Bridging Lanthanide to Quantum Dot Energy Transfer with a Short

Letter pubs.acs.org/JPCL

Bridging Lanthanide to Quantum Dot Energy Transfer with a ShortLifetime Organic Dye Sebastián A. Díaz,† Guillermo Lasarte Aragonés,†,‡ Susan Buckhout-White,† Xue Qiu,§ Eunkeu Oh,∥,⊥ Kimihiro Susumu,∥,⊥ Joseph S. Melinger,# Alan L. Huston,∥ Niko Hildebrandt,§ and Igor L. Medintz*,† †

Center for Bio/Molecular Science and Engineering, Code 6900, ∥Optical Sciences Division, Code 5600, and #Electronic Science and Technology Division, Code 6800, U.S. Naval Research Laboratory, Washington, DC 20375, United States ‡ College of Science, George Mason University, Fairfax, Virginia 22030, United States § NanoBioPhotonics, Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Université Paris-Sud, CNRS, CEA, 91400 Orsay, France ⊥ Sotera Defense Solutions, Columbia, Maryland 21046, United States S Supporting Information *

ABSTRACT: Semiconductor nanocrystals or quantum dots (QDs) should act as excellent Förster resonance energy transfer (FRET) acceptors due to their large absorption cross section, tunable emission, and high quantum yields. Engaging this type of FRET can be complicated due to direct excitation of the QD acceptor along with its longer excited-state lifetime. Many cases of QDs acting as energy transfer acceptors are within time-gated FRET from long-lifetime lanthanides, which allow the QDs to decay before observing FRET. Efficient QD sensitization requires the lanthanide to be in close proximity to the QD. To overcome the lifetime mismatch issues and limited transfer range, we utilized a Cy3 dye to bridge the energy transfer from an extremely long lived terbium emitter to the QD. We demonstrated that short-lifetime dyes can be used as energy transfer relays between extended lifetime components and in this way increased the distance of terbium−QD FRET to ∼14 nm.

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scale of 7−11 nm, but FRET still decays as a function of donor−acceptor separation to the inverse sixth power, making long-distance energy transfer hard to detect (additionally timegating results in some signal loss).13 To extend the distance at which a strong signal is still detected, we have exploited intermediate transfer or relay steps that allow energy transfer at higher efficiency. Examples of intermediate energy transfer steps within lanthanide-doped nanoparticles14,15 as well as molecular photonic wires with QDs and organic dyes are available in the literature.16−18 The specific question that we wished to answer here was, could a short-lived dye (shorter by orders of magnitude) be used to relay energy between two much longer lived components, and if so, would the results from these lifetime-mismatched components follow FRET theory predictions? In the experimental format applied here, the constructs utilized test whether a short-lived organic dye (Cy3, with fluorescence lifetime τ = 1.34 ± 0.04 ns) could serve as a bridge between two long-lived fluorophores such as a Tb donor (Lumi4-Tb, Lumiphore, Inc. τ = 2.5 ± 0.2 ms)19,20 and a QD acceptor (τ = 20.3 ± 0.2 ns); see Figure 1.21 The short photoluminescence (PL) decay of dyes and the more efficient

emiconductor nanocrystals or quantum dots (QDs) are excellent components of Förster resonance energy transfer (FRET) pairs.1 They are typically used as FRET donors due to their broad excitation with narrow emission spectra, high quantum yields (ϕ), large absorption cross section/extinction coefficients, large “effective” Stokes shifts, and long excited-state lifetimes. Many of the same properties that make them good FRET donors should also make them good acceptors as well. However, it is hard to find an adequate photon wavelength that will not excessively excite the QD directly with their long-lived excited-state lifetimes (5−20 ns) thus depopulating the acceptor ground state necessary for FRET. A few strategies have been employed to take advantage of QDs as FRET acceptors; these include using large donor to single QD acceptor ratios, chemi- and bioluminescence to avoid direct QD excitation, and time-gated FRET measurements.2−5 The long excited-state lifetimes of lanthanide cryptates create an opportunity to measure the sensitized emission of the QD after complete decay of any directly excited fluorescence, a technique commonly known as time-gated FRET.6 By using time-gated measurements, the energy transfer can be observed with minimal background signal. This has allowed for excellent sensitivity with biosensors, fluorescence microscopy, as well as immunoassays.7−12 A terbium (Tb)−QD FRET pair will generally have a relatively large Förster distance (R0, the distance at which the energy transfer efficiency is 0.5) on the © XXXX American Chemical Society

