Molecular Imaging and Biology

, Volume 14, Issue 1, pp 17–24 | Cite as

Targeted Multifunctional Multimodal Protein-Shell Microspheres as Cancer Imaging Contrast Agents

  • Renu John
  • Freddy T. Nguyen
  • Kenneth J. Kolbeck
  • Eric J. Chaney
  • Marina Marjanovic
  • Kenneth S. Suslick
  • Stephen A. Boppart
Brief Article

Abstract

Purpose

In this study, protein-shell microspheres filled with a suspension of iron oxide nanoparticles in oil are demonstrated as multimodal contrast agents in magnetic resonance imaging (MRI), magnetomotive optical coherence tomography (MM-OCT), and ultrasound imaging. The development, characterization, and use of multifunctional multimodal microspheres are described for targeted contrast and therapeutic applications.

Procedures

A preclinical rat model was used to demonstrate the feasibility of the multimodal multifunctional microspheres as contrast agents in ultrasound, MM-OCT and MRI. Microspheres were functionalized with the RGD peptide ligand, which is targeted to αvβ3 integrin receptors that are over-expressed in tumors and atherosclerotic lesions.

Results

These microspheres, which contain iron oxide nanoparticles in their cores, can be modulated externally using a magnetic field to create dynamic contrast in MM-OCT. With the presence of iron oxide nanoparticles, these agents also show significant negative T2 contrast in MRI. Using ultrasound B-mode imaging at a frequency of 30 MHz, a marked enhancement of scatter intensity from in vivo rat mammary tumor tissue was observed for these targeted protein microspheres.

Conclusions

Preliminary results demonstrate multimodal contrast-enhanced imaging of these functionalized microsphere agents with MRI, MM-OCT, ultrasound imaging, and fluorescence microscopy, including in vivo tracking of the dynamics of these microspheres in real-time using a high-frequency ultrasound imaging system. These targeted oil-filled protein microspheres with the capacity for high drug-delivery loads offer the potential for local delivery of lipophilic drugs under image guidance.

Key words

Magnetomotive optical coherence tomography Ultrasound imaging Magnetic resonance imaging Contrast agents Protein microspheres Iron oxide RGD peptide Alpha(v) beta(3) targeting 

Notes

Acknowledgements

This research was supported in part by grants from the National Institutes of Health (Roadmap Initiative, NIBIB R21 EB005321, NIBIB R01 EB009073, and NCI RC1 CA147096).

Conflicts of Interest

Stephen A. Boppart receives royalties related to optical coherence tomography for patents licensed by the Massachusetts Institute of Technology. He is also co-founder of Diagnostic Photonics, Inc., a company developing Interferometric Synthetic Aperture Microscopy for medical applications, and he receives funding for sponsored research projects from Welch Allyn, Inc. and Samsung, Inc., related to optical imaging technologies. All other authors report no real or perceived conflicts of interest.

