Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Pharmacokinetic Issues of Imaging with Nanoparticles: Focusing on Carbon Nanotubes and Quantum Dots

Abstract

With many desirable properties, nanoparticles hold tremendous potential for in vivo molecular imaging and improving the efficacy of small-molecule drugs. The pharmacokinetics (PK) and tissue distribution of nanoparticles largely define their in vivo performance and potential toxicity, which are fundamental issues that need to be elucidated. In this review article, we summarized how molecular imaging techniques (e.g., positron emission tomography, fluorescence imaging, etc.) can facilitate the investigation of PK profiles of nanoparticles using carbon nanotubes (CNTs) and quantum dots (QDs) as representative examples. Different imaging techniques can provide useful insights in monitoring the in vivo behavior and tissue distribution of these nanoparticles, and a number of strategies were utilized to optimize the PK profiles of CNTs and QDs. Based on the available literature reports, it can be concluded that chemical/physical properties of the nanoparticles (e.g., surface functionalization, hydrodynamic size, shape, surface charge, etc.), along with the administration routes/doses, can play critical roles in determining the PK and biodistribution pattern of nanoparticles. Robust chemistry for surface modification of nanoparticles is a prerequisite for successful future biomedical/clinical applications.

This is a preview of subscription content, log in to check access.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Ferrari M (2005) Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer 5:161–171

  2. 2.

    Farrell D, Alper J, Ptak K et al (2010) Recent advances from the National Cancer Institute Alliance for Nanotechnology in Cancer. ACS Nano 4:589–594

  3. 3.

    Hong H, Zhang Y, Sun J, Cai W (2009) Molecular imaging and therapy of cancer with radiolabeled nanoparticles. Nano Today 4:399–413

  4. 4.

    Li SD, Huang L (2008) Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm 5:496–504

  5. 5.

    James ML, Gambhir SS (2012) A molecular imaging primer: modalities, imaging agents, and applications. Physiol Rev 92:897–965

  6. 6.

    Mankoff DA (2007) A definition of molecular imaging. J Nucl Med 48(18N):21N

  7. 7.

    Nolting DD, Nickels ML, Guo N, Pham W (2012) Molecular imaging probe development: a chemistry perspective. Am J Nucl Med Mol Imaging 2:273–306

  8. 8.

    Cai W, Chen X (2007) Nanoplatforms for targeted molecular imaging in living subjects. Small 3:1840–1854

  9. 9.

    Cai W, Hsu AR, Li ZB, Chen X (2007) Are quantum dots ready for in vivo imaging in human subjects? Nanoscale Res Lett 2:265–281

  10. 10.

    Yigit MV, Medarova Z (2012) In vivo and ex vivo applications of gold nanoparticles for biomedical SERS imaging. Am J Nucl Med Mol Imaging 2:232–241

  11. 11.

    Hong H, Gao T, Cai W (2009) Molecular imaging with single-walled carbon nanotubes. Nano Today 4:252–261

  12. 12.

    Liu Z, Tabakman S, Welsher K, Dai H (2009) Carbon nanotubes in biology and medicine: in vitro and in vivo detection, imaging and drug delivery. Nano Res 2:85–120

  13. 13.

    Yang K, Liu Z (2012) In vivo biodistribution, pharmacokinetics, and toxicology of carbon nanotubes. Curr Drug Metab 13:1057–1067

  14. 14.

    Liu Z, Liang XJ (2012) Nano-carbons as theranostics. Theranostics 2:235–237

  15. 15.

    Lacerda L, Bianco A, Prato M, Kostarelos K (2006) Carbon nanotubes as nanomedicines: from toxicology to pharmacology. Adv Drug Deliv Rev 58:1460–1470

  16. 16.

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

  17. 17.

    Schipper ML, Nakayama-Ratchford N, Davis CR et al (2008) A pilot toxicology study of single-walled carbon nanotubes in a small sample of mice. Nat Nanotechnol 3:216–221

  18. 18.

