Optical Sensing of Small Ions with Colloidal Nanoparticles

Quantum dots. Surya Kant Tripathi , Rajneet Kaur Khurana , Gurvir Kaur , Teenu , Bhupinder Singh. 2016,71-100. Ultrasensitive optical detection of ani...
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Optical Sensing of Small Ions with Colloidal Nanoparticles Dorleta Jimenez de Aberasturi,†,‡ Jose-Maria Montenegro,‡ Idoia Ruiz de Larramendi,† Teófilo Rojo,† Thomas A. Klar,§ Ramon Alvarez-Puebla,⊥ Luis M. Liz-Marzán,⊥ and Wolfgang J. Parak*,‡ †

Department of Inorganic Chemistry, UPV/EHU, Bilbao, Spain Fachbereich Physik and WZMW, Philipps Universität Marburg, Marburg, Germany § Institute of Applied Physics, Johannes Kepler University, Linz, Austria ⊥ Departmento de Química-Física, Universidade de Vigo, Vigo, Spain ‡

ABSTRACT: Colloidal nanoparticles, in particular gold nanoparticles and quantum dots, can be used in a variety of different assays for optical sensing of small ions in solution. In this review, different detection principles are introduced and their potential use for detection in biological samples (such as intracellular sensing) is discussed.

KEYWORDS: colloidal nanoparticles, quantum dots, plasmonics, optical ion sensing

I

they are linked to hydrophilic NPs, they would be incorporated by cells via endocytosis-type pathways, which are common for NPs.18,19 In this way, integration in NPs allows for different interactions of the fluorophores with cells. Besides serving as mere carriers, the NPs can also actively modify the properties of the fluorophore. With semiconductor NPs, so-called quantum dots (QDs), Förster resonance energy transfer (FRET), with the QDs acting as donor and the organic fluorophores as acceptor, is possible,20,21 whereby the effective fluorescence lifetime of the fluorophore will be determined by the lifetime of the QD.22,23 Coupling of fluorophores to QDs thus allows for tuning effective fluorescence lifetimes, which can be an advantage, for example, for time-gated fluorescence detection24 in which longer lifetimes are desirable in order to reduce autofluorescence effects.25 Also the pK of the fluorophores can be adjusted by coupling them to NPs. Because typically NP surfaces are charged, ion concentrations at the particle surface are different from those in bulk. In first order, this can be understood by Debye−Hückel screening, that is, attraction of counterions.16,17 By tuning of the NP charge, local ion concentrations can be adjusted compared with bulk. Because fluorophores at the NP surface sense the local and not the bulk ion concentration, the effective pK of fluorophores can be tuned with this modification of the NP charge.26 This demonstrates that even by using NPs “only” as passive carrier systems for organic ion sensitive fluorophores, interaction with cells and sensing properties can be modulated purposefully. Detection of several ions inside cells has been demonstrated.12,18,27−29 Because the sensing part is warranted by the

ons can be detected and their concentration determined by means of a variety of optical techniques. In particular, optical read-out is a good choice for intracellular detection, since alternative techniques such as electrochemical electrodes are more cumbersome to apply inside cells. In this review, we highlight how colloidal nanoparticles (NPs) can contribute toward optical sensing of small ions.1−5 Hereby the NPs can play different types of roles, ranging from being merely employed as ion sensor carrier systems to active sensing and transducing elements. In the following, seven concepts will be presented, see Figure 1, whereby optical read-out will be based on fluorescence, plasmonics, or surface-enhanced Raman scattering spectroscopy. The main idea behind this review is the classification of these different detection concepts. a. NPs Acting As Carrier Systems for Organic Ion Sensitive Fluorophores, Thus Possessing Ion-Sensitive Fluorescence Read-Out (Figure 1a). Organic fluorophores for which emission depends on the presence of specific ions are available for a wide variety of ions.6−11 These fluorophores can be coupled to the surface or inside the volume of NPs, which serve as passive carriers.12−18 Such coupling can have several advantages. First, because several fluorophores can be coupled to each NP, the signal intensity of one NP (carrying several fluorophore units, which are thus situated at the same location) is significantly increased compared with one single fluorophore. This is helpful for single-molecule/NP experiments, in particular because the integration of several fluorophores to one single NP object also reduces blinking effects. Naturally this advantage is achieved at cost of size, though fluorophoredecorated NPs still can have hydrodynamic diameters below 10 nm.16 In addition, different fluorophores can be integrated on the same NP, thus allowing for ratiometric detection.3,13−15,17 NPs can be incorporated by cells via different pathways than those of the free fluorophores. Small hydrophobic fluorophores could be, for example, membrane permeable, whereas when © 2011 American Chemical Society

