Commentary pubs.acs.org/accounts
Synergism of Nanomaterials with Physical Stimuli for Biology and Medicine Published as part of the Accounts of Chemical Research special issue “Holy Grails in Chemistry”. Tae-Hyun Shin and Jinwoo Cheon* Center for Nanomedicine, Institute for Basic Science (IBS), Seoul 03722, Korea Yonsei-IBS Institute, Yonsei University, Seoul 03722, Korea Department of Chemistry, Yonsei University, Seoul 03722, Korea ABSTRACT: Developing innovative tools that facilitate the understanding of sophisticated biological systems has been one of the Holy Grails in the physical and biological sciences. In this Commentary, we discuss recent advances, opportunities, and challenges in the use of nanomaterials as a precision tool for biology and medicine.
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INTRODUCTION
NANOPARTICLES AS TRANSDUCERS FOR PHYSICAL STIMULI Nanoparticles can serve as versatile transducers that convert one physical quantity into another form of stimuli (Figure 1a). For example, magnetic nanoparticles convert magnetic fields into mechanical force and heat. Noble metal nanoparticles, quantum dots, and upconversion nanoparticles can transform light into heat or change the wavelength of the light. Beyond such versatility, nanoparticles or biomolecule-conjugated nanoparticles can have distinct features, such as (i) remote controllability, (ii) spatiotemporal controllability, and (iii) molecular specificity, which provide opportunities to use nanoparticles as an attractive effector in biology and medicine. Since the input source signals such as magnetic field and light noninvasively penetrate biological tissues and reach the nanoparticle transducers, physical cues can be delivered to targets in a remote-controlled manner (Figure 1b). Longwavelength light (e.g., near-infrared) allows the activation of nanoparticles located at a few centimeters inside the body, while a magnetic field can access deep tissues.10 Physical stimuli by nanoparticles can be pinpointed to their exact position to study biological systems at a single-cell and subcellular level.11 Nanoparticles can potentially generate digitized (i.e., pulsed) output signals in response to input signals; using this propensity of nanoparticles permits fast temporal resolution on a sub-millisecond scale.12
With no access to modern navigation instruments, such as global positioning systems, salmon−a migratory animal−can find their way back home across tens of thousands of kilometers of ocean. For the purpose of navigation, salmon are believed to take advantage of magnetoreception by detection of the Earth’s magnetic field.1,2 In addition to salmon, in nature, many organisms use physical stimuli, such as magnetic field, light, and sound waves, as cues to navigate and migrate long distances.3 Our bodies utilize a variety of mechanisms to sense physical cues from the surrounding environment to perform physiological processes, such as hearing, vision, touch, nociception, and thermoception. Over the past decade, remarkable efforts have been made to bring physical stimuli to understand and control biological systems. For example, in terms of electricity, miniaturized and flexible multielectrode arrays with nanowires can record and manipulate cellular activities from the single cell to the tissue level.4−6 Optogenetics, a combination of optics and genetics, has continuously advanced its ability to activate and regulate functions of neurons and serves as an effective strategy for studying neural connections and biological events in the brain.7,8 A magnetic field is also of interest since it can be utilized for a broad range of stimuli, such as mechanical force and thermal energy, and they can noninvasively reach deep inside tissue with little attenuation, which is especially powerful for in vivo usage.9 In this Commentary, we discuss recent progresses and outlooks in inorganic nanoparticles as a tool for physical stimulation for the sensing and control of biological systems. © 2017 American Chemical Society
Received: November 9, 2016 Published: March 21, 2017 567
DOI: 10.1021/acs.accounts.6b00559 Acc. Chem. Res. 2017, 50, 567−572
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Figure 1. Schematic illustrations of nanoparticle transducers and examples of their characteristic features. (a) Nanoparticle transducers convert one physical quantity into another form of stimuli and interface with biological systems. (b) Nanoparticles, depending on their types, tend to deliver physical inputs (e.g., mechanical force, heat, or light) to cells and tissues in a remote and spatiotemporally controlled manner. (c) Nanoparticles can specifically bind to target molecules and precisely activate targeted cell signaling cascades, while micrometer-sized particles induce nonspecific signal activations due to nonselective multivalency and cell membrane distortion.