    Cherukuri P, Gannon CJ, Leeuw TK et al (2006) Mammalian pharmacokinetics of carbon nanotubes using intrinsic near-infrared fluorescence. Proc Natl Acad Sci USA 103:18882–18886

  19. 19.

    Al Faraj A, Fauvelle F, Luciani N et al (2011) In vivo biodistribution and biological impact of injected carbon nanotubes using magnetic resonance techniques. Int J Nanomedicine 6:351–361

  20. 20.

    Bai Y, Zhang Y, Zhang J et al (2010) Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility. Nat Nanotechnol 5:683–689

  21. 21.

    Gambhir SS (2002) Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2:683–693

  22. 22.

    Gambhir SS, Czernin J, Schwimmer J et al (2001) A tabulated summary of the FDG PET literature. J Nucl Med 42:1S–93S

  23. 23.

    Alauddin MM (2012) Positron emission tomography (PET) imaging with 18F-based radiotracers. Am J Nucl Med Mol Imaging 2:55–76

  24. 24.

    Fakhri GE (2012) Ready for prime time? Dual tracer PET and SPECT imaging. Am J Nucl Med Mol Imaging 2:415–417

  25. 25.

    Bhargava P, He G, Samarghandi A, Delpassand ES (2012) Pictorial review of SPECT/CT imaging applications in clinical nuclear medicine. Am J Nucl Med Mol Imaging 2:221–231

  26. 26.

    Lacerda L, Soundararajan A, Singh R et al (2008) Dynamic imaging of functionalized multi-walled carbon nanotube systemic circulation and urinary excretion. Adv Mater 20:225–230

  27. 27.

    Singh R, Pantarotto D, Lacerda L et al (2006) Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proc Natl Acad Sci USA 103:3357–3362

  28. 28.

    McDevitt MR, Chattopadhyay D, Kappel BJ et al (2007) Tumor targeting with antibody-functionalized, radiolabeled carbon nanotubes. J Nucl Med 48:1180–1189

  29. 29.

    Wang H, Wang J, Deng X et al (2004) Biodistribution of carbon single-wall carbon nanotubes in mice. J Nanosci Nanotechnol 4:1019–1024

  30. 30.

    Hong SY, Tobias G, Al-Jamal KT et al (2010) Filled and glycosylated carbon nanotubes for in vivo radioemitter localization and imaging. Nat Mater 9:485–490

  31. 31.

    Liu Z, Cai W, He L et al (2007) In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat Nanotechnol 2:47–52

  32. 32.

    Cai W, Niu G, Chen X (2008) Imaging of integrins as biomarkers for tumor angiogenesis. Curr Pharm Des 14:2943–2973

  33. 33.

    McDevitt MR, Chattopadhyay D, Jaggi JS et al (2007) PET imaging of soluble yttrium-86-labeled carbon nanotubes in mice. PLoS One 2:e907

  34. 34.

    Zhang Y, Hong H, Cai W (2011) PET tracers based on zirconium-89. Curr Radiopharm 4:131–139

  35. 35.

    van Dongen GA, Ussi AE, de Man FH, Migliaccio G (2013) EATRIS, a European initiative to boost translational biomedical research. Am J Nucl Med Mol Imaging 3:166–174

  36. 36.

    Ruggiero A, Villa CH, Holland JP et al (2010) Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes. Int J Nanomedicine 5:783–802

  37. 37.

    Deng X, Jia G, Wang H et al (2007) Translocation and fate of multi-walled carbon nanotubes in vivo. Carbon 45:1419–1424

  38. 38.

    Georgin D, Czarny B, Botquin M et al (2009) Preparation of 14C-labeled multiwalled carbon nanotubes for biodistribution investigations. J Am Chem Soc 131:14658–14659

  39. 39.

    Zhang Y, Hong H, Myklejord DV, Cai W (2011) Molecular imaging with SERS-active nanoparticles. Small 7:3261–3269

  40. 40.