Special Issue: Materials for Biological Applications Received: August 11, 2011 Revised: December 6, 2011 Published: December 12, 2011 738

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Figure 1. Detection schemes. (a) NPs as carrier systems for ion sensitive organic fluorophores, thus possessing ion-sensitive fluorescence read-out. Ion-sensitive fluorophores (drawn in green) are attached to carrier NPs (drawn in red). Specific binding of ions (drawn in black) changes the fluorescence read-out of the fluorophores. (b) NPs whose fluorescence read-out is quenched or enhanced by direct binding and presence of ions at the NP surface. Fluorescent NPs, in particular QDs (drawn in green), are modified on their surface (drawn in yellow) in a way that allows specific binding of ions (drawn in black). Ion binding quenches or enhances the fluorescence read-out of the QDs. (c) Fluorescent NPs that use a molecular recognition element for ions, which triggers a process for quenching or enhancement of fluorescence read-out. Quenchers (drawn in red; could be optionally Au NPs) are linked via a molecular recognition element (drawn in yellow) to the surface of fluorescent NPs, in particular QDs (drawn in green). Binding of ions (drawn in black) changes the conformation of the recognition element and thus the QD−quencher distance, which controls the fluorescence read-out. (d) NPs that act as quencher to an organic fluorophore, whereby the distance between quencher and fluorophore and thus the fluorescence read-out is controlled by ions. Au NPs as quenchers (drawn in red) are linked via a molecular recognition element (drawn in yellow) to organic fluorophores (drawn in green). Binding of ions (drawn in black) changes the Au NP−fluorophore distance and thus the fluorescence read-out of the organic fluorophore. (e) Plasmonic NPs of which the surface plasmon shifts upon binding of ions to the NP surface. Metal NPs (drawn in red) are coated on their surface (drawn in yellow) in a way that ions (drawn in black) can selectively bind. Ion-binding changes the plasmonic read-out of the NPs. (f) Plasmonic NPs that are modified with a recognition element for ions that changes the inter-NP distance and thus plasmonic read-out. Metal NPs (drawn in red) are coated with a recognition element (drawn in yellow) for ions (drawn in black), which changes conformation upon ion-binding. Change in conformation involves changes in the interparticle distance, which can be read-out from the plasmonic signal. (g) NPs that enhance Raman scattering of ion-binding molecules. Metal NPs (drawn in red) are coated with Raman-active molecules (drawn in green). Binding of ions (drawn in black) to the molecules changes the Raman signal, which is enhanced by the presence of the NPs.

fluorescence. Binding of ions to the surface coating abolishes quenching and restores QD fluorescence.36−39 Because chelators for specific ions can be used as surface coating, the selectivity for certain ions is enhanced. Recent developments in surface coatings will also pave the way for even higher specificity. Stellacci et. al have reported striped surface coatings of mixed composition on the surface of Au NPs, which likely can be achieved also on the surface of QDs.40 First initial experiments have pointed toward very high selectivity of these surface coatings to specific ions (Francesco Stellacci, personal communication). At any rate, one problem of such sensors is imposed by biological fluids, which contain significant amounts of NaCl. The presence of NaCl causes NPs to agglomerate, which in turn changes fluorescence emission. Because the surface of the QDs is the active sensing part, the optimization of the surface chemistry concerning colloidal stability is limited. In particular, this renders intracellular ion detection complicated, because the cytoplasm of cells is rich in NaCl. On the positive side, such QD-based ion sensors are easy to prepare and low in cost and thus have been applied also plentifully for ion detection in cells, predominantly for H+. Though singlemolecule detection is in principle possible, blinking makes such experiments problematic.

