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Carbon Nanotubes as Optical Sensors in Biomedicine Consol Farrera,†,‡ Fernando Torres Andón,§,⊥ and Neus Feliu*,#,∇ †
St. John’s Institute of Dermatology, King’s College London, London SE1 9RT, United Kingdom NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, Guy’s Hospital, London SE1 9RT, United Kingdom § Laboratory of Cellular Immunology, IRCCS Humanitas Clinical and Research Institute, 20089 Rozzano-Milano, Italy ⊥ Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15706 Santiago de Compostela, Spain # Experimental Cancer Medicine, Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden ∇ Faculty of Physics, Center for Hybrid Nanostructures (CHyN), University of Hamburg, 20146 Hamburg, Germany ‡
ABSTRACT: Single-walled carbon nanotubes (SWCNTs) have become potential candidates for a wide range of medical applications including sensing, imaging, and drug delivery. Their photophysical properties (i.e., the capacity to emit in the near-infrared), excellent photostability, and fluorescence, which is highly sensitive to the local environment, make SWCNTs promising optical probes in biomedicine. In this Perspective, we discuss the existing strategies for and challenges of using carbon nanotubes for medical diagnosis based on intracellular sensing as well as discuss also their biocompatibility and degradability. Finally, we highlight the potential improvements of this nanotechnology and future directions in the field of carbon nanotubes for biomedical applications.
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maxim tissue penetration as needed for potential in vivo applications. Target-specific sensing has been achieved by surface functionalization. For example, DNA has been sensed by modifying the surface of SWCNTs with complementary oligonucleotides. The presence of target DNA was recognized upon changes in fluorescence due to changes in the dielectric constant during DNA hybridization. Such modifications open up the possibility of using engineered SWCNT-based materials to track target analytes in biological media such as complex fluids and/or in in vivo studies.3 However, before thinking of any future clinical translation, careful and systematic evaluation of their mechanism of action as well as of their potential toxicity is required. In fact, concepts have been published that enable the engineering of SWCNTs based on safe-by-design approaches (e.g., biocompatibility and degradability).
ingle-walled carbon nanotubes (SWCNTs) have been proposed as promising materials for a wide range of medical applications including imaging, delivery, therapy, diagnosis, and sensing. SWCNTs are usually referred to as a rolled-up layer of graphene; they exhibit exceptional optical and electrical properties that differ in function according to their chirality and dimensions. The semiconducting forms of SWCNTs present intrinsic energy bandgaps as a result of van Hove singularities in the electronic density of states, which define their optical properties.1 Upon photoexcitation, these nanotubes present efficient near-infrared (NIR) photoluminescence that is tunable, photostable, and susceptible to the environment.2,3 Recently, it was discovered that SWCNTs can be designed and separated to obtain desired colors of emission. The emission depends highly on changes of the dielectric constant around the SWCNTs. The sensitivity is such that it enables perturbation detection at the surface of SWCNTs at the single molecule level, which suggests the use of SWCNTs as molecular sensors. Furthermore, the possibility of designing a variety of species with diverse emission capabilities enables multiplexed imaging, which would be useful in terms of highthroughput-screening (HTS) approaches. As emission can be obtained in the NIR, it is possible to work at wavelengths with © XXXX American Chemical Society
BIOCOMPATIBILITY AND BIODEGRADABILITY OF CARBON NANOTUBES BOTH IN VITRO AND IN VIVO It is of utmost importance that the development of carbon nanotubes (CNTs) for medical applications is accompanied, or
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Figure 1. Critical steps in the design of carbon nanotubes (CNTs) for sensing applications in biomedicine. Synthesis and functionalization of the CNTs offer the first opportunity toward developing single-walled carbon nanotube (SWCNT) sensors. The in vitro testing of CNT is essential before assessing their biodistribution, biocompatibility, and biodegradation in vivo. The detection approach used is another key step towards the development of SWCNTs for sensing applications.
