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Peptide functionalized gold nanoparticles as a stimuli responsive contrast medium in multi-photon microscopy Johan Borglin, Robert Selegård, Daniel Aili, and Marica B. Ericson Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.7b00611 • Publication Date (Web): 20 Feb 2017 Downloaded from http://pubs.acs.org on February 20, 2017
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Nano Letters
Peptide functionalized gold nanoparticles as a stimuli responsive contrast medium in multi-photon microscopy Johan Borglin1, Robert Selegård2, Daniel Aili*2, and Marica B. Ericson*1 1
Biomedical Photonics Group, Department of Chemistry and Molecular biology, University of
Gothenburg, 412 96 Gothenburg, Sweden 2
Division of Molecular Physics, Department of Physics, Chemistry and Biology (IFM),
Linköping University, 581 83 Linköping, Sweden
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ABSTRACT
There is a need for biochemical contrast mediators with high signal to noise ratios enabling noninvasive biomedical sensing, e.g., for neural sensing, protein-protein interactions, in addition to cancer diagnostics. The translational challenge is to develop a biocompatible approach ensuring high biochemical contrast while avoiding a raise of the background signal. We here present a concept where gold nanoparticles (AuNPs) can be utilized as a stimuli responsive contrast medium by chemically triggering their ability to exhibit multiphoton induced luminescence (MIL) when performing multi-photon laser scanning microscopy (MPM). Proof-of-principle is demonstrated using peptide functionalized AuNPs sensitive to zinc ions (Zn2+). Dispersed particles are invisible in the MPM until addition of mM concentrations of Zn2+, upon which MIL is enabled through particle aggregation caused by specific peptide interactions and folding. The process can be reversed by removal of the Zn2+ using a chelator, thereby re-suspending the AuNPs. In addition, the concept was demonstrated by exposing the particles to matrix metalloproteinase-7 (MMP-7) causing peptide digestion resulting in AuNP aggregation, significantly elevating the MIL signal from the background. The approach is based on the principle that aggregation shifts the plasmon resonance, elevating the absorption cross section in the near infrared wavelength region enabling onset of MIL. This letter demonstrates how biochemical sensing can be obtained in far-field MPM, and should be further exploited as a future tool for non-invasive optical bio-sensing.
KEYWORDS: gold nanoparticles, multiphoton microscopy, contrast media, optical sensing, peptide
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Nano Letters
TEXT The translational challenge for the development of biosensing contrast mediators is to develop biocompatible sensors with high biochemical contrast while avoiding a raise of the background signal. Gold nanoparticles (AuNPs) have been extensively studied as optical sensors, primarily based on their biocompatibility and optical properties in the linear regime1. The optical properties of the particles varies with size and shape1-3. Furthermore, the particles can be surface modified with a wide range of bio-functional molecules to tailor them for specific applications4. In the nonlinear optical regime, AuNPs can be visualized by MIL5-10, which makes them suitable contrast mediators in combination with multiphoton-laser scanning microscopy (MPM)11,
12
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MPM enables non-invasive visualization of intact biological tissue with cellular resolution, and has become an important and versatile tool allowing for in vivo imaging in preclinical13, 14 and clinical applications, e.g., cancer diagnostics15. Focused near-infrared (NIR) light from fs-pulsed lasers, operating in the tissue transparent wavelength region, give rise to confined non-linear excitation processes of biomolecules. When employing MPM in biomedical research, exogenous fluorophores are generally used to provide contrast, both in vitro as well as preclinically16, 17; however, for clinical applications signal generation is so far predominantly restricted to autofluorescence15,
18, 19
. In addition, other applications such as neural20 and immune cell
dynamics21, and monitoring protein-protein interactions22 are potential applications where in vivo optical sensing is expected to play an important role. To facilitate non-invasive biosensing, biocompatible contrast mediators with high signal-to-noise ratios are desired. Targeted gold nanorods have been proposed to facilitate, e.g., tumour diagnostics11, 12. The problem with this strategy is that the presence of unbound particles not specifically targeted to the cells of interests will increase background signal, and thereby decrease contrast and signal to noise ratio.
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In this paper, we demonstrate a concept for acquiring a stimuli responsive contrast medium with high biochemical contrast in connection to far field MPM. The concept is based on locally tuning the MIL signal from spherical AuNPs through controlled aggregation. The rationale behind is based on the underlying physical principles of MIL. In this process, two or more photons are sequentially absorbed generating a hole in the d-band 8, 23-25, illustrated by Figure 1. During the first absorption step, an intra-band transition in the sp-band is generated leaving a hole in the sp-band below Fermi level. During the second absorption, which probability will depend on the life-time of the sp-hole, an inter-band transition takes place leaving behind a hole in the d-band. A subsequent recombination of the electron-hole pair leads to emission of a photon with higher energy than the separate excitation photons corresponding to generation of MIL. We have recently demonstrated that dispersed small spherical AuNPs (