force into an electrochemical signal, and are responsible for several senses and physiological processes in the body, including proprioception, touch, balance, and hearing. Magnetic nanoparticles in tandem with a magnetic field can exert pulling and clustering forces. In recent studies, we showed that the mechanical forces of magnetic nanoparticles are effective to modulate the spatial organization of mechanoreceptors to activate cellular signal transduction.11−14 For example, a mechanical pulling force can stimulate spatially targeted, individual auditory hair cells (Figure 2a), which allows for understanding the gating mechanism behind a mechanosensitive ion channel.12−14 Such a pulling force can also be utilized for the spatiotemporal regulation of cellular activities by transforming specific membrane proteins (e.g., Notch receptor).11 Mechanogenetics operates through the force-driven
By conjugating nanoparticles with targeting moieties, nanoparticles can precisely deliver physical cues to sites of interest with molecular-level specificity (Figure 1c). Resulting from their small size and monovalent capability (i.e., one molecule per single nanoparticle), nanoparticles are particularly well suited to interface with biological targets; in contrast, micrometer-sized particles often exhibit nonspecific multivalent binding and hence can perturb cellular structures.11 Thus, nanoparticles with appropriate physical instrumentation are capable of remote, noninvasive read-out and control for a variety of biological processes. Mechanical Force
Mechanoreceptors are one class of receptors that respond to mechanical pressure and distortion. They are primarily involved in mechanotransduction, by which cells convert mechanical 568
DOI: 10.1021/acs.accounts.6b00559 Acc. Chem. Res. 2017, 50, 567−572
Commentary
Accounts of Chemical Research
Figure 2. Cell activations via mechanical force-generating magnetic nanoparticles. (a) Magnetic pulling for gating mechanosensitive ion channels. (i) Magnetic nanoparticles (MNPs) deflect the hair cell bundle and open the ion channels when the magnetic field is turned “ON”, resulting in Ca2+ influx. (ii) Pseudocolor mapped scanning electron microscope image and transmission electron microscope (TEM) image showing MNP-bound hair cell and MNPs. (iii) Temporal resolution for ion channel gating varies from the millisecond to the microsecond range. (b) Magnetic clustering of membrane receptors for activating cell signaling. (i) Schematic illustrations of MNPs bound on membrane receptors (left) and their magnetic clustering upon the magnetic field “ON” (right). (ii) Tie-2 receptor clustering for angiogenesis. Optical microscope images show that the cell shape is transformed into a tubular structure after magnetic activation (i.e., clustering) of the Tie-2 receptor. (iii) Magnetic clustering of the DR4 receptor causes apoptosis of cancer cells. (a) Reprinted with permission from ref 12. Copyright 2014 American Chemical Society. (b) Reprinted by permission from Macmillan Publishers Ltd., ref 17, copyright 2012 and from John Wiley & Sons Ltd., ref 18, copyright 2010.
processes, such as angiogenesis and apoptosis, through clustering of the angiopoietin 2 (Tie-2)18 receptor and death receptor 4 (DR4),17 respectively, from in vitro to live animals.
