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Magnetic relaxation switches capable of sensing molecular interactions

Abstract

Highly sensitive, efficient, and high-throughput biosensors are required for genomic and proteomic data acquisition in complex biological samples and potentially for in vivo applications. To facilitate these studies, we have developed biocompatible magnetic nanosensors that act as magnetic relaxation switches (MRS) to detect molecular interactions in the reversible self-assembly of disperse magnetic particles into stable nanoassemblies. Using four different types of molecular interactions (DNA–DNA, protein–protein, protein–small molecule, and enzyme reactions) as model systems, we show that the MRS technology can be used to detect these interactions with high efficiency and sensitivity using magnetic relaxation measurements including magnetic resonance imaging (MRI). Furthermore, the magnetic changes are detectable in turbid media and in whole-cell lysates without protein purification. The developed magnetic nanosensors can be used in a variety of biological applications such as in homogenous assays, as reagents in miniaturized microfluidic systems, as affinity ligands for rapid and high-throughput magnetic readouts of arrays, as probes for magnetic force microscopy, and potentially for in vivo imaging.

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Figure 1: Magnetic relaxation switches.
Figure 2: Sensitivity of magnetic nanosensors.
Figure 3: Specificity of magnetic nanosensors.
Figure 4: Detection of mRNA.
Figure 5: Detection of antibody-based and enzymatic reactions.

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References

  1. Alivisatos, A. Semiconductor clusters, nanocrystals and quantum dots. Science 271, 933–937 (1996).

    Article  CAS  Google Scholar 

  2. Mirkin, C.A., Letsinger, R.L., Mucic, R.C. & Storhoff, J.J. A DNA-based method for rationally assembling nanoparticles into macroscopic materials. Nature 382, 607–609 (1996).

    Article  CAS  Google Scholar 

  3. Elghanian, R., Storhoff, J.J., Mucic, R.C., Letsinger, R.L. & Mirkin, C.A. Selective colorimetric detection of polynucleotides based on the distance-dependent optical properties of gold nanoparticles. Science 277, 1078–1081 (1997).

    Article  CAS  Google Scholar 

  4. Storhoff, J.J., Elghanian, R., Mucic, R.C., Mirkin, C.A. & Letsinger, R.L. One-pot colorimetric differentiation of polynucleotides with single base imperfections using gold nanoparticles. J Am. Chem. Soc. 120, 1959–1964 (1998).

    Article  CAS  Google Scholar 

  5. Alivisatos, A.P. et al. Organization of 'nanocrystal molecules' using DNA. Nature 382, 609–611. (1996).

    Article  CAS  Google Scholar 

  6. Bruchez, M. Jr., Moronne, M., Gin, P., Weiss, S. & Alivisatos, A.P. Semiconductor nanocrystals as fluorescent biological labels. Science 281, 2013–2016. (1998).

    Article  CAS  Google Scholar 

  7. Chan, W.C. & Nie, S. Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science 281, 2016–2018. (1998).

    Article  CAS  Google Scholar 

  8. Baselt, D.R. et al. A biosensor based on magnetoresistance technology. Biosens. Bioelectron. 13, 731–739. (1998).

    Article  CAS  Google Scholar 

  9. Kriz, K., Gehrke, J. & Kriz, D. Advancements toward magneto immunoassays. Biosens. Bioelectron. 13, 817–823 (1998).

    Article  CAS  Google Scholar 

  10. Edelstein, R.L. et al. The BARC biosensor applied to the detection of biological warfare agents. Biosens. Bioelectron. 14, 805–813 (2000).

    Article  CAS  Google Scholar 

  11. Taton, T.A., Mirkin, C.A. & Letsinger, R.L. Scanometric DNA array detection with nanoparticle probes. Science 289, 1757–1760 (2000).

    Article  CAS  Google Scholar 

  12. Han, M., Gao, X., Su, J.Z. & Nie, S. Quantum-dot-tagged microbeads for multiplexed optical coding of biomolecules. Nat. Biotechnol. 19, 631–635 (2001).

    Article  CAS  Google Scholar 

  13. Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat. Biotechnol. 18, 410–414 (2000).

    Article  CAS  Google Scholar 

  14. Weissleder, R. et al. In vivo magnetic resonance imaging of transgene expression. Nat. Med. 6, 351–355 (2000).

    Article  CAS  Google Scholar 

  15. Josephson, L., Tung, C.H., Moore, A. & Weissleder, R. High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. Bioconjug. Chem. 10, 186–191 (1999).