    Jorio A, Saito R, Dresselhaus G, Dresselhaus MS (2004) Determination of nanotubes properties by Raman spectroscopy. Philos Transact A Math Phys Eng Sci 362:2311–2336

  41. 41.

    Keren S, Zavaleta C, Cheng Z et al (2008) Noninvasive molecular imaging of small living subjects using Raman spectroscopy. Proc Natl Acad Sci USA 105:5844–5849

  42. 42.

    Zavaleta C, de la Zerda A, Liu Z et al (2008) Noninvasive Raman spectroscopy in living mice for evaluation of tumor targeting with carbon nanotubes. Nano Lett 8:2800–2805

  43. 43.

    Cai W, Hong H (2012) In a “nutshell”: intrinsically radio-labeled quantum dots. Am J Nucl Med Mol Imaging 2:136–140

  44. 44.

    Thorek D, Robertson R, Bacchus WA et al (2012) Cerenkov imaging—a new modality for molecular imaging. Am J Nucl Med Mol Imaging 2:163–173

  45. 45.

    Wu Y, Zhang W, Li J, Zhang Y (2013) Optical imaging of tumor microenvironment. Am J Nucl Med Mol Imaging 3:1–15

  46. 46.

    Kim C, Favazza C, Wang LV (2010) In vivo photoacoustic tomography of chemicals: high-resolution functional and molecular optical imaging at new depths. Chem Rev 110:2756–2782

  47. 47.

    Wang LV, Hu S (2012) Photoacoustic tomography: in vivo imaging from organelles to organs. Science 335:1458–1462

  48. 48.

    Wang LV (2008) Prospects of photoacoustic tomography. Med Phys 35:5758–5767

  49. 49.

    De la Zerda A, Zavaleta C, Keren S et al (2008) Carbon nanotubes as photoacoustic molecular imaging agents in living mice. Nat Nanotechnol 3:557–562

  50. 50.

    de la Zerda A, Liu Z, Bodapati S et al (2010) Ultrahigh sensitivity carbon nanotube agents for photoacoustic molecular imaging in living mice. Nano Lett 10:2168–2172

  51. 51.

    Avti PK, Hu S, Favazza C et al (2012) Detection, mapping, and quantification of single walled carbon nanotubes in histological specimens with photoacoustic microscopy. PLoS One 7:e35064

  52. 52.

    Sosnovik DE, Weissleder R (2007) Emerging concepts in molecular MRI. Curr Opin Biotechnol 18:4–10

  53. 53.

    Weissleder R, Pittet MJ (2008) Imaging in the era of molecular oncology. Nature 452:580–589

  54. 54.

    Sitharaman B, Kissell KR, Hartman KB, et al. (2005) Superparamagnetic gadonanotubes are high-performance MRI contrast agents. Chem Commun (Camb):3915–3917

  55. 55.

    van der Zande M, Sitharaman B, Walboomers XF et al (2011) In vivo magnetic resonance imaging of the distribution pattern of gadonanotubes released from a degrading poly(lactic-co-glycolic acid) scaffold. Tissue Eng Part C Methods 17:19–26

  56. 56.

    Al Faraj A, Cieslar K, Lacroix G et al (2009) In vivo imaging of carbon nanotube biodistribution using magnetic resonance imaging. Nano Lett 9:1023–1027

  57. 57.

    S-t Y, Guo W, Lin Y et al (2007) Biodistribution of pristine single-walled carbon nanotubes in vivo. J Phys Chem C 111:17761–17764

  58. 58.

    Tucker-Schwartz JM, Hong T, Colvin DC et al (2012) Dual-modality photothermal optical coherence tomography and magnetic-resonance imaging of carbon nanotubes. Opt Lett 37:872–874

  59. 59.

    Yang S-T, Fernando KAS, Liu J-H et al (2008) Covalently PEGylated carbon nanotubes with stealth character in vivo. Small 4:940–944

  60. 60.

