Radio-Wave Heating of Iron Oxide Nanoparticles Can Regulate Plasma Glucose in Mice

Laboratory of Molecular Genetics, Rockefeller University, New York, NY 10065, USA.
Science (Impact Factor: 33.61). 05/2012; 336(6081):604-8. DOI: 10.1126/science.1216753
Source: PubMed

ABSTRACT Medical applications of nanotechnology typically focus on drug delivery and biosensors. Here, we combine nanotechnology and bioengineering to demonstrate that nanoparticles can be used to remotely regulate protein production in vivo. We decorated a modified temperature-sensitive channel, TRPV1, with antibody-coated iron oxide nanoparticles that are heated in a low-frequency magnetic field. When local temperature rises, TRPV1 gates calcium to stimulate synthesis and release of bioengineered insulin driven by a Ca(2+)-sensitive promoter. Studying tumor xenografts expressing the bioengineered insulin gene, we show that exposure to radio waves stimulates insulin release from the tumors and lowers blood glucose in mice. We further show that cells can be engineered to synthesize genetically encoded ferritin nanoparticles and inducibly release insulin. These approaches provide a platform for using nanotechnology to activate cells.

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Available from: Jennifer Gagner, Sep 27, 2015
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    • "Specifically, they depolarize the membrane by directly changing membrane capacitance rather than by opening the ion channels to which they are ligated. This allows for much faster depolarization than in other strategies where nanoparticle heating leads to opening of temperature-sensitive ion channels (Stanley et al., 2012). The rapid depolarization enabled by the present technique involving membrane capacitance change is critical for temporally precise stimulation of neuronal activity. "
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    ABSTRACT: Unmodified neurons can be directly stimulated with light to produce action potentials, but such techniques have lacked localization of the delivered light energy. Here we show that gold nanoparticles can be conjugated to high-avidity ligands for a variety of cellular targets. Once bound to a neuron, these particles transduce millisecond pulses of light into heat, which changes membrane capacitance, depolarizing the cell and eliciting action potentials. Compared to non-functionalized nanoparticles, ligand-conjugated nanoparticles highly resist convective washout and enable photothermal stimulation with lower delivered energy and resulting temperature increase. Ligands targeting three different membrane proteins were tested; all showed similar activity and washout resistance. This suggests that many types of ligands can be bound to nanoparticles, preserving ligand and nanoparticle function, and that many different cell phenotypes can be targeted by appropriate choice of ligand. The findings have applications as an alternative to optogenetics and potentially for therapies involving neuronal photostimulation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; DOI:10.1016/j.neuron.2015.02.033 · 15.05 Impact Factor
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    • "It has been previously found that specific patterns of cellular calcium oscillation can initiate signaling of gene expression1234. Recently, progresses on optogenetics56789101112, heat-activated promoters13, and gene/protein modification combined with nanoparticles and radio wave14 have successfully demonstrated controllable expression of some genes. However, all those methods include at least three complicated phases: 1) gene or protein engineering/modification, 2) introduction of those bioengineered exogenous materials into cells, and 3) activation of those materials to express corresponding genes by some chemical or physical stimulation. "
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    ABSTRACT: Controllable gene expression is always a challenge and of great significance to biomedical research and clinical applications. Recently, various approaches based on extra-engineered light-sensitive proteins have been developed to provide optogenetic actuators for gene expression. Complicated biomedical techniques including exogenous genes engineering, transfection, and material delivery are needed. Here we present an all-optical method to regulate gene expression in targeted cells. Intrinsic or exogenous genes can be activated by a Ca(2+)-sensitive transcription factor nuclear factor of activated T cells (NFAT) driven by a short flash of femtosecond-laser irradiation. When applied to mesenchymal stem cells, expression of a differentiation regulator Osterix can be activated by this method to potentially induce differentiation of them. A laser-induced "Ca(2+)-comb" (LiCCo) by multi-time laser exposure is further developed to enhance gene expression efficiency. This noninvasive method hence provides an encouraging advance of gene expression regulation, with promising potential of applying in cell biology and stem-cell science.
    Scientific Reports 06/2014; 4:5346. DOI:10.1038/srep05346 · 5.58 Impact Factor
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    • "Calcium signalling is rewired to promote calcium-mediated activation of insulin expression. Mice with transplanted tumour xenografts containing this synthetic circuit were exposed to radio waves, which activated the expression and release of insulin from the tumours and, therefore, lowered blood glucose levels in the diabetic mice [35] "
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    ABSTRACT: In the emerging field of synthetic biology, scientists are focusing on designing and creating functional devices, systems, and organisms with novel functions by engineering and assembling standardised biological building blocks. The progress of synthetic biology has significantly advanced the design of functional gene networks that can reprogram metabolic activities in mammalian cells and provide new therapeutic opportunities for future gene- and cell-based therapies. In this review, we describe the most recent advances in synthetic mammalian gene networks designed for biomedical applications, including how these synthetic therapeutic gene circuits can be assembled to control signalling networks and applied to treat metabolic disorders, cancer, and immune diseases. We conclude by discussing the various challenges and future prospects of using synthetic mammalian gene networks for disease therapy.
    FEBS Letters 05/2014; 588(15). DOI:10.1016/j.febslet.2014.05.003 · 3.17 Impact Factor
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