    Article  CAS  Google Scholar 

  16. Josephson, L., Perez, J.M. & Weissleder, R. Magnetic nanosensors for the detection of oligonucleotide sequences. Angew. Chem. Int. Ed. Engl. 40, 3204–3206 (2001).

    Article  CAS  Google Scholar 

  17. Eis, P.S. et al. An invasive cleavage assay for direct quantitation of specific RNAs. Nat. Biotechnol. 19, 673–676 (2001).

    Article  CAS  Google Scholar 

  18. Duggan, D.J., Bittner, M., Chen, Y., Meltzer, P. & Trent, J.M. Expression profiling using cDNA microarrays. Nat. Genet. 21, 10–14 (1999).

    Article  CAS  Google Scholar 

  19. Keifer, P.A. NMR tools for biotechnology. Curr. Opin. Biotechnol. 10, 34–41 (1999).

    Article  CAS  Google Scholar 

  20. Keifer, P.A. et al. Direct-injection NMR (DI-NMR): a flow NMR technique for the analysis of combinatorial chemistry libraries. J. Comb. Chem. 2, 151–171 (2000).

    Article  CAS  Google Scholar 

  21. Ross, A., Schlotterbeck, G., Senn, H. & von Kienlin, M. Application of Chemical Shift Imaging for Simultaneous and Fast Acquisition of NMR Spectra on Multiple Samples. Angew. Chem. 40, 3243–3245 (2001).

    Article  CAS  Google Scholar 

  22. Hou, T., Smith, J., MacNamara, E., Macnaughtan, M. & Raftery, D. Analysis of multiple samples using multiplex sample NMR: selective excitation and chemical shift imaging approaches. Anal. Chem. 73, 2541–2546 (2001).

    Article  CAS  Google Scholar 

  23. Jamet, M. et al. Magnetic anisotropy of a single cobalt nanocluster. Phys. Rev. Lett. 86, 4676–4679 (2001).

    Article  CAS  Google Scholar 

  24. Chemla, Y.R. et al. Ultrasensitive magnetic biosensor for homogeneous immunoassay. Proc. Natl. Acad. Sci. USA 97, 14268–14272 (2000).

    Article  CAS  Google Scholar 

  25. Diebel, C.E., Proksch, R., Green, C.R., Neilson, P. & Walker, M.M. Magnetite defines a vertebrate magnetoreceptor. Nature 406, 299–302 (2000).

    Article  CAS  Google Scholar 

  26. Weissleder, R., Bogdanov, A., Neuwelt, E. & Papisov, M. Long-circulation iron oxides for MR imaging. Adv. Drug Deliv. Rev. 16, 321–334 (1995).

    Article  CAS  Google Scholar 

  27. Bremer, C., Tung, C.H. & Weissleder, R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat. Med. 7, 743–748 (2001).

    Article  CAS  Google Scholar 

  28. Weissleder, R., Tung, C.H., Mahmood, U. & Bogdanov, A. Jr. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat. Biotechnol. 17, 375–378 (1999).

    Article  CAS  Google Scholar 

  29. Wunderbaldinger, P., Josephson, L. & Weissleder, R. Tat Peptide directs enhanced clearance and hepatic permeability of magnetic nanoparticles. Bioconjug. Chem. 13, 264–268 (2002).

    Article  CAS  Google Scholar 

  30. Hogemann, D., Ntziachristos, V., Josephson, L. & Weissleder, R. High throughput magnetic resonance imaging for evaluating targeted nanoparticle probes. Bioconjug. Chem. 13, 116–121 (2002).

    Article  Google Scholar 

  31. Saeki, Y., Fraefel, C., Ichikawa, T., Breakefield, X.O. & Chiocca, E.A. Improved helper virus-free packaging system for HSV amplicon vectors using an ICP27-deleted, oversized HSV-1 DNA in a bacterial artificial chromosome. Mol. Ther. 3, 591–601 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Y. Saeki and N. Sergey for providing different GFP-expressing cell lines and V. Ntziachristos for providing automation routines to display T2 maps from MR images. This work was supported in part by P50 CA86355. J.M.P. is the recipient of a National Cancer Institute–Comprehensive Minority Biomedical Branch fellowship.

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Correspondence to Ralph Weissleder.

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Perez, J., Josephson, L., O'Loughlin, T. et al. Magnetic relaxation switches capable of sensing molecular interactions. Nat Biotechnol 20, 816–820 (2002). https://doi.org/10.1038/nbt720

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