conformational change of genetically modified target receptors to promote biological outputs such as gene expression. These magnetic force nanoprobes can have temporal resolution of up to a sub-millisecond range, which is comparable to that of optogenetics.12 Considering the time scale of various biological phenomena, such as neural spikes or ion channel gating, which occur on approximately a millisecond scale, magnetic force nanoprobes can be useful to study a wide range of neuronal biomechanics. The clustering force of magnetic nanoparticles can extend the applicability of magnetic nanoparticles to a wider variety of cellular and biological processes (Figure 2b). Cells have various types of signaling pathways, which are often induced by the clustering of membrane receptors. This aggregation-dependent signaling can be turned “ON” by magnetic clustering of nanoparticles.15,16 One advantage of the clustering approach is that lateral association of membrane receptors can be derived with a few femtonewton forces.17 Ingber et al. first reported the possibilities of cell signaling control for immune receptors with magnetic nanoparticles.16 We also exploited this magnetic clustering scheme to induce clinically meaningful cellular
Thermal Energy
Temperature elevated above a normal physiological range disrupts cell signaling pathways, deforms protein structures, and perturbs cell functions. Thus, magnetic and optical heating features of nanoparticles have served as effective approaches for remote-triggering of various biological responses. The most well-known nanoparticle heating is hyperthermia. Heat released by nanoparticles induces heat-shock responses in cancer cells, resulting in cell destruction by thermal ablation. The heat can be utilized in tandem with other anticancer molecules (e.g., chemo- and inhibitor drugs). Nanoparticles integrated with sensitizers, such as heat-shock protein (HSP) inhibitors19 and reactive oxygen species generating molecules,20 make cancer cells more vulnerable to heat, and hence, tumors are easily eliminated under mild heating or a low amount of nanoparticles. Thermal energy can also be utilized as a remote drug release trigger, which allows for precise, on-demand drug 569
DOI: 10.1021/acs.accounts.6b00559 Acc. Chem. Res. 2017, 50, 567−572
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Figure 3. Examples of biomedical applications of nanoparticle heating. (a) Magnetothermal control of drug release. (i) Schematics and TEM image of supramolecular polymer system embedding MNPs and drugs. The polymer bursts and releases the drugs when alternating magnetic field (AMF) is applied. (ii) Drug release profiles upon the application of AMF in either multiple pulses (black line) or in a single pulse (gray line). The drug is released in a stepwise fashion after subsequent AMF pulses (blue lines). (b) Magnetothermal transduction of cell signaling. (i) When TRPV1 is heated above 42 °C by MNPs and AMF, the channel opens and allows for a Ca2+ influx. (ii) Upon AMF exposure, the cell membrane temperature is elevated. (iii) Remote locomotion control of Caenorhabditis elegans using magnetothermal TRPV1 gating. When AMF is applied, the C. elegans stops its forward locomotion and reverses. (a) Reproduced from ref 22 by permission of John Wiley & Sons Ltd., copyright 2013. (b) Reprinted by permission from Macmillan Publishers Ltd., ref 25, copyright 2010.
Therefore, typical optogenetics requires optical fiber implantation to expose the target to light. There are several reports on nanoparticle-mediated optogenetics in which upconversion nanoparticles are utilized as a light transducer.28,29 Since upconversion nanoparticles transform deep penetrating nearinfrared light into visible light, activation of ion channels is possible without using contact-type light sources. Such an approach can potentially provide remote controllability of an optogenetics technique and may be beneficial for experiments with freely moving animals.
