Heart and Vessels

, Volume 34, Issue 3, pp 538–544 | Cite as

Accumulation of gold nano-rods in the failing heart of transgenic mice with the cardiac-specific expression of TNF-α

  • Yoshihiro HiguchiEmail author
  • Takuro Niidome
  • Yuji Miyamoto
  • Yoshihiro Komohara
  • Tomotake Tokunou
  • Toru Kubota
  • Takahiko Horiuchi
Original Article


Gold nano-rods, rod-shaped gold nanoparticles, act as contrast agents for in vivo bioimaging, drug delivery vehicles and thermal converters for photothermal therapy. Pro-inflammatory cytokines play critical roles in the development of heart failure. We examined the delivery of GNRs into the failing heart of a transgenic (TG) mouse model of inflammatory cardiomyopathy with the cardiac-specific overexpression of TNF-α. We modified GNRs with polyethylene glycol (PEG) to avoid cytotoxicity and reduce the rapid clearance of nanoparticles from blood. PEG-modified GNRs (4.5 mM as gold atoms, 200 μL) were administered intravenously to TG (n = 7) and wild-type (WT) mice (n = 5). These were killed 24 h later, and the heart, lung, liver, kidney and spleen were excised. A quantitative analysis of gold was performed using inductively coupled plasma mass or optical emission spectrometry. The amount of gold (ng) in the TG heart (3.24 ± 1.56 ng/mg heart weight) was significantly greater than that in the WT heart (1.01 ± 0.19; p < 0.05). No significant differences were observed among the other organs of TG and WT mice. The amount of gold in the TG heart was significantly and positively correlated with the ratio of the ventricular weight to body weight, which is known to be an index of ventricular hypertrophy. In conclusion, PEG-modified GNRs accumulated in the inflammatory TG heart in proportion with the severity of ventricular hypertrophy.


Gold nano-rod Heart failure Inflammation TNF-α 



The authors thank K. Tsuchida for her expert technical assistance.

Compliance with ethical standards

Ethical approval

All procedures performed in this study involving animals were in accordance with the ethical standards of our institution.

Conflict of interest

The authors declare no conflicts of interest in association with the present study.