MWCNTs (20 mg/kg) show no acute toxicities after intravenous injection.7 Toxicological studies are required for each specific species of CNTs and also should take into account the intended use of the material.8 Once CNTs are administered, the body regulates their persistence in different ways. At one end of the spectrum, the CNTs might be excreted in urine, and at the other end, we could encounter an undesired accumulation of CNTs in a specific site of the body, such as liver, spleen, brain, or lungs. In the middle of the spectrum we find biodegradation, whereby the body, by means of different mechanisms, is able to degrade CNTs.9 It has been observed that biodegradation can change the nature of nanoparticulate materials in general and create byproducts, especially in cases where the nanostructures are formed by complex mixtures of a core nanoparticle (NP), additional molecules for targeting or imaging, and/or drugs to be delivered. Each component has to be taken into account by researchers when assessing the safety of such nanostructures.10,11 The enzymatic oxidation of CNTs in vivo can be performed by the three major peroxidasesmyeloperoxidase, eosinophil peroxidase, and lactoperoxidaseleading to biological degradation of the nanomaterials.12,13 Critically, most of those enzymes are sourced by cells from the immune system, and, therefore, researchers have questioned whether this biodegradation phenomenon could lead to undesirable activation of the immune system and/or compromising of the biocompatibility of the nanomaterials. Ideally, biodegradation would be an innocuous process enabling the safe use of CNTs in the clinic. With the aim of applying CNTs in vivo for medical purposes, the main challenge is reaching the tissue or cellular target, which is a common challenge for all nanomedicines. Both active and passive targeting strategies have been considered, but in
best preceded, by studies assessing their biodistribution, biocompatibility, and biodegradation. Systematic studies covering these properties of CNTs could potentially be used to predict and to design CNTs in an efficient, safe, and targeted manner. Carbon nanotubes in general, and SWCNTs in particular, have been modified extensively to render them compatible with physiologic aqueous environments and also to acquire additional properties for a range of purposes. Appropriate (surface) modifications of CNTs enable biodistribution, biocompatibility, and biodegradation. Researchers have traditionally used in vitro studies for the initial screening of toxicity or intracellular distribution of CNTs, but it has been in in vivo studies using murine models that have revealed many critical characteristics of CNTs. Only scattered studies have assessed the effects of human exposure to CNTs, with a lack of long-term exposure studies.4 Two main factors critically affect the biodistribution of CNTs: (i) the physicochemical properties of the CNTs, which depend on their synthesis and subsequent modifications, referring both to the material’s intrinsic properties and to their biological identity; and (ii) the route of administration, which determines the main organs of exposure and also the first line of defense or clearance. It has consistently been established that multiwalled CNTs (MWCNTs) are more toxic than SWCNTs. Nonetheless, a number of in vivo studies have described inflammatory responses, oxidative stress, fibrosis formation, and cardiovascular toxicity after airway exposure to SWCNTs.5 The use of CNTs for diagnostics or treatment at systemic levels requires studies assessing their effects in circulation, with different laboratories reporting different results depending on the materials used. For example, SWCNTs have been demonstrated to activate platelets when injected intravenously,6 whereas other studies applying high doses of B
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this direction there is still room for future improvement.14 Importantly, well-known biological barriers are in place to protect us from aggressions from potential harmful external agents. Our sophisticated “defensive” systemthe immune system, which is present throughout all the bodypresents a plethora of mechanisms aimed at protecting us from microbial or bacterial pathogens as well as chemical agents and NPs. In this sense, CNTs intended to be used for biomedical applications should be able to overcome the immune defense and ideally should not perturb it or the homeostasis in which the host is ideally kept.15 Comprehensive in vitro studies have been critical in reaching the conclusion that chemical or biological impurities increase the activation of the immune system by NPs and that size, shape, hydrophobicity, and dispersion of the nanomaterials affect their biocompatibility. Importantly, NPs effects in the host can go beyond the acute phase, affect cell types besides the immune system, and impair homeostasis in unforeseen ways. Thus, more sophisticated technologies such as next-generation sequencing should be used to assess biocompatibility.16 Overall, for the successful use of NPs, that is, CNTs in medicine, we need to ensure their biocompatibility and final fate, including the design of safe nanomaterials and the development of successful strategies to enable NPs to reach the target with high efficacy while avoiding toxic effects (See Figure 1).
