Molecular imprinting is a technique for preparing polymer scaffolds that function as synthetic receptors1,2,3. Imprinted polymers that can selectively bind organic compounds have proven useful in sensor development2,3,4,5,6,7. Although creating synthetic molecular-imprinting polymers that recognize proteins remains challenging8,9,10,11, nanodevices and nanomaterials show promise in this area12,13,14. Here, we show that arrays of carbon-nanotube tips with an imprinted non-conducting polymer coating can recognize proteins with subpicogram per litre sensitivity using electrochemical impedance spectroscopy. We have developed molecular-imprinting sensors specific for human ferritin and human papillomavirus derived E7 protein. The molecular-imprinting-based nanosensor can also discriminate between Ca2+-induced conformational changes in calmodulin. This ultrasensitive, label-free electrochemical detection of proteins offers an alternative to biosensors based on biomolecule recognition.
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Wulff, G. & Sharhan, A. Über die Anwendung von enzymanalog gebauten Polymeren zur Racemattrennung. Angew. Chem. 84, 364 (1972).
Vlatakis, G., Anderson, L. I., Muller, R. & Mosbach, K. Drug assay using antibody mimics made by molecular imprinting. Nature 361, 645–647 (1993).
Hoshino, Y., Kodama, T., Okahata, Y. & Shea, K. J. Peptide imprinted polymer nanoparticles: a plastic antibody. J. Am. Chem. Soc. 130, 15242–15243 (2008).
Bossi, A., Bonini, F., Turner, A. P. F. & Piletsky, S. A. Molecularly imprinted polymers for the recognition of proteins: the state of the art. Biosens. Bioelectron. 22, 1131–1137 (2007).
Karube, J. et al. Molecular recognition in continuous polymer rods prepared by a molecular imprinting technique. Anal. Chem. 65, 2223–2224 (1993).
Kempe, M. Antibody-mimicking polymers as chiral stationary phases in HPLC. Anal. Chem. 68, 1948–1953 (1996).
Rashid, B. A., Briggs, R. J., Hay, J. N. & Stevenson, D. Preliminary evaluation of a molecular imprinted polymer for solid-phase extraction of tamoxifen. Anal. Commun. 34, 303–305 (1997).
Shi, H., Tsai, W.-B., Garrison, M. D., Ferrari, S. & Ratner, B. D. Template-imprinted nanostructured surfaces for protein recognition. Nature 398, 593–597 (1999).
Rick, J. & Chou, T. C. Using protein templates to direct the formation of thin-film polymer surfaces. Biosens. Bioelectron. 22, 544–549 (2006).
Wang, Y. et al. A potentiometric protein sensor built with surface molecular imprinting method. Biosens. Bioelectron. 24, 162–166 (2008).
Bossi, A., Piletsky, S. A., Piletska, E. V., Righetti, P. G. & Turner, A. P. F. Surface-grafted molecularly imprinted polymers for protein recognition. Anal. Chem. 73, 5281–5286 (2001).
Zheng, G., Patolsky, F., Cui, Y., Wang, W. U. & Lieber, C. M. Multiplexed electrical detection of cancer markers with nanowire sensor arrays. Nature Biotechnol. 23, 1294–1301 (2005).
Yu, X. et al. Carbon nanotube amplification strategies for highly sensitive immunodetection of cancer biomarkers. J. Am. Chem. Soc. 128, 11199–11205 (2006).
Yu, Y. et al. Assembly of multi-functional nanocomponents on periodic nanotube array for biosensors. Micro. Nano. Lett. 4, 27–33 (2009).
Riskin, M., Tel-Vered, R. & Willner, I. The imprint of electropolymerized polyphenol films on electrodes by donor–acceptor interactions: selective electrochemical sensing of N,N′-dimethyl-4,4′-bipyridinium (methyl viologen). Adv. Func. Mater. 17, 3858–3863 (2007).
Lakshmi, D. et al. Electrochemical sensor for catechol and dopamine based on a catalytic molecularly imprinted polymer-conducting polymer hybrid recognition element. Anal. Chem. 81, 3576–3584 (2009).
Panasyuk, T. L., Mirsky, V. M., Piletsky, S. A. & Wolfbeis, O. S. Electropolymerized molecularly imprinted polymers as receptor layers in capacitive chemical sensors. Anal. Chem. 71, 4609–4613 (1999).
Choong, C. L., Bendallb, J. S. & Milnea, W. I. Carbon nanotube array: a new MIP platform. Biosen. Bioelectron. 25, 652–656 (2009).
Wei, Y., Qiu, L., Owen, C. & Lai, E. P. C. Encapsulation of quantum dots and carbon nanotubes with polypyrrole in a syringe needle for automated molecularly imprinted solid phase pre-concentration of ochratoxin A in red wine analysis. Sens. Instrum. Food Qual. 1, 133–141 (2007).
Xie, C., Li, H., Li, S., Wu, J. & Zhang, Z. Surface molecular self-assembly for organophosphate pesticide imprinting in electropolymerized poly(p-aminothiophenol) membranes on a gold nanoparticle modified glassy carbon electrode. Anal. Chem. 82, 241–249 (2010).
Tabard-Cossa, V., Trivedi, V., Wiggin, M., Jetha, N. N. & Marziali, A. Noise analysis and reduction in solid-state nanopores. Nanotechnology 18, 305505 (2007).
Gong, K., Chakrabarti, S. & Dai, L. Electrochemistry at carbon nanotube electrodes: is the nanotube tip more active than the side wall? Angew. Chem. Int. Ed. 47, 5446–5450 (2008).
Bartlett, P. N., Tebbutt, P. & Tyrrell, C. H. Electrochemical immobilization of enzymes. 3. Immobilization of glucose oxidase in thin films of electrochemically polymerized phenols. Anal. Chem. 64, 138–142 (1992).
Klee, C. B. Conformational transition accompanying the binding of Ca2+ to the protein activator of 3′,5′-cyclic adenosine monophosphate. Biochemistry 16, 1017–1024 (1977).
Crouch, T. H. & Klee, C. B. Positive cooperative binding of calcium to bovine brain calmodulin. Biochemistry 19, 3692–3698 (1980).
Weinstein, H. & Mehler, E. L. Ca2+-binding and structural dynamics in the functions of calmodulins. Annu. Rev. Physiol. 56, 213–236 (1994).
Devanathan, S. et al. Subpicomolar sensing of δ-opioid receptor ligands by molecular-imprinted polymers using plasmon-waveguide resonance spectroscopy. Anal. Chem. 77, 2569–2574 (2005).
Patolsky, F., Zheng, G. & Lieber, C. M. Fabrication of silicon nanowire devices for ultrasensitive, label-free, real-time detection of biological and chemical species. Nature Protoc. 1, 1711–1724 (2006).
Sanchez-Carbayo, M. Antibody arrays: technical considerations and clinical applications in cancer. Clin. Chem. 52, 1651–1659 (2006).
The authors acknowledge financial support from The Seaver Institute (T.C.C and M.J.N.). L.R. was supported by the China Scholarship Council (no. 2008677005). We thank O. Gursky and S. Jayaraman (Boston University School of Medicine, Department of Physiology and Biophysics) for use of their Aviv spectropolarimeter.
The authors declare no competing financial interests.
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Cai, D., Ren, L., Zhao, H. et al. A molecular-imprint nanosensor for ultrasensitive detection of proteins. Nature Nanotech 5, 597–601 (2010) doi:10.1038/nnano.2010.114
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