  1. 1.
    Feldman AM, Combes A, Wagner D, Kadakomi T, Kubota T, Li YY, McTiernan C (2000) The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol 35:537–544CrossRefGoogle Scholar
  2. 2.
    Mann DL (2002) Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 91:988–998CrossRefGoogle Scholar
  3. 3.
    Higuchi Y, McTiernan CF, Frye CB, McGowan BS, Chan TO, Feldman AM (2004) Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-α-induced cardiomyopathy. Circulation 109:1892–1897CrossRefGoogle Scholar
  4. 4.
    Jang B, Park JY, Tung CH, Kim IH, Choi Y (2011) Gold nanorod-photosensitizer complex for near-infrared fluorescence imaging and photodynamic/photothermal therapy in vivo. ACS Nano 5:1086–1094CrossRefGoogle Scholar
  5. 5.
    Takahashi H, Niidome Y, Niidome T, Kaneko K, Kawasaki H, Yamada S (2006) Modification of gold nanorods using phosphatidylcholine to reduce cytotoxicity. Langmuir 22:2–5CrossRefGoogle Scholar
  6. 6.
    Niidome T, Yamagata M, Okamoto Y, Akiyama Y, Takahashi H, Kawano T, Katayama Y, Niidome Y (2006) PEG-modified gold nanorods with a stealth character for in vivo applications. J Control Release 114:343–347CrossRefGoogle Scholar
  7. 7.
    Niidome T, Akiyama Y, Shimoda K, Kawano T, Mori T, Katayama Y, Niidome Y (2008) In vivo monitoring of intravenously injected gold nanorods using near-infrared light. Small 4:1001–1007CrossRefGoogle Scholar
  8. 8.
    Dickerson EB, Dreaden EC, Huang X, El-Sayed IH, Chu H, Pushpanketh S, McDonald JF, El-Sayed MA (2008) Gold nanorod assisted near-infrared plasmonic photothermal therapy (PPTT) of squamous cell carcinoma in mice. Cancer Lett 269:57–66CrossRefGoogle Scholar
  9. 9.
    von Maltzahn G, Park JH, Agrawal A, Bandaru NK, Das SK, Sailor MJ, Bhatia SN (2009) Computationally guided photothermal tumor therapy using long-circulating gold nanorod antennas. Cancer Res 69:3892–3900CrossRefGoogle Scholar
  10. 10.
    Niidome T, Akiyama Y, Yamagata M, Kawano T, Mori T, Niidome Y, Katayama Y (2009) Poly(ethylene glycol)-modified gold nanorods as a photothermal nanodevice for hyperthermia. J Biomater Sci Polym Ed 20:1203–1215CrossRefGoogle Scholar
  11. 11.
    Akiyama Y, Mori T, Katayama Y, Niidome T (2009) The effects of PEG grafting level and injection dose on gold nanorod biodistribution in the tumor-bearing mice. J Control Release 139:81–84CrossRefGoogle Scholar
  12. 12.
    Haine AT, Niidome T (2017) Gold nanorods as nanodevices for bioimaging, photothermal therapeutics, and drug delivery. Chem Pharm Bull (Tokyo) 65:625–628CrossRefGoogle Scholar
  13. 13.
    Shao X, Zhang H, Rajian JR, Chamberland DL, Sherman PS, Quesada CA, Koch AE, Kotov NA, Wang X (2011) 125I-labeled gold nanorods for targeted imaging of inflammation. ACS Nano 5:8967–8973CrossRefGoogle Scholar
  14. 14.
    Kubota T, McTiernan CF, Frye CS, Demetris AJ, Feldman AM (1997) Cardiac-specific overexpression of tumor necrosis factor-α causes lethal myocarditis in transgenic mice. J Cardiac Fail 3:117–124CrossRefGoogle Scholar
  15. 15.
    Higuchi Y, Chan TO, Brown MA, Zhang J, DeGeorge BR Jr, Funakoshi H, Gibson G, McTiernan CF, Kubota T, Jones WK, Feldman AM (2006) Cardioprotection afforded by NF-κB ablation is associated with activation of Akt in mice overexpressing TNF-α. Am J Physiol Heart Circ Physiol 290:H590–H598CrossRefGoogle Scholar
  16. 16.
    Kadokami T, McTiernan CF, Kubota T, Frye CS, Feldman AM (2000) Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. J Clin Invest 106:589–597CrossRefGoogle Scholar
  17. 17.
    Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM (1997) Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-α. Circ Res 81:627–635CrossRefGoogle Scholar
  18. 18.
    Komohara Y, Terasaki Y, Kaikita K, Suzuki H, Kodama T, Takeya M (2005) Clearance of apoptotic cells is not impaired in mouse embryos deficient in class A scavenger receptor types I and II (CD204). Dev Dyn 232:67–74CrossRefGoogle Scholar
  19. 19.
    Takahashi H, Niidome Y, Yamada S (2005) Controlled release of plasmid DNA from gold nanorods induced by pulsed near-infrared light. Chem Commun (Camb) 17:2247–2249CrossRefGoogle Scholar
  20. 20.
    Okuda K, Fu HY, Matsuzaki T, Araki R, Tsuchida S, Thanikachalam PV, Fukuta T, Asai T, Yamato M, Sanada S, Asanuma H, Asano Y, Asakura M, Hanawa H, Hao H, Oku N, Takashima S, Kitakaze M, Sakata Y, Minamino T (2016) Targeted therapy for acute autoimmune myocarditis with nano-sized liposomal FK506 in rats. PLoS One 11:e0160944CrossRefGoogle Scholar
  21. 21.
    Ruiz-Esparza GU, Segura-Ibarra V, Cordero-Reyes AM, Youker KA, Serda RE, Cruz-Solbes AS, Amione-Guerra J, Yokoi K, Kirui DK, Cara FE, Paez-Mayorga J, Flores-Arredondo JH, Guerrero-Beltran CE, Garcia-Rivas G, Ferrari M, Blanco E, Torre-Amione G (2016) A specifically designed nanoconstruct associates, internalizes, traffics in cardiovascular cells, and accumulates in failing myocardium: a new strategy for heart failure diagnostics and therapeutics. Eur J Heart Fail 18:169–178CrossRefGoogle Scholar
  22. 22.
    Fischer D, Rossa S, Landmesser U, Spiekermann S, Engberding N, Hornig B, Drexler H (2005) Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death. Eur Heart J 26:65–69CrossRefGoogle Scholar
  23. 23.
    Akiyama Y, Mori T, Katayama Y, Niidome T (2012) Conversion of rod-shaped gold nanoparticles to spherical forms and their effect on biodistribution in tumor-bearing mice. Nanoscale Res Lett 7:565CrossRefGoogle Scholar
  24. 24.
    Yang C, Tian A, Li Z (2016) Reversible cardiac hypertrophy induced by PEG-coated gold nanoparticles in mice. Sci Rep 6:20203CrossRefGoogle Scholar
  25. 25.
    Higuchi Y, Kubota T, Koyanagi M, Maeda T, Feldman AM, Makino N (2012) Upregulation of anticoagulant proteins, protein S and tissue factor pathway inhibitor, in the mouse myocardium with cardio-specific TNF-α overexpression. Am J Physiol Heart Circ Physiol 302:H2352–H2362CrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Yoshihiro Higuchi
    • 1
    Email author
  • Takuro Niidome
    • 2
  • Yuji Miyamoto
    • 2
  • Yoshihiro Komohara
    • 3
  • Tomotake Tokunou
    • 1
  • Toru Kubota
    • 4
  • Takahiko Horiuchi
    • 1
  1. 1.Department of Internal MedicineKyushu University Beppu HospitalBeppuJapan
  2. 2.Department of Applied Chemistry and Biochemistry, Faculty of Advanced Science and TechnologyKumamoto UniversityKumamotoJapan
  3. 3.Department of Cell Pathology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
  4. 4.Department of CardiologySaiseikai Fukuoka General HospitalFukuokaJapan

Personalised recommendations