fluorophores, the NP surface can be tailored in a way to make them highly colloidally stable. Thus, limitations in ion detection using NPs as “passive” carrier systems for ion-sensitive organic fluorophores are mostly related to the intrinsic properties of the organic fluorophores. b. NPs Whose Fluorescence Read-out Is Quenched or Enhanced by Direct Binding and Presence of Ions at the NP Surface (Figure 1b). Quantum dots (QDs) are intrinsically fluorescent semiconductor NPs.30,31 Due to their fluorescence, QDs can be used as active sensors and transduction elements for ion sensing. Soon after QDs could be routinely synthesized in aqueous solution, several research groups discovered that the fluorescence intensity of the QDs can be quenched or enhanced by the presence or binding of certain ions at the NP surface.32−35 Quenching is, for example, caused by ion-induced generation of surface states. Some specificity can be obtained by variations in the surface coating, allowing the modulation of the binding affinity of different types of ions. However, specificity with this type of sensor format is certainly restricted. Also surface coatings that initially quench the QD fluorescence have been reported. Hereby the surface coating interacts with the photogenerated electron− hole pairs and thus prevents radiative recombination, that is, 739

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c. Fluorescent NPs Comprising a Molecular Recognition Element for Ions, Which Triggers Quenching or Enhancement of Fluorescence Processes (Figure 1c). In this case, fluorescence again originates from intrinsically fluorescent QDs. However, in contrast to sections a and b, the QDs are not the active sensing element but are mere transducers for fluorescence read-out. The actual sensing is performed by a molecule that binds certain ions and thereby changes conformation. Organic chemistry offers a whole toolkit of ion-binding molecules, such as chelators, with high specificity. In contrast to active sensing with QDs as described above, recognition of ions is now accomplished by the principle of molecular recognition, which allows for high selectivity. Upon ion binding, the recognition molecules change their conformation. There can be, for example, a bending−stretching transition, as demonstrated by the Willner group for Ag+ and Hg2+ ions.41 Typically the recognition molecules are attached on one side to the QD surface and are modified at the other side with a quencher. Conformation changes upon ion binding alter the distance of the quencher to the QD surface and thus can be detected via the fluorescence read-out of the QDs. Due to the involved molecular recognition (in this case ions selectively bound to DNA), a very high selectivity can be achieved. Instead of changing the distance between a fluorescent QD and a quencher, the distance between different QDs can be controlled by ions as well. In this case, the emission of the different QDs is selected in a way that Förster resonance energy transfer (FRET) can occur. In such FRET pairs of QDs, the presence of ions causes controlled agglomeration of the QDs and hence induces a FRET signal. This signal can be monitored either by the reduction of the donor emission, an increase of the acceptor emission, a decrease of the donor fluorescence lifetime, or an increase of the acceptor lifetime. For instance, Mayilo et al. have shown that water-soluble CdTe NPs, which are covered by negatively charged carboxylic groups, can be clustered by divalent positively charged ions such as Ca2+ or Mg2+ coordinated to the negatively charged carboxylic acid groups acting as electrostatic chelating linkers.42 An efficient FRET was obvious in the emission spectra and could also be observed in the luminescence decay times of binary- and triple-sized CdTe NP clusters where the larger sized QDs act as the acceptors of energy. FRET was also observable in nominally single-sized samples because of inhomogeneous distribution of the QD diameters. Excitation energy transfer toward acceptor NPs in binary clusters resulted in the increase of the acceptor emission intensity by 77%. Most important, monovalent ions such as Na+ and K+ did not induce clustering, and hence no FRET signal was observed. Therefore, water-soluble CdTe nanocrystals that are covered by carboxylic groups can be used as specific sensors for multivalent cations. Even more sophisticated “conformation” changes can be achieved by ion-mediated assembly of molecules. The Willner group has, for example, demonstrated that (nonfunctional) fragments of a hemin-G quadruplex DNAzyme can be assembled into an active structure under the presence of Hg2+.43 The active molecule can trigger the fluorescence of the QDs, which in this case was stimulated chemoluminescence energy transfer (CRET) from the DNAzyme to the QD. This approach is certainly more complicated than the previous one, because it requires molecular recognition elements to which ions specifically bind. However, this complexity allows for higher selectivity. Problems with colloidal stability are less severe, because ions do not need to bind directly to the QD