References

  1. 1.
    Wang X, Yang L, Chen Z, Shin DM (2008) Application of nanotechnology to cancer therapy and imaging. CA Cancer J Clin 58:97–110PubMedCrossRefGoogle Scholar
  2. 2.
    Moghimi SM, Hunter AC, Murray JC (2005) Nanomedicine: current status and future prospects. FASEB J 19:311–330PubMedCrossRefGoogle Scholar
  3. 3.
    Boppart SA, Oldenburg AL, Xu C, Marks DL (2005) Optical probes and techniques for molecular contrast enhancement in coherence imaging. J Biomed Opt 10:041208CrossRefGoogle Scholar
  4. 4.
    Lee TM, Toublan FJ, Sitafalwalla S et al (2003) Engineered microsphere contrast agents for optical coherence tomography. Opt Lett 28:1456–1458Google Scholar
  5. 5.
    McCarthy JR, Weissleder R (2008) Multifunctional magnetic nanoparticles for targeted imaging and therapy. Adv Drug deliv Rev 60:1241–1251PubMedCrossRefGoogle Scholar
  6. 6.
    Gao X, Gui Y, Levenson RM et al (2004) In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 22:969–976PubMedCrossRefGoogle Scholar
  7. 7.
    Huang D, Swanson EA, Lin CP et al (1991) Optical coherence tomography. Science 254:1178–1181PubMedCrossRefGoogle Scholar
  8. 8.
    Bouma BE, Tearney GJ (eds) (2002) Handbook of Optical Coherence Tomography. Marcel Dekker, New York, New YorkGoogle Scholar
  9. 9.
    Boppart SA, Bouma BE, Pitris C et al (1998) Intraoperative assessment of microsurgery with three-dimensional optical coherence tomography. Radiology 208:81–86PubMedGoogle Scholar
  10. 10.
    Nguyen FT, Zysk AM, Chaney EJ et al (2009) Intraoperative evaluation of breast tumor margins with optical coherence tomography. Cancer Res 69:8790–8796PubMedCrossRefGoogle Scholar
  11. 11.
    Rao KD, Choma MA, Yazdanfar S et al (2003) Molecular contrast in optical coherence tomography by use of a pump-probe technique. Opt Lett 28:340–342PubMedCrossRefGoogle Scholar
  12. 12.
    Xu C, Ye J, Marks DL, Boppart SA (2004) Near-infrared dyes as contrast-enhancing agents for spectroscopic optical coherence tomography. Opt Lett 29:1647–1649PubMedCrossRefGoogle Scholar
  13. 13.
    Oldenburg AL, Hansen MN, Zweifel DA et al (2006) Plasmon-resonant gold nanorods as low backscattering albedo contrast agents for optical coherence tomography. Opt Express 14:6724–6738PubMedCrossRefGoogle Scholar
  14. 14.
    Cang H, Sun T, Li Z-Y et al (2005) Gold nanocages as contrast agents for spectroscopic optical coherence tomography. Opt Lett 30:3048–3050PubMedCrossRefGoogle Scholar
  15. 15.
    Barton JK, Hoying JB, Sullivan CJ (2002) Use of microbubbles as an optical coherence tomography contrast agent. Acad Radiol 9:S52–S55PubMedCrossRefGoogle Scholar
  16. 16.
    Rapoport N, Gao Z, Kennedy A (2007) Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J Natl Cancer Inst 99:1095–1106PubMedCrossRefGoogle Scholar
  17. 17.
    Kolbeck KJ (1999) Biomedical applications of protein microspheres, PhD Dissertation in Chemistry. University of Illinois at Urbana-Champaign, UrbanaGoogle Scholar
  18. 18.
    Dibbern EM (2005) Core shell microspheres for biomedical applications, PhD Dissertation, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IllinoisGoogle Scholar
  19. 19.
    Toublan FJJ, Boppart SA, Suslick KS (2006) Tumor targeting by surface-modified protein microspheres. J Am Chem. Soc.128:3472–3473Google Scholar
  20. 20.
    Oldenburg AL, Toublan FJ, Suslick KS et al (2005) Magnetomotive contrast for in vivo optical coherence tomography. Opt Express 13:6597–6614PubMedCrossRefGoogle Scholar
  21. 21.
    Oldenburg AL, Gunther JR, Boppart SA (2005) Imaging magnetically labeled cells with magnetomotive optical coherence tomography. Opt Lett 30:747–749PubMedCrossRefGoogle Scholar
  22. 22.
    Oldenburg AL, Crecea V, Rinne SA, Boppart SA (2008) Phase-resolved magnetomotive OCT for imaging nanomolar concentrations of magnetic nanoparticles in tissues. Opt Express 16:11525–11539PubMedGoogle Scholar
  23. 23.
    John R, Chaney EJ, Boppart SA (2010) Dynamics of magnetic nanoparticle-based contrast agents in tissues tracked using magnetomotive optical coherence tomography. IEEE J Sel Top Quantum Electron 16:691–697CrossRefGoogle Scholar
  24. 24.
    John R, Rezaeipoor R, Adie SG et al (2010) In vivo magnetomotive optical molecular imaging using targeted magnetic nanoprobes. Proc Natl Acad Sci USA 107:8085–8090PubMedCrossRefGoogle Scholar
  25. 25.
    Unger EC, McCreery TP, Sweitzer RH (1998) A novel ultrasound contrast agent with therapeutic properties. Acad Radiol 5:S247–S249PubMedCrossRefGoogle Scholar
  26. 26.
    Unger EC, McCreery TP, Sweitzer RH et al (1998) Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent. Invest Radiol 33:886–892PubMedCrossRefGoogle Scholar
  27. 27.
    Eliceiri BP, Cheresh DA (1999) The role of alpha v beta 3 integrins during angiogenesis. J Clin Invest 103:1227–1230PubMedCrossRefGoogle Scholar
  28. 28.
    Hoshiga M, Alpers CE, Smith LL et al (1995) Alpha-v beta-3 integrin expression in normal and atherosclerotic artery. Circ Res 77:1129–1135PubMedGoogle Scholar
  29. 29.
    Pasqualini R, Koivunen E, Ruoslahti E (1997) α v integrins as receptors for tumor targeting by circulating ligands. Nat Biotechnol 15:542–546PubMedCrossRefGoogle Scholar
  30. 30.
    Winter PM, Morawski AM, Caruthers SD et al (2003) Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v) beta(3)-integrin-targeted nanoparticles. Circulation 108:2270–2274PubMedCrossRefGoogle Scholar

Copyright information

© Academy of Molecular Imaging and Society for Molecular Imaging 2011

Authors and Affiliations

  • Renu John
    • 1
  • Freddy T. Nguyen
    • 1
    • 2
    • 3
  • Kenneth J. Kolbeck
    • 2
  • Eric J. Chaney
    • 1
  • Marina Marjanovic
    • 1
  • Kenneth S. Suslick
    • 1
    • 2
  • Stephen A. Boppart
    • 1
    • 3
    • 4
    • 5
    • 6
  1. 1.Beckman Institute for Advanced Science and TechnologyUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  2. 2.Department of ChemistryUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  3. 3.Medical Scholars ProgramUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  4. 4.Department of Electrical and Computer EngineeringUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  5. 5.Department of BioengineeringUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  6. 6.Department of Internal Medicine, College of MedicineUniversity of Illinois at Urbana-ChampaignUrbanaUSA

Personalised recommendations