Five-dimensional tracking of single nanoparticles in living cells

Five-dimensional tracking of single nanoparticles in living cells Ai and Xing Light: Science & Applications (2018) 7:16 Official journal of the CIOMP 2047-7538 DOI 10.1038/s41377-018-0026-9 www.nature.com/lsa NEWS AND VIEWS Open Access Five-dimensional tracking of single nanoparticles in living cells 1 1 Xiangzhao Ai and Bengang Xing An innovative approach to achieve dynamic five- science due to their distinctive optical properties, which dimensional tracking of single nanoparticles under enable them to convert long-wavelength near-infrared simple microscopic inspection by human eyes was (NIR) light into multiplexed short-wavelength emissions presented; this approach provided an effective means that span a broad range, from the ultraviolet/visible to the to investigate the complicated biological micro- NIR region . UCNPs are considered to be suitable probes environment in living cells. for long-term tracking in imaging processes, mainly due Currently, owing to the ongoing development of to their promising advantages, such as non-bleaching, single-molecule techniques over the past few decades, it non-blinking, autofluorescence-free, low cytotoxicity, and is possible to explore the underlying mechanisms of high chemical/photo-stability. Despite these remarkable diverse biological processes in living cells, such as optical capabilities, current studies on UCNPs utilizing dynamically monitoring cell membrane behaviors, par- conventional far-field fluorescence microscopy are limited ticularly the stepping of motor proteins along micro- because their resolution is insufficient to distinguish a tubules, and spatiotemporally scanning gene expression single nanoparticle from clusters or aggregates, which is or regulation in nuclei . Effective inspection and track- significant for real-time observations of sub-cellular ing of target-specific imaging probes provide unprece- component movements to understand their potential dented abilities for researchers to directly observe the functions in complex cellular environments . Thus, biological activities of various cellular components (e.g., innovative approaches are still in high demand to deter- organelles, enzymes, ions, etc.) at the single-molecule mine the activities of individual UCNP during long-term level with ultimate three-dimensional (3D) precision imaging periods in biological investigations. and time resolution. A number of optical contrast For this purpose, in a recent publication, Jin and co- agents, including organic chromophores and inorganic workers demonstrated that the human eye could directly materials, have been widely applied in these studies . distinguish single UCNPs and identify relevant information, However, critical challenges still remain in regard to including their color, intensity, and location in cells, under a eliminating the undesired drawbacks of the commonly simple microscope setup (Fig. 1a) .Interestingly, these used probes during long-term imaging periods, includ- authors determined that at least 4186 photons per 100 ms ing photobleaching and degradation of organic dyes, are required for our eyes to differentiate two separate blue photoblinking and toxicity of quantum dots, and UCNPs upon ~980 nm NIR light excitation. By utilizing a inherent autofluorescence in living organisms .There- series of size- and emission-tunable UCNPs, they achieved fore, development of novel materials that allow strong long-term quantitative analysis of one nanoparticle with emissions, high photostabilities, lower cytotoxicities, bright, uniform, and stable upconverted luminescence sig- and limited backgrounds is highly desirable. nals in living cells. Remarkably, it is easy and accurate for Recently, lanthanide-doped upconversion nanoparticles researchers to recognize clusters or aggregates of UCNPs (UCNPs) have attracted much attention in materials when the emitters present a brightness higher than the threshold value during microscopic inspection. Inspired by these promising results, the authors further Correspondence: Bengang Xing (Bengang@ntu.edu.sg) investigated the heterogeneous diffusion dynamics of each Division of Chemistry and Biological Chemistry, School of Physical & UCNP and cluster in the different intracellular Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to theCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Ai and Xing Light: Science & Applications (2018) 7:16 Page 2 of 2 ab Excitation power density Cells Single UCNP (Fifth dimension) ~ 980 nm Dichromic NIR laser mirror Clusters Tube lens Camera Flip mirror Eyepiece Simple microscope setup UNCP Detector Fig. 1 5D tracking of a single UCNP in living cells. a The simple microscopic system for the inspection of a single nanoparticle with the human eye to distinguish individual particles from clusters. b The trajectories of a particular UCNP with a tunable emission upon different power intensity excitation (the fifth dimension) to investigate the complicated intracellular microenvironment microenvironment. Interestingly, it was indicated that the biological systems, which will not only allow the human diffusion coefficient of a single nanoparticle in early endo- eye to directly identify information about particular somes (0.18 μm /s) was slightly larger than that in late nanoparticles via a simple microscopic inspection but also endosomes/lysosomes (0.04 μm /s), and the relatively faster initiate an effective method to investigate the complicated movement of UCNP with a specific direction (3 μm/s) was biological microenvironment by utilizing a single-particle associated with the active migration of molecular motor technique in physiologic and pathologic processes in living proteins on microtubules or actin filaments. Moreover, they conditions. also calculated the localized environment viscosity of each particle or cluster, which provided powerful insight into Conflict of interest The authors declare that they have no conflict of interest. their surrounding protein dynamics in living cells. Com- pared with the value in the cytoplasm (11.6 ± 0.9 cP), the viscosity in early endosomes (41 ± 4 cP) was obviously lower Received: 17 March 2018 Revised: 19 April 2018 Accepted: 24 April 2018 than that in late endosomes/lysosomes (184 ± 14 cP), sug- gesting the improved protein functional capacities in the intracellular cytosol and early endosomes. More impor- tantly, besides the 3D position and multiple color domain of References each UCNP, Jin and co-workers proposed that the excita- 1. Kusumi,A., Tsunoyama, T. A.,Hirosawa, K. M.,Kasai,R.S.& Fujiwara,T.K.Tracking tion power density could act as the fifth dimension to single molecules at work in living cells. Nat. Chem. Biol. 10,524–532 simultaneously monitor various nanoparticles due to their (2014). 2. Kircher, M. F., Gambhir, S. S. & Grimm, J. Noninvasive cell-tracking methods. Nat. power-dependent optical properties (Fig. 1b). By adjusting Rev. Clin. Oncol. 8,677–688 (2011). the suitable concentrations of doped ions, a single UCNP 3. Resch-Genger, U., Grabolle,M., Cavaliere-Jaricot,S., Nitschke,R.&Nann,T. could be lit up using different irradiation densities, which Quantum dotsversusorganic dyes as fluorescent labels. Nat. Methods 5, 763–775 (2008). revealed the specific superiority of an upconversion fluor- 4. Zhou, B., Shi, B. Y., Jin, D. Y. & Liu, X. G. Controlling upconversion nanocrystals for escence microscope for bioimaging studies. emerging applications. Nat. Nanotechnol. 10, 924–936 (2015). In summary, this work presented a novel approach to 5. Ai, X. Z. et al. In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics. Nat. Commun. 7, 10432 achieve dynamic tracking of individual UCNPs based on (2016). unique 5D imaging modalities in living cells. These cap- 6. Wang, F. et al. Microscopic inspection and tracking of single upconversion abilities are extremely significant for long-term imaging of nanoparticles in living cells. Light Sci. Appl. 7, 18007 (2018). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Light: Science & Applications Springer Journals

