns. Nanotechnology 22(26):265106–265113

    Article  Google Scholar 

  • Urva SR, Shin BS, Yang VC, Balthasar JP (2009) Sensitive high performance liquid chromatographic assay for assessment of doxorubicin pharmacokinetics in mouse plasma and tissues. J Chromatogr B 877(8):837–841

    Article  Google Scholar 

  • Wang J, Hu Z, Xu J, Zhao Y (2014) Therapeutic applications of low-toxicity spherical nanocarbon materials. NPG Asia Mater 6(2):e84

    Article  Google Scholar 

  • Waterhouse DN, Tardi PG, Mayer LD, Bally MB (2001) A comparison of liposomal formulations of doxorubicin with drug administered in free form. Drug Saf 24(12):903–920

    Article  Google Scholar 

  • Wu W, Li R, Bian X, Zhu Z, Ding D, Li X, Jia Z, Jiang X, Hu Y (2009) Covalently combining carbon nanotubes with anticancer agent: preparation and antitumor activity. ACS Nano 3(9):2740–2750

    Article  Google Scholar 

  • Yamashita T, Yamashita K, Nabeshi H, Yoshikawa T, Yoshioka Y, S-i Tsunoda, Tsutsumi Y (2012) Carbon nanomaterials: efficacy and safety for nanomedicine. Materials 5(2):350–363

    Article  Google Scholar 

  • Yang S-t, Guo W, Lin Y, Deng X-y, Wang H-f, Sun H-f, Liu Y-f, Wang X, Wang W, Chen M (2007) Biodistribution of pristine single-walled carbon nanotubes in vivo. J Phys Chem C 111(48):17761–17764

    Article  Google Scholar 

  • Zamboni WC (2005) Liposomal, nanoparticle, and conjugated formulations of anticancer agents. Clin Cancer Res 11(23):8230–8234

    Article  Google Scholar 

  • Zamboni WC (2008) Concept and clinical evaluation of carrier-mediated anticancer agents. Oncologist 13(3):248–260

    Article  Google Scholar 

  • Zhang Y, Huo M, Zhou J, Xie S (2010) PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed 99(3):306–314

    Article  Google Scholar 

  • Zhang M, Yamaguchi T, Iijima S, Yudasaka M (2013) Size-dependent biodistribution of carbon nanohorns in vivo. Nanomed-Nanotechnol 9(5):657–664

    Article  Google Scholar 

  • Zhang M, Tahara Y, Yang M, Zhou X, Iijima S, Yudasaka M (2014) Quantification of whole body and excreted carbon nanohorns intravenously injected into mice. Adv Healthc Mater 3(2):239–244

    Article  Google Scholar 

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Acknowledgments

The work was funded by the National Natural Science Foundation of China (No. 81173023) and supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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    Authors and Affiliations

    1. Department of Analytical Chemistry, China Pharmaceutical University, Nanjing, People’s Republic of China

      Junling Wang, Chang Shu, Nannan Li, Qian Zhao, Ran Wang & Wenying Zhong

    2. Key Laboratory of Integrated Regulation and Resource Development on Shallow Lakes of Ministry of Education, College of Environment, Hohai University, Nanjing, 210098, People’s Republic of China

      Xiaona Ma

    3. Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China

      Wenying Zhong

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    1. Junling Wang
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    2. Xiaona Ma
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    Correspondence to Wenying Zhong.

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    Junling Wang and Xiaona Ma have contributed equally to this work.

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    Wang, J., Ma, X., Shu, C. et al. Pharmacokinetic and biodistribution studies of doxorubicin-loaded single-wall carbon nanohorns in mice. J Nanopart Res 17, 384 (2015). https://doi.org/10.1007/s11051-015-3184-1

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