delivery in a spatiotemporal- and dosage-controlled fashion to reduce harmful side effects (Figure 3a).21,22 More recently, nanoparticle heating has shown potential for cell signaling transduction control (Figure 3b). Similar to optogenetics, it is possible to genetically modify cells to express thermosensitive cellular components. What makes nanoparticle heating attractive is that the heat can be delivered without the need for contact-type transducers such as optical fibers. For instance, magnetic nanoparticles remotely gate the transient receptor potential vanilloid 1 (TRPV1) receptor, a heatsensitive ion channel on the cell membrane, and induce Ca2+ influx.23−25 By using this approach, specific neurons can be triggered, and accompanying behavioral responses can be promoted in live animals. According to a recent report by Bezanilla et al., the thermal transduction of cell signaling is also operative without genetic modification.26 Noble metal nanoparticles bound to neurons convert pulses of light into heat to change cell membrane capacitance and depolarize the cell and finally elicit action potentials. Heat-inducible gene promoters, such as the HSP promotor, that drive gene expression or protein secretion can be another candidate for thermal control of biological acitivies.27
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CHALLENGES AND PROSPECTS Recent studies on nanoparticles at the biological interface have showcased their potential as a useful tool for mediating the physical world and biological systems. Despite their unique characteristic features, there are challenges for their comprehensive uses in biological systems. For example, nanoparticles should be constructed to be more sensitively responsive to stimuli and generate amplified signals for sensing and controlling cellular activities. There are also needs for multiplexing and logic capabilities of nanoparticles that simultaneously record and interpret multiple biological parameters for accurate understanding of biological processes. From the biological side, biomarkers and affinity ligands are limitedly available, which makes nanoparticles currently
Light
Most light-sensitive ion channels are gated by ultraviolet or visible light, which cannot penetrate biological tissues well. 570
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(8) Yizhar, O.; Fenno, L. E.; Davidson, T. J.; Mogri, M.; Deisseroth, K. Optogenetics in Neural Systems. Neuron 2011, 71, 9−34. (9) Yoo, D.; Lee, J. H.; Shin, T. H.; Cheon, J. Theranostic Magnetic Nanoparticles. Acc. Chem. Res. 2011, 44, 863−874. (10) Shin, T. H.; Choi, Y.; Kim, S.; Cheon, J. Recent Advances in Magnetic Nanoparticle-Based Multi-Modal Imaging. Chem. Soc. Rev. 2015, 44, 4501−4516. (11) Seo, D.; Southard, K. M.; Kim, J. W.; Lee, H. J.; Farlow, J.; Lee, J. U.; Litt, D. B.; Haas, T.; Alivisatos, A. P.; Cheon, J.; Gartner, Z. J.; Jun, Y. W. A Mechanogenetic Toolkit for Interrogating Cell Signaling in Space and Time. Cell 2016, 165, 1507−1518. (12) Lee, J. H.; Kim, J. W.; Levy, M.; Kao, A.; Noh, S. H.; Bozovic, D.; Cheon, J. Magnetic Nanoparticles for Ultrafast Mechanical Control of Inner Ear Hair Cells. ACS Nano 2014, 8, 6590−6598. (13) Kim, J. W.; Lee, J. H.; Ma, J. H.; Chung, E.; Choi, H.; Bok, J.; Cheon, J. Magnetic Force Nanoprobe for Direct Observation of Audio Frequency Tonotopy of Hair Cells. Nano Lett. 2016, 16, 3885−3891. (14) Rowland, D.; Roongthumskul, Y.; Lee, J. H.; Cheon, J.; Bozovic, D. Magnetic Actuation of Hair Cells. Appl. Phys. Lett. 2011, 99, 193701−1937013. (15) Etoc, F.; Lisse, D.; Bellaiche, Y.; Piehler, J.; Coppey, M.; Dahan, M. Subcellular Control of Rac-Gtpase Signalling by Magnetogenetic Manipulation inside Living Cells. Nat. Nanotechnol. 2013, 8, 193−198. (16) Mannix, R. J.; Kumar, S.; Cassiola, F.; Montoya-Zavala, M.; Feinstein, E.; Prentiss, M.; Ingber, D. E. Nanomagnetic Actuation of Receptor-Mediated Signal Transduction. Nat. Nanotechnol. 2008, 3, 36−40. (17) Cho, M. H.; Lee, E. J.; Son, M.; Lee, J. H.; Yoo, D.; Kim, J. W.; Park, S. W.; Shin, J. S.; Cheon, J. A Magnetic Switch for the Control of Cell Death Signalling in In Vitro and In Vivo Systems. Nat. Mater. 