surface but to the recognition elements, which in turn act as improved surface coatings increasing the stability of the colloidal solution. However, the detection on a single NP base is not straightforward due to blinking of the NPs. d. NPs That Act as Quencher to an Organic Fluorophore, Whereby the Distance between Quencher and Fluorophore and Thus the Fluorescence Read-out Is Controlled by Ions (Figure 1d). This concept is similar to the one presented in section c, though in this case fluorescence read-out is provided by an organic fluorophore and the NPs act as quenchers. Gold NPs can substitute for the organic acceptor molecules in molecular beacons like DNA assays and even outrange organic acceptors in their quenching efficiency rendering single base mismatch detection feasible.44,45 The large quenching efficiency of Au NPs is not only due to their strong absorption band associated with the plasmonic resonance, but it is also because the Au NPs affect the radiative lifetime of adjacent dye molecules.46,47 Similarly to oligonucleotide detection, fluorescence quenching by Au NPs can also be used to detect ions. He et al.48 have used pyridyl functionalized fluorophores, which coordinate to Au NPs. As long as the pyridyl is coordinated to the Au NPs, fluorescence is quenched. When Cu2+ ions are added, they coordinate much more strongly to the pyridyl molecules than Au NPs, and hence the pyridyl leaves the NPs, and the fluorescence is recovered. This sensor even turned out to detect Cu2+ selectively because pyridyl is insensitive to monovalent and trivalent metal ions, as well as to Ca2+. Only a weak response was detected upon the addition of Co2+ and Ni2+ ions, which was however decisively smaller than the Cu2+ ion signal. Huang and Chang49 have demonstrated a sensor relying on fluorescence quenching by Au NPs for the detection of mercury(II). They used rhodamine B molecules, which show a weak affinity for Au NPs and are therefore quenched in a mixed solution. Rhodamine B molecules coordinate with Hg2+ ions, which leads to desorption from the Au NPs. Consequently, the rhodamine B is unquenched. Modification of the Au NP surface with thiol and chelating ligands further improves the sensitivity of this sensor.49 Chen and co-workers50,51 improved this type of ion sensor to a limit of detection of 60 pM. Similar work has been reported by Wang et al.52 They have used dye-tagged oligonucleotides where the oligonucleotides adsorb on the surface of Au NPs. Upon addition of Hg2+ ions, the oligonucleotides hybridize. The fluorescence increases because hybridized oligonucleotides adsorb to Au NPs much more weakly than single-stranded oligonucleotides. A limit of detection of 80 nM was achieved with this technique. Though this type of sensor works with plasmonic NPs, read-out is provided by the fluorescence of organic fluorophores. e. Plasmonic NPs Whose Surface Plasmon Shifts upon Binding of Ions to the NP Surface (Figure 1e). Several metal NPs such as Au and Ag NPs can be optically excited leading to a collective oscillation of the free electrons, the socalled localized surface plasmon resonance (LSPR). LSPR can be detected in absorption, transmission, and scattering configurations. Binding of molecules to the surface of plasmonic NPs can change the LSPR wavelength due to changes in either the local refractive index or surface charge.53 Again the problem of specificity arises, similar to the one described in section b. As mentioned there, advanced patterning with self-assembled striped domains may have significant impact toward specific recognition of ions, as reported by Stellacci et al.40 Because detection is based on 740

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plasmon resonances, no blinking effects occur, which makes such sensors very suitable for single NP detection experiments. On the negative side, also in this case colloidal stability (which is reduced by the presence of high NaCl concentration) may interfere with the sensor read-out. Agglomeration of NPs due to salt-mediated screening of their surface charge leads to coupling of the plasmons of adjacent NPs, thereby changing the spectral signature and corrupting the detection signal. For single-molecule detection, this problem can be circumvented by immobilization of NPs on a substrate, which however would exclude intracellular detection schemes. Plasmon coupling, though, can be also used as active read-out as will be described in the following. f. Plasmonic NPs That Are Modified with a Recognition Element for Ions That Changes the Inter-NP Distance and Thus Plasmonic Read-out (Figure 1f). As pointed out above, the LSPR of plasmonic NPs is dramatically shifted by coupling of the plasmons of adjacent NPs.54,55 Au NPs can be modified with surface coatings that bind specific ions, such as chelators. In the case that chelators are designed in a way that one ion can be coordinated to two chelators, the ions induce cross-linking and thus agglomeration of the NPs. In this way, the presence of ions can be observed in the LSPR spectrum.56,57 Higher specificity can be achieved by using the key−lock interaction of biological receptor−ligand pairs as recognition elements. This effect has been used in immunoassays already in the early 1980s.58−61 Gold nanoparticles were functionalized with two different monoclonal antibodies against human chorionic gonadotropin (HCG, present in the urine of pregnant women). When the Au NPs were dissolved in urine of pregnant women, a color change could be observed in a spectroscopic setup.61 Quickly, the technique was improved such that the color read-out taken by the naked eye gave correct results with more than 99% confidence.58,60 Mirkin and co-workers applied the “coupled plasmon resonance technique” to DNA detection,62 in which plasmonic NPs are modified with oligonucleotides.62,63 Presence of cDNA in solution links the NPs, and in turn, the LSPR shifts.64 The same idea can be used for the detection of ions. Hereby aptamers are used, which bind to specific ions. Upon ion binding, the aptamers (in this case oligonucleotides) change their conformation. Conformational changes affect the binding properties of the aptamers to the DNA strands attached to the plasmonic NPs.65−67 Thus, the presence of ions tunes the state of agglomeration of the NPs, which can be detected by changes in LSPR. Because for steep transition curves (free NPs versus agglomerated NPs) cooperative effects are required,68 each NP has several strands of oligonucleotide attached and thus can be linked with several other NPs. The advantage of this method lies therefore in ensemble, rather than in single-molecule, detection experiments. Though first generation sensors of this type highly suffered from colloidal instability of the NPs (again high concentrations of NaCl can cause agglomeration), the field has advanced, and nowadays highly colloidally stable plasmonic NPs are available. NPs saturated on their surface with DNA are an example.69 Because changes in LSPR can be, under best conditions, seen by eye due to a color change of the NP solution, this assay format has already been implemented in practice for several applications. g. NPs That Enhance Raman Scattering of Ion-Binding Molecules (Figure 1g). Raman scattering is based on the fact that light incident on molecules can gain or lose energy due to coupling with internal molecular modes (e.g., vibrations),70