Received: March 9, 2017 Accepted: April 21, 2017

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DOI: 10.1021/acs.jpclett.7b00584 J. Phys. Chem. Lett. 2017, 8, 2182−2188

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Figure 1. Schematic of the bridged Tb−Cy3−QD energy transfer system. (A) Component DNAs. Short strands are 9 or 10 base pairs (bps) long. Templates could be 19, 28, or 37 bps long. The 5′ end of the DNA is marked by an arrowhead. Brown arrows represent FRET transfer steps seen below. The His6−Tag DNA hybridizes to the templates, which then also provide a hybridization site for the variably spaced Cy3− and Tb−DNA strands. The final construct is self-assembled to the QD’s outer ZnS shell via His6-driven metal affinity coordination. (B) The four QD-DNA systems investigated were labeled W′9−10′, W′18−10′, W′27−10′, and W′18−19′. Distances between fluorophores were determined from individual FRET measurements. Predicted distances are provided in the SI. (C) Extinction coefficients versus wavelength of the Tb, Cy3, and 608 nm emitting QDs. The QD is represented at a 1/20 scale so as to observe the features of the other components. (D) PL spectra of the three components.

not consider this to be a significant contributor in the current system.1,26 Within the modular DNA system, the distance was controlled by choosing different template DNA strands. This minimized costs as well as differences in the DNA environment of the Cy3 and Tb fluorophores (see Figure 1). A hybrid peptide−DNA strand with a His6-tag (a hexahistidine peptide section) was utilized to bind the DNA wires to the Zn2+ ions on the QD surface via direct metal affinity coordination.27,28 Due to the fact that both the QDs short CL4 zwitterionic surface ligand29 and the DNA present negative charges, a 1×TA (Trisacetate) buffer supplemented with 12.5 mM Mg2+ was required for conjugation as it overcame the electrostatic repulsion of the structures. For detailed structural formation and characterization, see the Materials and Methods section and Supporting Information (SI). This design yields QD-scaffolded DNA photonic wires with a terminal Tb fluorophore and a Cy3 placed between the Tb and the QD at variable distances. The wire nomenclature is based on the base pair (bp) separation of the fluorophores, with the Cy3−QD separation given first followed by the Tb−Cy3 pair second. Four wires were tested in which three had the same Tb−Cy3 distance and increasing Cy3−QD distance: W′9−10′, W′18−10′, and W′27−10′. The fourth wire tested longer Tb−Cy3 distances with a medium Cy3−QD separation, W′18−19′. Considering the ∼4.1 nm radius of the QD and the predicted length of the doublestranded (ds) DNA scaffolds used, the expected separation distances from the Tb to the QD should be in the range of 10.4−16.3 nm. This is far longer than the viable R0 and should minimize direct Tb-to-QD energy transfer.

direct excitation of longer-lived QDs impede the efficient detection of dye−QD FRET.22 Theoretically, excitation of the dye via an extremely long lived point donor, such as Tb, may overcome the PL decay time problems and allow for efficient detection of dye−QD FRET. In addition to demonstrating the utility of short-lived dyes as bridges, we wished to extend the maximum distance over which Tb to QD energy transfer could take place. The longest measured values that we could find between Tb donors and QD acceptors are 15 nm) have been estimated for sandwich immunoassays.25 A DNA-based modular system was designed that would vary the relative position of the fluorophores; as FRET is distance-dependent, we expected to see modulated FRET efficiency (EFRET) and therefore changes in the acceptor/donor emission peak ratios. This would provide proof of the flow of energy from the Tb to the QD while utilizing the short-lifetime Cy3 as a bridge. As the terminal point for this process, we utilized CdSe/CdS/ZnS core/shell/ shell QDs emitting at 608 nm. The three fluorophores utilized have distinct PL peaks that allow for simple spectral deconstruction (Figure 1C,D). R0 values were calculated assuming a dipole orientation of κ2 = 2/3 and refractive index of n = 1.33, yielding values of 7.0 and 7.6 nm for the Tb donor (ϕTb = 0.72) to the Cy3 and QD, respectively.20 For the Cy3 donor (ϕCy3 = 0.22) and QD acceptor (ϕQD = 0.15), an R0 of 5.8 nm was calculated. We note that in theory electron transfer could play a part in such energy relays; however, electron transfer has an exponential distance decay, and given the considerable separation between the fluorophores, we do 2183