    Prencipe G, Tabakman SM, Welsher K et al (2009) PEG branched polymer for functionalization of nanomaterials with ultralong blood circulation. J Am Chem Soc 131:4783–4787

  61. 61.

    Liu X, Tao H, Yang K et al (2011) Optimization of surface chemistry on single-walled carbon nanotubes for in vivo photothermal ablation of tumors. Biomaterials 32:144–151

  62. 62.

    Sato Y, Yokoyama A, Shibata K et al (2005) Influence of length on cytotoxicity of multi-walled carbon nanotubes against human acute monocytic leukemia cell line THP-1 in vitro and subcutaneous tissue of rats in vivo. Mol Biosyst 1:176–182

  63. 63.

    Palomaki J, Valimaki E, Sund J et al (2011) Long, needle-like carbon nanotubes and asbestos activate the NLRP3 inflammasome through a similar mechanism. ACS Nano 5:6861–6870

  64. 64.

    Kolosnjaj-Tabi J, Hartman KB, Boudjemaa S et al (2010) In vivo behavior of large doses of ultrashort and full-length single-walled carbon nanotubes after oral and intraperitoneal administration to Swiss mice. ACS Nano 4:1481–1492

  65. 65.

    Li Z, Hulderman T, Salmen R et al (2007) Cardiovascular effects of pulmonary exposure to single-wall carbon nanotubes. Environ Health Perspect 115:377–382

  66. 66.

    Crouzier D, Follot S, Gentilhomme E et al (2010) Carbon nanotubes induce inflammation but decrease the production of reactive oxygen species in lung. Toxicology 272:39–45

  67. 67.

    Warheit DB, Laurence BR, Reed KL et al (2004) Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicol Sci 77:117–125

  68. 68.

    Mutlu GM, Budinger GR, Green AA et al (2010) Biocompatible nanoscale dispersion of single-walled carbon nanotubes minimizes in vivo pulmonary toxicity. Nano Lett 10:1664–1670

  69. 69.

    Michalet X, Pinaud FF, Bentolila LA et al (2005) Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307:538–544

  70. 70.

    Sun M, Hoffman D, Sundaresan G, Yang L et al (2012) Synthesis and characterization of intrinsically radiolabeled quantum dots for bimodal detection. Am J Nucl Med Mol Imaging 2:122–135

  71. 71.

    Peng XG, Manna L, Yang WD et al (2000) Shape control of CdSe nanocrystals. Nature 404:59–61

  72. 72.

    Jaiswal JK, Mattoussi H, Mauro JM, Simon SM (2003) Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nat Biotechnol 21:47–51

  73. 73.

    Gao X, Cui Y, Levenson RM, Chung LW, Nie S (2004) In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 22:969–976

  74. 74.

    Jaiswal JK, Goldman ER, Mattoussi H, Simon SM (2004) Use of quantum dots for live cell imaging. Nat Methods 1:73–78

  75. 75.

    Kim S, Lim YT, Soltesz EG et al (2004) Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat Biotechnol 22:93–97

  76. 76.

    Medintz IL, Uyeda HT, Goldman ER, Mattoussi H (2005) Quantum dot bioconjugates for imaging, labelling and sensing. Nat Mater 4:435–446

  77. 77.

    Choi HS, Liu W, Liu F et al (2010) Design considerations for tumour-targeted nanoparticles. Nat Nanotechnol 5:42–47

  78. 78.

    Cai W, Shin DW, Chen K et al (2006) Peptide-labeled near-infrared quantum dots for imaging tumor vasculature in living subjects. Nano Lett 6:669–676

  79. 79.

    Ballou B, Lagerholm BC, Ernst LA et al (2004) Noninvasive imaging of quantum dots in mice. Bioconjug Chem 15:79–86

  80. 80.

    Daou TJ, Li L, Reiss P, Josserand V, Texier I (2009) Effect of poly(ethylene glycol) length on the in vivo behavior of coated quantum dots. Langmuir 25:3040–3044

  81. 81.