2012, 11, 1038−1043. (18) Lee, J. H.; Kim, E. S.; Cho, M. H.; Son, M.; Yeon, S. I.; Shin, J. S.; Cheon, J. Artificial Control of Cell Signaling and Growth by Magnetic Nanoparticles. Angew. Chem. Int. Ed. 2010, 49, 5698−5702. (19) Yoo, D.; Jeong, H.; Noh, S. H.; Lee, J. H.; Cheon, J. Magnetically Triggered Dual Functional Nanoparticles for ResistanceFree Apoptotic Hyperthermia. Angew. Chem. Int. Ed. 2013, 52, 13047− 13051. (20) Yoo, D.; Jeong, H.; Preihs, C.; Choi, J. S.; Shin, T. H.; Sessler, J. L.; Cheon, J. Double-Effector Nanoparticles: A Synergistic Approach to Apoptotic Hyperthermia. Angew. Chem. Int. Ed. 2012, 51, 12482− 12485. (21) Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-Responsive Nanocarriers for Drug Delivery. Nat. Mater. 2013, 12, 991−1003. (22) Lee, J. H.; Chen, K. J.; Noh, S. H.; Garcia, M. A.; Wang, H.; Lin, W. Y.; Jeong, H.; Kong, B. J.; Stout, D. B.; Cheon, J.; Tseng, H. R. OnDemand Drug Release System for In Vivo Cancer Treatment through Self-Assembled Magnetic Nanoparticles. Angew. Chem. Int. Ed. 2013, 52, 4384−4388. (23) Chen, R.; Romero, G.; Christiansen, M. G.; Mohr, A.; Anikeeva, P. Wireless Magnetothermal Deep Brain Stimulation. Science 2015, 347, 1477−1480. (24) Stanley, S. A.; Gagner, J. E.; Damanpour, S.; Yoshida, M.; Dordick, J. S.; Friedman, J. M. Radio-Wave Heating of Iron Oxide Nanoparticles Can Regulate Plasma Glucose in Mice. Science 2012, 336, 604−608. (25) Huang, H.; Delikanli, S.; Zeng, H.; Ferkey, D. M.; Pralle, A. Remote Control of Ion Channels and Neurons through MagneticField Heating of Nanoparticles. Nat. Nanotechnol. 2010, 5, 602−606. (26) Carvalho-de-Souza, J. L.; Treger, J. S.; Dang, B.; Kent, S. B.; Pepperberg, D. R.; Bezanilla, F. Photosensitivity of Neurons Enabled by Cell-Targeted Gold Nanoparticles. Neuron 2015, 86, 207−217. (27) Yamaguchi, M.; Ito, A.; Ono, A.; Kawabe, Y.; Kamihira, M. Heat-Inducible Gene Expression System by Applying Alternating Magnetic Field to Magnetic Nanoparticles. ACS Synth. Biol. 2014, 3, 273−279. (28) Wu, X.; Zhang, Y. W.; Takle, K.; Bilsel, O.; Li, Z. J.; Lee, H.; Zhang, Z. J.; Li, D. S.; Fan, W.; Duan, C. Y.; Chan, E. M.; Lois, C.; Xiang, Y.; Han, G. Dye-Sensitized Core/Active Shell Upconversion
effective only for selective biological systems. The fate, stability, and safety of nanoparticles in biological systems are other important issues to be well-established. Some of the examples of related issues include that iron oxide magnetic nanoparticles are generally considered safe but the improvement for stronger force generation and heat induction is necessary.30 Noble metal nanoparticles are regarded biocompatible as well, but their applicability is often limited for animal studies due to poor light penetration in tissue. Albeit excellent optical properties, quantum dots and upconversion nanoparticles with heavy metals or rare earth metals need to resolve potential toxic effects such as oxidative stresses and inflammatory reactions.31 While there remain several challenges, the potential payoff of nanoparticles is the capability to offer unexplored opportunities for noninvasive and molecular-level control and for recording cellular activities at the single-cell and network levels. Nanoparticles could serve as a new tool for a better understanding of long-sought questions in biology, such as the mechanisms of the sensory systems, interactions between cells that collectively yield complex neural networks, and even the magnetic GPS of migratory animals. Synergistically combined with advanced instrumentation and high-throughput analysis techniques that can capture and process big data, nanoparticle-based tools would accelerate the fundamental understanding of biological systems and machine−human interfaces, ultimately contributing new insights to future medicine for diagnosing and treating diseases.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jinwoo Cheon: 0000-0001-8948-5929 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This Commentary was supported by the Institute for Basic Science (IBS-R026-D1) and the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs (HI08C2149).
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