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The Journal of Physical Chemistry Letters To detect energy transfer flow through the fluorophores, changes in the PL ratios of the Tb, Cy3, and QD peaks were analyzed at 548 (Tb), 568 (Cy3), and 604 nm (QD), respectively. Ratiometric readouts are less sensitive to experimental errors (i.e., concentration deviations), resulting in a more robust signal.23,30,31 Due to the possibility of temporal bleed-through from the directly excited QDs even with the extended time lags, all measurements were corrected by normalizing the QD peak in the time-gated measurements to the signal obtained from the direct excitation of the QD (350 nm excitation, no time lag). Additionally, the data were always normalized to individual control samples to ensure that the changes were only compared to control samples taken in the same condition at the same time. Individual FRET step efficiencies for the Tb−Cy3 and Cy3−QD pathways in each construct were determined by steady-state, time-gated, and fluorescence lifetime measurements. The FRET-derived donor−acceptor distances (rDA) are shown in the schematic in Figure 1B, and the measured EFRET data points are shown in Figure 2A. The spectra used for the determinations are found in the SI. For Tb−Cy3, the rDA values were much longer than the values predicted based on the DNA lengths alone. We assign this decreased efficiency to the extended linkers (3 carbons for the Cy3 and 7 carbons plus the cage for the Tb) found on both fluorophores as well as deviations from the freely rotating dye assumption.32,33 The fact that the Cy3 dye is on the opposite side of the dsDNA strand in the case of W′9−10′ might also be why we obtain a longer distance than that for W′18−10′ even with equivalent bp separation. However, in the case of Cy3− QD and considering the 4.1 nm radius of the QD, the obtained values are shorter than we would expect from fully extended dsDNA. These shorter distances may be explained by the DNA wires not being fully perpendicular to the QD surface as well as the Cy3 linker permitting a closer approach of the Cy3 to the QD surface; the closer positioned acceptors in the ensemble will always dominate the FRET process. A similar range of effects has been noted previously in QD−DNA−dye constructs assembled using analogous chemistry.34 To look at Tb to QD energy transfer utilizing Cy3 as a bridge, an estimated EFRET(Tb−Cy3−QD) was predicted by multiplying the EFRET values of the individual FRET steps (see Figure 2A). Simply put, EFRET(Tb−Cy3−QD) = EFRET(Tb− Cy3) × EFRET(Cy3−QD) does not take into account any direct transfer from the Tb to the QD, which we aimed to minimize in our constructs. When we obtain the estimated EFRET(Tb− Cy3−QD) in this manner (inset of Figure 2A), W′9−10′ should yield a ∼18.8% transfer, W′18−10′ = 13.4%, W′27−10′ = 1.6%, and W′18−19′ = 2.4%. This can be compared to the direct transfer that we would expect from the Tb to the QD at the determined total distance that gives values of 4.4, 2.9, 0.8, and 0.8%, respectively, for the same wires. For a robust determination within the full construct, the most important aspects are the relative change in FRET upon the introduction of the Cy3 and its relay function as well as the overall intensity of the signal so as to be able to separate it from background noise. An example of deconstructed time-gated spectra from the full W′18−19′ construct is seen in Figure 2B, where the peaks can be clearly demarcated but the tail of the Cy3 does overlap partially with the QD emission. This again highlights the need for all ratio changes to be compared to proper controls.35 Figure 2C presents time-gated spectra from the Tb−DNA alone and the respective complete QD−DNA wire structures (examples of data set series are available in the SI). The