Five-dimensional tracking of single nanoparticles in living cells

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Abstract

Ai and Xing Light: Science & Applications (2018) 7:16 Official journal of the CIOMP 2047-7538 DOI 10.1038/s41377-018-0026-9 www.nature.com/lsa NEWS AND VIEWS Open Access Five-dimensional tracking of single nanoparticles in living cells 1 1 Xiangzhao Ai and Bengang Xing An innovative approach to achieve dynamic five- science due to their distinctive optical properties, which dimensional tracking of single nanoparticles under enable them to convert long-wavelength near-infrared simple microscopic inspection by human eyes was (NIR) light into multiplexed short-wavelength emissions presented; this approach provided an effective means that span a broad range, from the ultraviolet/visible to the to investigate the complicated biological micro- NIR region . UCNPs are considered to be suitable probes environment in living cells. for long-term tracking in imaging processes, mainly due Currently, owing to the ongoing development of to their promising advantages, such as non-bleaching, single-molecule techniques over the past few decades, it non-blinking, autofluorescence-free, low cytotoxicity, and is possible to explore the underlying mechanisms of high chemical/photo-stability. Despite these remarkable diverse biological processes in living cells, such as optical capabilities, current studies on UCNPs utilizing dynamically monitoring cell membrane behaviors, par- conventional far-field fluorescence microscopy are limited ticularly the stepping of motor proteins along micro- because their resolution is insufficient to distinguish a tubules, and spatiotemporally scanning gene expression single nanoparticle from clusters or aggregates, which is or regulation in nuclei . Effective inspection and track- significant for real-time observations of sub-cellular ing of target-specific imaging probes provide unprece- component movements to understand their potential dented abilities for researchers to directly observe the functions in complex cellular environments . Thus, biological activities of various cellular components (e.g., innovative approaches are still in high demand to deter- organelles, enzymes, ions, etc.) at the single-molecule mine the activities of individual UCNP during long-term level with ultimate three-dimensional (3D) precision imaging periods in biological investigations. and time resolution. A number of optical contrast For this purpose, in a recent publication, Jin and co- agents, including organic chromophores and inorganic workers demonstrated that the human eye could directly materials, have been widely applied in these studies . distinguish single UCNPs and identify relevant information, However, critical challenges still remain in regard to including their color, intensity, and location in cells, under a eliminating the undesired drawbacks of the commonly simple microscope setup (Fig. 1a) .Interestingly, these used probes during long-term imaging periods, includ- authors determined that at least 4186 photons per 100 ms ing photobleaching and degradation of organic dyes, are required for our eyes to differentiate two separate blue photoblinking and toxicity of quantum dots, and UCNPs upon ~980 nm NIR light excitation. By utilizing a inherent autofluorescence in living organisms .There- series of size- and emission-tunable UCNPs, they achieved fore, development of novel materials that allow strong long-term quantitative analysis of one nanoparticle with emissions, high photostabilities, lower cytotoxicities, bright, uniform, and stable upconverted luminescence sig- and limited backgrounds is highly desirable. nals in living cells. Remarkably, it is easy and accurate for Recently, lanthanide-doped upconversion nanoparticles researchers to recognize clusters or aggregates of UCNPs (UCNPs) have attracted much attention in materials when the emitters present a brightness higher than the threshold value during microscopic inspection. Inspired by these promising results, the authors further