    Choi HS, Ipe BI, Misra P et al (2009) Tissue- and organ-selective biodistribution of NIR fluorescent quantum dots. Nano Lett 9:2354–2359

  82. 82.

    Li CL, Murase N (2005) Surfactant-dependent photoluminescence of CdTe nanocrystals in aqueous solution. Chem Lett 34:92–93

  83. 83.

    Fischer HC, Liu LC, Pang KS, Chan WCW (2006) Pharmacokinetics of nanoscale quantum dots: in vivo distribution, sequestration, and clearance in the rat. Adv Funct Mater 16:1299–1305

  84. 84.

    Pomper MG, Lee JS (2005) Small animal imaging in drug development. Curr Pharm Des 11:3247–3272

  85. 85.

    Liu S, Park R, Conti PS, Li Z (2013) “Kit like” (18)F labeling method for synthesis of RGD peptide-based PET probes. Am J Nucl Med Mol Imaging 3:97–101

  86. 86.

    Zhang Y, Hong H, Engle JW et al (2012) Positron emission tomography and near-infrared fluorescence imaging of vascular endothelial growth factor with dual-labeled bevacizumab. Am J Nucl Med Mol Imaging 2:1–13

  87. 87.

    Cai W, Chen K, Li ZB et al (2007) Dual-function probe for PET and near-infrared fluorescence imaging of tumor vasculature. J Nucl Med 48:1862–1870

  88. 88.

    Chen K, Li ZB, Wang H et al (2008) Dual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dots. Eur J Nucl Med Mol Imaging 35:2235–2244

  89. 89.

    Schipper ML, Cheng Z, Lee SW et al (2007) microPET-based biodistribution of quantum dots in living mice. J Nucl Med 48:1511–1518

  90. 90.

    Lacerda SH, Park JJ, Meuse C et al (2010) Interaction of gold nanoparticles with common human blood proteins. ACS Nano 4:365–379

  91. 91.

    Karmali PP, Simberg D (2011) Interactions of nanoparticles with plasma proteins: implication on clearance and toxicity of drug delivery systems. Expert Opin Drug Deliv 8:343–357

  92. 92.

    Choi HS, Gibbs SL, Lee JH et al (2013) Targeted zwitterionic near-infrared fluorophores for improved optical imaging. Nat Biotechnol 31:148–153

  93. 93.

    Choi HS, Liu W, Misra P et al (2007) Renal clearance of quantum dots. Nat Biotechnol 25:1165–1170

  94. 94.

    Fitzpatrick JA, Andreko SK, Ernst LA et al (2009) Long-term persistence and spectral blue shifting of quantum dots in vivo. Nano Lett 9:2736–2741

  95. 95.

    Yong K-T, Roy I, Ding H et al (2009) Biocompatible near-infrared quantum dots as ultrasensitive probes for long-term in vivo imaging applications. Small 5:1997–2004

  96. 96.

    Zhu ZJ, Yeh YC, Tang R et al (2011) Stability of quantum dots in live cells. Nat Chem 3:963–968

  97. 97.

    Ye L, Yong KT, Liu LW et al (2012) A pilot study in non-human primates shows no adverse response to intravenous injection of quantum dots. Nat Nanotechnol 7:453–458

  98. 98.

    Derfus AM, Chan WCW, Bhatia SN (2004) Probing the cytotoxicity of semiconductor quantum dots. Nano Lett 4:11–18

  99. 99.

    Kirchner C, Liedl T, Kudera S et al (2005) Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles. Nano Lett 5:331–338

  100. 100.

    Yang RS, Chang LW, Wu JP et al (2007) Persistent tissue kinetics and redistribution of nanoparticles, quantum dot 705, in mice: ICP-MS quantitative assessment. Environ Health Perspect 115:1339–1343

  101. 101.

    Su Y, Peng F, Jiang Z et al (2011) In vivo distribution, pharmacokinetics, and toxicity of aqueous synthesized cadmium-containing quantum dots. Biomaterials 32:5855–5862

  102. 102.