To counteract these obstacles in delivery, one could use the fact that NPs typically remain stuck in intracellular vesicles for tailored applications. In other words, as the NPs are inside endosomes/lysosomes, one could think about applications in which delivery to endosomes/lyosomes and sensing in these intracellular vesicles is relevant. One example is lysosomal storage diseases. Here, specific proteins (in particular enzymes) are missing inside lysosomes. NPs could help to deliver these proteins into lysosomes or to detect the local protein concentrations.18 Using these applications circumnavigates the necessity for cytosolic release and, thus, makes delivery to the target site (i.e., endosomes/lysosomes, not the cytosol) more feasible. Another important compound in intracellular vesicles is lipids, which are accumulated in lysosomal storage diseases and are found in abnormal concentrations in a number of diseases, such as cancer. Therefore, the development of biocompatible fluorescent reporters for the sensing of lipids in endolysosomal compartments would be interesting. This strategy was recently investigated by Heller and co-workers and will be discussed below.19
CARBON NANOTUBES AS ENDOLYSOSOMAL LIPID REPORTERS Despite the current progress in medicine, a lack of probes for monitoring lysosomal lipids both in vitro and in vivo remains a challenge. Even though a variety of diagnosis systems to evaluate lipids exist, the current approaches are limited due in part to the low penetration of the probes to the critical sites of detection and to the methods engaged for the measurements. In addition, the currently employed in vivo methods use destructive methodologies. Therefore, the development of noninvasive approaches is needed. With that in mind, CNTs have been presented as an alternative sensing strategy.19 In this issue of ACS Nano, Heller and co-workers describe carbon-based optical reporters that respond to lipid accumulation through variation of the optical bandgap of SWCNTs.19 The authors designed semiconducting SWCNTs that were non-covalently functionalized with short single-stranded DNA and a single chirality, which respond to the lipid content within the endosomal lumen of live cells. The NIR photoluminescence of the SWCNTs, susceptible to the environment, enabled quantitative measurements of lipid content via solvatochromic energy shift (Figure 2A).
For the successful use of carbon nanotubes in medicine, we need to ensure their biocompatibility and final fate, including the design of safe nanomaterials and the development of successful strategies to enable nanoparticles to reach the target with high efficacy while avoiding toxic effects. CARBON NANOTUBES TRAFFICKING INTO CELLS: A DOUBLE-EDGED SWORD OF CHALLENGES AND OPPORTUNITIES In general, as mentioned above, one of the major challenges for delivery or sensing applications using NPs is achieving successful trafficking of NPs to the target site without side effects. Following cell exposure, the majority of the NPs are internalized via endocytic processes through a variety of mechanisms that are determined by the intrinsic and biological identity of the NPs.17 Endocytosis offers a natural way to deliver nanoparticulate matter into cells, but the major drawback is that the delivered NPs remain stuck inside intracellular vesicles such as endosomes/lysosomes. Briefly, upon internalization, NPs eventually traffic in vesicles from early endosomes to lysosomes and remain there until possible degradation and potential expulsion from cells through exocytosis mechanisms. However, for many applications, such as gene delivery, mRNA sensing, etc., the NPs are required in the cytosol. Unfortunately, most strategies aiming at cytosolic release of NP out of intracellular vesicles are inefficient. Thus, one of the biggest challenges in the delivery of nanoparticulate matter is that the delivered cargo remains stuck in endosomes/ lysosomes, limiting the success of the carriers.