Correspondence: Bengang Xing (Bengang@ntu.edu.sg) investigated the heterogeneous diffusion dynamics of each Division of Chemistry and Biological Chemistry, School of Physical & UCNP and cluster in the different intracellular Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to theCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Ai and Xing Light: Science & Applications (2018) 7:16 Page 2 of 2 ab Excitation power density Cells Single UCNP (Fifth dimension) ~ 980 nm Dichromic NIR laser mirror Clusters Tube lens Camera Flip mirror Eyepiece Simple microscope setup UNCP Detector Fig. 1 5D tracking of a single UCNP in living cells. a The simple microscopic system for the inspection of a single nanoparticle with the human eye to distinguish individual particles from clusters. b The trajectories of a particular UCNP with a tunable emission upon different power intensity excitation (the fifth dimension) to investigate the complicated intracellular microenvironment microenvironment. Interestingly, it was indicated that the biological systems, which will not only allow the human diffusion coefficient of a single nanoparticle in early endo- eye to directly identify information about particular somes (0.18 μm /s) was slightly larger than that in late nanoparticles via a simple microscopic inspection but also endosomes/lysosomes (0.04 μm /s), and the relatively faster initiate an effective method to investigate the complicated movement of UCNP with a specific direction (3 μm/s) was biological microenvironment by utilizing a single-particle associated with the active migration of molecular motor technique in physiologic and pathologic processes in living proteins on microtubules or actin filaments. Moreover, they conditions. also calculated the localized environment viscosity of each particle or cluster, which provided powerful insight into Conflict of interest The authors declare that they have no conflict of interest. their surrounding protein dynamics in living cells. Com- pared with the value in the cytoplasm (11.6 ± 0.9 cP), the viscosity in early endosomes (41 ± 4 cP) was obviously lower Received: 17 March 2018 Revised: 19 April 2018 Accepted: 24 April 2018 than that in late endosomes/lysosomes (184 ± 14 cP), sug- gesting the improved protein functional capacities in the intracellular cytosol and early endosomes. More impor- tantly, besides the 3D position and multiple color domain of References each UCNP, Jin and co-workers proposed that the excita- 1. Kusumi,A., Tsunoyama, T. A.,Hirosawa, K. M.,Kasai,R.S.& Fujiwara,T.K.Tracking tion power density could act as the fifth dimension to single molecules at work in living cells. Nat. Chem. Biol. 10,524–532 simultaneously monitor various nanoparticles due to their (2014). 2. Kircher, M. F., Gambhir, S. S. & Grimm, J. Noninvasive cell-tracking methods. Nat. power-dependent optical properties (Fig. 1b). By adjusting Rev. Clin. Oncol. 8,677–688 (2011). the suitable concentrations of doped ions, a single UCNP 3. Resch-Genger, U., Grabolle,M., Cavaliere-Jaricot,S., Nitschke,R.&Nann,T. could be lit up using different irradiation densities, which Quantum dotsversusorganic dyes as fluorescent labels. Nat. Methods 5, 763–775 (2008). revealed the specific superiority of an upconversion fluor- 4. Zhou, B., Shi, B. Y., Jin, D. Y. & Liu, X. G. Controlling upconversion nanocrystals for escence microscope for bioimaging studies. emerging applications. Nat. Nanotechnol. 10, 924–936 (2015). In summary, this work presented a novel approach to 5. Ai, X. Z. et al. In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics. Nat. Commun. 7, 10432 achieve dynamic tracking of individual UCNPs based on (2016). unique 5D imaging modalities in living cells. These cap- 6. Wang, F. et al. Microscopic inspection and tracking of single upconversion abilities are extremely significant for long-term imaging of nanoparticles in living cells. Light Sci. Appl. 7, 18007 (2018).

Journal

Light: Science & ApplicationsSpringer Journals

Published: Jun 6, 2018

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