which leads to scattered light of higher or lower frequency (anti-Stokes or Stokes peaks), respectively. Surface-enhanced Raman scattering (SERS) spectroscopy, also known as plasmon-assisted Raman scattering,71,72 can be defined as Raman scattering carried out on a plasmonic surface. This technique is a powerful analytical tool, with potential detection limits down to the single molecule. SERS is based on the coupling of the vibrational modes of the molecule under study with the electromagnetic field generated by a metallic nanostructure upon excitation with the appropriate light. As a molecular spectroscopy, SERS can only be readily applied to molecular entities and has been successfully employed in the detection of inorganic oxoanions in natural waters (i.e., perchlorate, sulfate, or nitrate) and other species such as cyanide or sulfocyanide.73−77 Determination is based either on electrostatic affinity by adjusting the surface charge or on chemical affinity of the cyanide group. However, until recently, SERS analysis was considered restricted to molecular entities, and identification of inorganic ions was limited to those that form stable oxides or oxyanions in solution, such as Nb2O5, CrO42−, MoO42−, WO42− TcO4− or UO2+ or NpO2+.78−81 In such cases, SERS provides information regarding not only the presence of the chemical element but also its chemical form, oxidation state, or complexation, which is a critical aspect in the toxicological issues of these ions. Notwithstanding, SERS as a molecular spectroscopy is unable to detect atomic species directly. However, detection of atomic ions can be achieved by binding an organic ligand to the plasmonic surface and monitoring the change in its spectra when a certain zerovalent or ionic ion is present. In this way, detection of protons, copper, zinc, mercury, and cadmium has been reported.82−86 Further, to date some activity had been registered in the engineering of remote sensors to remotely obtain information from the interior of living organisms such as cells.87−90 One potential drawback for detection in cells is the great abundance of background Raman signal, which requires careful selection of the region of the spectra that is used for detection. Notably, a method for the ultrasensitive quantitative detection of chlorine has been rencently reported, based on changes induced in the vibrational spectra of 2-(2-(6-methoxyquinoliniumchloride)ethoxy)-ethanamine-hydrochloride (amino-MQAE) upon exposition to Cl−.91 Contrary to early works about ion detection with SERS, which benefitted from extended nanostructured thin films, this sensor was mounted onto a micrometer-sized nanostructured particle comprising dense collections of hot spots and the ability to resist agglomeration phenomena. Due to the extremely high ionic strength characteristic of biofluids, this latter characteristic becomes essential for the development of new sensing devices for the multiplex monitorization of, for example, metabolic changes in different regions of a cell. These approaches may pave the road for future development of sensors for direct and simple determination of ionic atoms in biofluids. Detection is also possible on a single NP level and no blinking effects are associated. Still, Raman microscopes are just becoming standard equipment in laboratories and thus widespread use of this detection principle in the future is foreseeable. The multiplex ultrasensitive SERS detection of atomic anions and cations is still in its infancy, and further research needs to be carried out before actual implementation as a spectroscopic tool for field measurements. Clearly it would be interesting to directly compare sensitivity and selectivity of the above-mentioned detection principles. However, performance depends not only on the intrinsic 741