In this issue of ACS Nano, Heller and coworkers describe carbon-based optical reporters that respond to lipid accumulation through variation of the optical bandgap of single-walled carbon nanotubes. In general, in order to evaluate the efficiency and efficacy of the reporter in vitro several aspects need to be considered, such as (i) sensitivity and efficacy, (ii) desired localization within the cell, (iii) biocompatibility, (iv) stability, as well as (v) degeneration. Therefore, the first goal of Jena et al. was to design a specific DNA−CNT hybrid (ss(GT)6-(8,6)) that reacted optically to lipid content with high solvatochromic response and sensitivity and to evaluate the response in different solvent environments. The authors found that ss(GT)6-(8,6), a single chirality SWCNT of ∼90 nm length, C
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Figure 2. Schematic representation of the optical responses of photoluminiscent carbon nanotube lipid sensors. (a) Composites of singlewalled carbon nanotube (SWCNT) non-covalently functionalized with short-single stranded DNA oligonucleotides, respond optically to lipids (i.e., LDL or cholesterol) resulting in a decrease in their emission wavelength (blue shift). (b) DNA−SWCNTs selectively accumulate in the lysosomes of living cells. Overlay of brightfield light and hyperspectral images derived from the DNA−SWCNT sensors showing the difference between healthy cells and cells with an abnormal accumulation of lipids. Adapted from ref 19. Copyright 2017 American Chemical Society.
the complexes. Therefore, in a nice approach, the authors monitored the capacity of endolysosomal organelles to hydrolyze lipoprotein molecules and found that ss(GT)6(8,6) complexes did not disturb the hydrolysis of lipoproteins. Finally, several proof-of-concept experiments demonstrating the potential use of the ss(GT)6-(8,6) complex to detect lipids in the endolysosomal organelles of live cells were conducted. The authors used interesting approaches for these proof-ofconcept experiments including the use of disease models and patient samples, where lysosomes are disturbed and lipid content accumulates within the lysosome. As mentioned above, lysosomes are acidic compartments within cells that are loaded with proteases, nucleases, and lipases, which coordinate the sorting, processing, and delivery of lipids to other membrane compartments. The impairment of lysosomal function results in the undesirable accumulation of lipids, with implications for metabolic syndromes, neurodegeneration, cancer, and aging. Indeed, some of the metabolic diseases trigger loss of degradative capacity of lysosomes. This causes aberrant accumulation of macromolecules within the lumen, leading to functional impairment of trafficking and signaling, among others. Similar lysosomal storage disorders involve the accumulation of sphingolipids, mucolipids, and sterols, which in addition impair the ability of lysosomes to degrade other macromolecules.21 Jena et al. pretreated macrophages with (i) U18666A to induce enhancement of lysosomal deposits of free cholesterol to simulate the Niemann−Pick C1 disease phenotype and with (ii) lysosomal acid lipase to induce the increase of esterified
exhibited a discrete solvatochromic signature that did not depend on pH (which is important for sensing in lysosomes). In order to explain how lipids affect the SWCNT complex and generate a solvatochromic shift, replica exchange molecular dynamic simulations were performed. The results indicated that lipid binding to the ss(GT)6-(8,6) complex decreased the water density on the SWCNT surface.20 Next, in order to investigate whether this CNT reporter could be used as a safe live-cell sensor, biocompatibility studies of the ss(GT)6-(8,6) complexes using several in vitro models including macrophages and primary cells were performed. The authors found that following exposure to cells, neither the viability, proliferation, nor the organelle integrity and morphology were affected. In terms of uptake, the internalization of ss(GT)6-(8,6) complexes was evaluated quantitatively using both NIR emission and visible fluorescence microscopy. A dose of 0.2 mg/L (∼39 pM) and 30 min exposure were chosen as experimental conditions. Curiously, this short time exposure was sufficient to provide NIR signal for detection and monitoring within live cells. Furthermore, to understand the possible trafficking pathway, mechanistic uptake studies as well as co-localization studies were performed. Their results revealed that the complexes are internalized by the cells via an energydependent process and rapidly transported to late endosomes and lysosomes. Importantly, the authors found that upon internalization, the complexes persisted within the endolysosomal pathway and accumulated in the lumen of the cells. In order to design a safe live-cell sensor, it is important to evaluate whether cell function is affected upon internalization of D
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Figure 3. Dynamic contrast-enhanced imaging with single-walled carbon nanotubes through principal component analysis. The power of the near-infrared is increased by improving the visualization of the biodistribution in specific organs and revealing otherwise undetected locations, in this case the pancreas. Reproduced with permission from ref 28. Copyright 2011 Welsher et al.