    Cai W, Chen X (2008) Preparation of peptide conjugated quantum dots for tumour vasculature targeted imaging. Nat Protoc 3:89–96

  103. 103.

    Smith BR, Kempen P, Bouley D et al (2012) Shape matters: intravital microscopy reveals surprising geometrical dependence for nanoparticles in tumor models of extravasation. Nano Lett 12:3369–3377

  104. 104.

    Smith BR, Cheng Z, De A et al (2008) Real-time intravital imaging of RGD-quantum dot binding to luminal endothelium in mouse tumor neovasculature. Nano Lett 8:2599–2606

  105. 105.

    Smith BR, Cheng Z, De A et al (2010) Dynamic visualization of RGD-quantum dot binding to tumor neovasculature and extravasation in multiple living mouse models using intravital microscopy. Small 6:2222–2229

  106. 106.

    Zimmer JP, Kim SW, Ohnishi S et al (2006) Size series of small indium arsenide-zinc selenide core-shell nanocrystals and their application to in vivo imaging. J Am Chem Soc 128:2526–2527

  107. 107.

    Temma T, Saji H (2012) Radiolabelled probes for imaging of atherosclerotic plaques. Am J Nucl Med Mol Imaging 2:432–447

  108. 108.

    Zeman MN, Scott PJ (2012) Current imaging strategies in rheumatoid arthritis. Am J Nucl Med Mol Imaging 2:174–220

  109. 109.

    Zhang L, Chang RC, Chu LW, Mak HK (2012) Current neuroimaging techniques in Alzheimer's disease and applications in animal models. Am J Nucl Med Mol Imaging 2:386–404

  110. 110.

    Choi JH, Nguyen FT, Barone PW et al (2007) Multimodal biomedical imaging with asymmetric single-walled carbon nanotube/iron oxide nanoparticle complexes. Nano Lett 7:861–867

  111. 111.

    Krug HF, Wick P (2011) Nanotoxicology: an interdisciplinary challenge. Angew Chem Int Ed Engl 50:1260–1278

  112. 112.

    Boczkowski J, Hoet P (2010) What's new in nanotoxicology? Implications for public health from a brief review of the 2008 literature. Nanotoxicology 4:1–14

  113. 113.

    Crist RM, Grossman JH, Patri AK et al (2013) Common pitfalls in nanotechnology: lessons learned from NCI's Nanotechnology Characterization Laboratory. Integr Biol (Camb) 5:66–73

  114. 114.

    Stern ST, McNeil SE (2008) Nanotechnology safety concerns revisited. Toxicol Sci 101:4–21

  115. 115.

    Ding H, Wu F (2012) Image guided biodistribution and pharmacokinetic studies of theranostics. Theranostics 2:1040–1053

  116. 116.

    Ho YP, Leong KW (2010) Quantum dot-based theranostics. Nanoscale 2:60–68

  117. 117.

    Swierczewska M, Lee S, Chen X (2011) Moving theranostics from bench to bedside in an interdisciplinary research team. Ther Deliv 2:165–170

Download references

Acknowledgments

This work is supported, in part, by the University of Wisconsin Carbone Cancer Center, the National Institutes of Health (1R01CA169365—01A1), the Department of Defense (W81XWH-11-1-0644), UW Graduate School, and UW Department of Radiology.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Correspondence to Weibo Cai.

Additional information

Hao Hong and Feng Chen contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hong, H., Chen, F. & Cai, W. Pharmacokinetic Issues of Imaging with Nanoparticles: Focusing on Carbon Nanotubes and Quantum Dots. Mol Imaging Biol 15, 507–520 (2013). https://doi.org/10.1007/s11307-013-0648-5

Download citation

Key words

  • Pharmacokinetics (PK)
  • Molecular imaging
  • Nanoparticles
  • Carbon nanotube (CNT)
  • Quantum dot (QD)
  • Cancer
  • Angiogenesis
  • Positron emission tomography (PET)
  • Fluorescence