Figure 2. Spectral characterization of FRET steps from QD−DNA photonic wire structures. (A) FRET efficiency curves based on the calculated R0 for the individual FRET steps. The data points are the individual efficiencies obtained experimentally; the points on the dotted line (Tb−QD) are the expected transfer at the calculated Tb to QD distance. (Inset) Estimated ETb−Cy3−QD transfer efficiency based on multiplying the individual FRET step efficiencies. (B) Deconstructed time-gated example spectra of the complete W′18−19′ construct. The spectra were collected after a 30 μs delay with a 500 μs integration window using 50 repetitive source flashes/collection cycle. The deconstructed Tb, Cy3, and QD components are shown. (Inset) Full spectra. (C) Normalized spectra of the Tb control and the four complete QD−DNA structures. The base spectrum was collected with 340 nm excitation, a 35 μs delay with a 350 μs integration window, and 75 flashes. (Inset) Cy3 and QD components of the spectra shown in the main panel.

increase in both the Cy3 (568 nm) and QD emission (604 nm) can be seen clearly. As we focus on the ratio changes within the different constructs, we refer to specific component peaks (Tb, Cy3, and QD), though in actuality we are comparing the emission intensity at the respective wavelengths (548, 568, and 604 nm) where they are monitored. The first step was to observe the Cy3/Tb ratio (Figure 3A), where the data was normalized so that a value of 1 corresponded to the control sample of 2184


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low FRET from the Cy3 to the QD, and therefore, the lack of ratio changes was not surprising, while W′18−19′ had lowefficiency Cy3 sensitization, resulting in a very weak change in signal that could not be distinguished from the uncertainty in the measurements. In contrast, we expected to see a considerable change in the case of W′9−10′. We speculate that the lack of change in W′9−10′ could be due to the large uncertainty, or perhaps, the Cy3−QD FRET was lost within the time gate.36 Additionally, direct transfer from the Tb to the QD could hinder the detection of a decrease in the Cy3/Tb ratio, yet the linear design of the system should have minimized this effect. Nevertheless, within these first experiments, changes in the Cy3/Tb ratio successfully provided some initial evidence of Tb−Cy3−QD FRET. The second step was to look at the QD/Tb ratio (Figure 3B). The data in this case were normalized to a structure that had the Tb and QD but no Cy3. This means that bleed-through from the initially excited QD signal as well as any direct FRET from the Tb to the QD should be normalized to a value of 1 for each construct. The off-white columns are of the structures with no QD but with templated Tb−Cy3 FRET. It is important to note that the nonzero values are due to the Cy3 spectral crosstalk (which can be observed clearly in Figure 2C). In the case of W′9−10′ and W′18−10′, the values are less than (but close to) unity, signifying that the direct transfer from the Tb to the QD was significant. The QD/Tb ratio in the longer template wires increased considerably in the no QD sample because the Tb− QD distance is so large that the initial normalization ratios are very low and any Cy3 bleed-through will be significant. Most importantly, upon looking at the ratio in the complete structures, we could see that the W′9−10′ signal increased from 0.8 to 1.9 and the W′18−10′ signal from 0.9 to 3.4 (both W′27−10′ and W′18−19′ were unchanged as compared to the no QD data). This is the strongest evidence that we could obtain in our setups that the QD is being sensitized through a FRET photonic wire from the Tb to the QD utilizing a Cy3 relay. Rough estimates using EFRET(Tb−Cy3-QD)/EFRET(Tb− QD) would have projected QD/Tb ratio changes of ∼4.2 and ∼4.6 for W′9−10′ and W′18−10′; experimentally, the values were smaller (2.4 and 3.8, respectively), perhaps due to the most efficient FRET signals being lost in the time gating as well as undetected structural formation deficiencies. Surprisingly, the W′18−10′ ratio change was greater than that of the W′9− 10′, and the origin of this difference is unknown, although it may have to do with localized changes to dye properties and assembly or structural inefficiencies. As final evidence for FRET, we observed the changes in QD/ Cy3 ratios within time-gated spectra (Figure 3C). In this case, the data were normalized to the samples that had a QD and a templated Tb−Cy3 but no His6-tag, allowing us to correct for direct QD excitation and Cy3 bleed-through from Tb sensitization. When the complete sample was measured, we saw increases in the QD/Cy3 ratios for W′9−10′ and W′18− 10′, with W′27−10′ and W′18−19′ unchanged and presenting a value of 1 for the QD/Cy3 ratio. Here, in fact, the obtained values of 2.1 and 1.4 for W′9−10′ and W′18−10′ showed the expected greater efficiency for W′9−10′. We can thus effectively say that W′9−10′ and W′18−10′ demonstrated Tb to QD sensitization through a Cy3 bridge, and it is also possible that the 37 bp templated structures had some sensitization, but we were unable to discern this in our experiments. Utilizing the calculated rDA for the Tb−Cy3 and Cy3−QD, we obtained Tb to QD distances of 12.7 nm for