In addition, oligonucleotides accept multiple modifications in their residues and can be engineered to detect complementary sequences.24 In all, DNA offers a wide range of opportunities to explore and to expand the already impressive properties of CNTs. One may wonder whether it would be possible to design purpose-made SWCNTs to detect specific lipids and other specific biomolecules in a multiplexed manner that enables the possibility of performing HTS measurements for sensing. The ability to design new, effective targeting motives on the surface of CNTs may potentially open opportunities beyond the current approaches. A number of examples can be provided to illustrate the exciting moment the field of SWCNTs is experiencing. Mass spectroscopy was used for imaging label-free carbon NPs, a technology that could overcome detection problems derived from biodegradation of labeled materials.25 Microarrays for protein detection were developed using SWCNTs as multicolor Raman labels, showcasing the possibilities of using the robust Raman properties of SWCNTs outside traditional characterization spectra.26 Yet, it is in NIR spectroscopy where we find most studies reporting innovative applications for SWCNTs. Corona phase molecular recognition (CoPhMoRe) was used to demonstrate that SWCNTs were able to detect a specific target protein, fibrinogen, exposing a new application which should be further explored.27 Another nice example of the use of SWCNTs and their detection by NIR is the use of principal component analysis to transform NIR images and better assess the biodistribution of SWCNTs in vivo in mice (Figure 3).28 The detection of SWCNTs in the specific window of 1300− 1400 nm in the NIR in the brains of mice represents another example of the optimization process we are witnessing.29 In addition, new composites of CNTs were used to image brown fat in mice, highlighting the potential use of SWCNTs as sensors.30
cholesterol as detected in Wolman’s disease (Figure 2B). With these in vitro models ready, the authors evaluated the efficacy of their CNT reporter in cells presenting different lipid contents. They found that it is possible to create maps of spatially resolved emissions resulting from the ss(GT)6-(8,6) complexes that respond to the different accumulation of lipids as a function of loading concentration. In this way, they could obtain live-cell image maps of endolysosomal lipid content. Importantly, the imaging was not affected by the complex environment of the cells. Overall, the authors developed a platform for using the emission spectra of ss(GT)6-(8,6) complexes as a cell-specific fingerprint for lipid content. The sensitivity of the technique is such that it enables live monitoring of lipid flux within the endosomal/lysosomal compartments of the cells in a fast and reproducible manner. This methodology, which enables spectral imaging based on single-cell detection, may be applicable to a wide range of diseases. These findings could promote the development of new in vitro as well as in vivo deeptissue photoluminescence diagnosis-based imaging systems in the NIR.
AVENUES TO DEVELOP CARBON NANOTUBES AS SENSORS Undoubtedly, researchers still face many challenges before we can take full advantage of the possibilities SWCNTs offer. However, the synthesis of CNTs is moving in the right direction with a range of strategies being already implemented to obtain monodisperse solutions of homogeneously sized and single-chirality SWCNTs.22,23 The precise synthesis of SWCNTs is of great relevance for the consistency and reproducibility of any new development and for its future applicability regarding good manufacturing practice (GMP). Photoluminescence detection of semiconducting SWCNTs of well-defined chirality is a clear example of this paradigm. However, the ability to design safe CNTs requires further knowledge on how CNTs and cells/tissues interact. Surface functionalization of SWCNTs can add new properties to the pre-existing ones. DNA, miRNA, lipids, or compounds bearing aromatic moieties can be adhered to nanotubes by non-covalent binding. Among them, nucleic-acidbased groups stand out as great assemblers for NPs. These versatile molecules can be added as single-stranded or doublestranded chains or can be designed to fold in several conformations, such as B-DNA and a range of non-B DNA.