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Figure 2. Read-out signal and generation of calibration curve for the detection of H+ with some of the methods (a−g) as sketched in Figure 1. (a) The pH indicator SNARF was attached via 10 kDa PEG spacers to the surface of Au NPs.16 Fluorescence spectra were recorded in solutions of different pH. For each pH value the maximum emission intensity of the yellow and green peak were determined. The ratio of the emission intensity of the yellow and red peak is a measure of the pH of the solution and leads to a sigmoidal response curve. The shown data were adopted from Zhang et al.16 (b) Polymer-coated QDs106 were added to solutions of different pH, and fluorescence spectra were recorded as described in Susha et al.35 At low pH, the QDs start to agglomerate, which involves quenching of their fluorescence. The emission intensity at the excitation peak is a measure for the pH of the solution and leads to an approximately sigmoidally shaped response curve. Note that in the present case, specificity for H+ is low, as also the presence of salt would lead to fluorescence quenching. (f) Polymer-coated Au NPs106 were added to solutions of different pH, and absorbance spectra were recorded. At low pH, the Au NPs start to agglomerate, which involves reduction (and broadening and red-shift) of the plasmon peak. The absorbance at the plasmon peak is a measure for the pH of the solution and leads to an approximately sigmoidally shaped response curve. (g) Ag NPs capped with a monolayer of mercaptobenzoic acid were added to solutions of different pH and Raman spectra were recorded. The Raman shift of certain Raman peaks shifts with pH, leading to a linear response curve.

Table 1. References for Sensing of Hg2+ and Cu2+ with the Different Detection Principlesa

a

detection principle

a

b

c

d

f

g

detection of Hg2+ detection of Cu2+

107 13,110

35,108 32,33,111

43,109 112

49−52 48

65,67

82,83,86 82

The letters a−g refer to the detection principles as sketched in Figure 1.

detection or vice versa, for example. In order to demonstrate the difference in practical read-out, we have performed sensing of H+ using several of the above-mentioned detection principles. Sensing of pH arguably is the easiest case with respect to specificity. Nevertheless data of Figure 2 visualize the origin of the read-out for the different methods. In addition in Table 1 references for the detection of Cu2+ and Hg2+ for the different detection principles are given.

detection principle, but also highly on the applied surface coating, which is responsible for specifically recognizing ions. For this reason, sensitivity and selectivity is often rather determined by the chemical composition than by the intrinsic detection principle. Because authors from different groups typically used different surface chemistries for the respective detection principles a fair direct comparison is complicated. Performance also in general depends on the type of applications, which can favor absorption versus fluorescence 742

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The above listed seven detection principles show that NPs can contribute in many different ways toward developing optical detection techniques for determination of ion concentrations. Though most of the above-described assays are still restricted to test solutions, application for intracellular ion detection can be predicted. One major problem is colloidal stability, which needs to be provided for such applications. This problem is particularly evident for the detection principles in which read-out depends on direct binding of ions to the NP surface (sections b and e), which limits employing coating strategies for enhanced colloidal stability. Maybe the biggest future challenge is related to the delivery of the NP sensors to cells.19,92,93 NPs are (as microparticles) incorporated via endocytotic pathways into cells and are located to a large extent in acidic endo- or lysosomal compartments.24,94−96 In this way, ion concentrations inside the endosome or lysosome can be determined.18,26,88,97 For delivery to the cytosol, classic techniques such as microinjection and electroporation98−100 have been reported. Recent developments in surface coatings promise the potential to use natural uptake mechanisms for NP translocation to the cytosol.101−104 Nevertheless NP delivery to the cytosol is still a technological challenge. Cellular uptake also raises the issue of cytotoxicity.105 So far, for in vivo applications no final statement can be yet concluded. However, it is safe to say that intracellular ion detection with NPs is possible in vitro. This is based on the fact that NPs can be applied in moderate doses and for moderate incubation times, leaving aside the problem of long-term effects, which need to be considered for in vivo applications. Thus the way of optically detecting intracellular ion concentrations with NPs has just begun.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].



ACKNOWLEDGMENTS



REFERENCES

This work was supported by the European Commission (EC, Grant Namdiatream, W.J.P.) and the German Research Foundation (DFG, Grant PA794/11-1, W.J.P.). L.M.L.-M. acknowledges funding from the Spanish MICINN (Grant MAT2010-15374).

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