CONCLUSIONS AND OUTLOOK The development of CNT photoluminescence for imaging and sensing applications is driven by the need of nanotechnology improvement to address important questions that are currently not achieved or understood.31 The study presented by Heller and colleagues in this issue of ACS Nano is a prominent example. It highlights the potential use of photoluminescence technology to be applied in in vitro assays, to perform single cell analysis, or even to assess intracellular differences in a specific context, that is, endolysosomal lipid detection. Thus, it seems E
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straightforward to see the potential for the development and commercialization of tools to assess NIR in vitro and in vivo using the promising properties of CNTs. Overall, the precise synthesis of SWCNTs is moving now toward the construction of elaborate composites that will benefit both from the properties of CNTs and from new abilities added by the additional components. It is also clear that improvements in the tools used to detect those composites, such as the ones we have exemplified here, benefit the entire field and can be used by others in many yet unforeseen applications, in addition to the specific purpose the researchers had in mind. We envision the design of DNA− CNT sensors for a diversity of biomedical applications. Indeed, the power to take advantage of both the physicochemical properties of the CNTs and the new abilities added by their surface functionalization increases the potential for the development of new safe-by-design hybrid materials with better efficiency, selectivity, and sensitivity in the field of biomedical sensing.
AUTHOR INFORMATION Corresponding Author
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[email protected]. ORCID
Fernando Torres Andón: 0000-0001-9235-1278 Neus Feliu: 0000-0002-7886-1711 Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS C.F. acknowledges funding from the NIHR Biomedical Research Centre at GSTNFT and KCL. F.T.A. acknowledges funding from a Marie Skłodowska-Curie Individual European Fellowship (H2020-MSCA-IF-2014-EF-ST) from the European Commission for the project NANOTAM, no. 658592, and from the Worldwide Cancer Research, UK. N.F. acknowledges funding from the Swedish Innovation Agency (Vinnova). REFERENCES (1) Cao, L.; Meziani, M. J.; Sahu, S.; Sun, Y. P. Photoluminescence Properties of Graphene Versus Other Carbon Nanomaterials. Acc. Chem. Res. 2013, 46, 171−80. (2) O’Connell, M. J.; Bachilo, S. M.; Huffman, C. B.; Moore, V. C.; Strano, M. S.; Haroz, E. H.; Rialon, K. L.; Boul, P. J.; Noon, W. H.; Kittrell, C.; Ma, J.; Hauge, R. H.; Weisman, R. B.; Smalley, R. E. Band Gap Fluorescence from Individual Single-Walled Carbon Nanotubes. Science 2002, 297, 593−596. (3) Jena, P. V.; Galassi, T. V.; Roxbury, D.; Heller, D. A. Review Progress Toward Applications of Carbon Nanotube Photoluminescence. ECS J. Solid State Sci. Technol. 2017, 6, M3075−M3077. (4) Maynard, A. D.; Baron, P. A.; Foley, M.; Shvedova, A. A.; Kisin, E. R.; Castranova, V. Exposure to Carbon Nanotube Material: Aerosol Release During the Handling of Unrefined Single-Walled Carbon Nanotube Material. J. Toxicol. Environ. Health, Part A 2004, 67, 87− 107. (5) Ema, M.; Gamo, M.; Honda, K. A Review of Toxicity Studies of Single-Walled Carbon Nanotubes in Laboratory Animals. Regul. Toxicol. Pharmacol. 2016, 74, 42−63. (6) Radomski, A.; Jurasz, P.; Alonso-Escolano, D.; Drews, M.; Morandi, M.; Malinski, T.; Radomski, M. W. Nanoparticle-Induced Platelet Aggregation and Vascular Thrombosis. Br. J. Pharmacol. 2005, 146, 882−893. (7) Lacerda, L.; Ali-Boucetta, H.; Herrero, M. A.; Pastorin, G.; Bianco, A.; Prato, M.; Kostarelos, K. Tissue Histology and Physiology F
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DOI: 10.1021/acsnano.7b06701 ACS Nano XXXX, XXX, XXX−XXX