Figure 3. Ratiometric determination of emission peaks in the four different QD−DNA structures. Error bars are uncertainties from >5 individual repeats. (A) Changes in Cy3/Tb ratio (568 nm/548 nm). The light gray data are from the No His6-tag (negative control) and are compared to how the ratio changes upon addition of a QD scaffold (dark gray); the data are normalized to control samples of untemplated Cy3−DNA and Tb−DNA. (B) Changes in QD/Tb ratio (604 nm/548 nm). The data are of the no QD sample (templated Tb−Cy3, off-white columns) and are compared to how the ratio changes upon addition of a QD scaffold (complete, dark gray); the data are normalized to individual control samples of templated Tb−QD constructs (no Cy3). (C) Changes in QD/Cy3 ratio (604 nm/568 nm). The data are normalized to the No His6-Tag samples.

untemplated Cy3 and Tb. The No His6-tag data (negative control − no QD assembly) only reported on the FRET signal from the Tb to the Cy3, and it could be seen to give a value of >1 for all samples as they were brought together by the addition of the DNA template. As expected, the ratios were W′18−10′ ≈ W′27−10′ > W′9−10′ > W′18−19′, which corresponds to the predicted Tb−Cy3 distance. With the addition of the QD, if there was FRET from the Cy3 to the QD, we expected the ratio to go down. This was observed for W′18−10′, though the other signals did not demonstrate the change. W′27−10′ had very 2185


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The Journal of Physical Chemistry Letters W′9−10′ and 13.7 nm for W′18−10′, which is ∼25% further than any previously reported FRET transfer distance for a Tb/ QD sample.23,24 Though there was some mismatch between the W′9−10′ and W′18−10′ results, it did appear as if FRET theory had a generally good predictive power over the system. This approach to increasing FRET efficiency may be useful for sensitive detection at long donor−acceptor distances and could find applications in creating sensitive biosensors, particularly when the inclusion of a bridge may allow for a multiplexed sensor that exploits different donors, distances, and relays or in molecular computation that looks at combinations that modify the FRET between all three components.24,37−40 Overall, we demonstrate a simple yet flexible way to overcome the lifetime mismatch between a short-lived donor (organic dye) and longer-lived acceptor (QD) by using an even longer lived initial point excitation source (Tb). In the reverse sense, it also shows that ubiquitous organic dyes can be used to bridge Tb−QD FRET, increasing their efficiencies and accessible distances as well as creating a tertiary readout system that may be applicable to multiplexed sensing. We were able to transfer energy through FRET over a photonic wire with an end-to-end distance approaching a remarkable ∼14 nm, a 25% increase over the longest previously reported Tb to QD transfer. Incorporating other FRET processes into the design such as the exploitation of homogeneous FRET and multiple overlapping energy transfer pathways may further help optimize transfer efficiency within these constructs.16,41

although the absolute spectral intensities will change, if all proper controls are realized, the relative ratio changes should be comparable (considering the experimental uncertainty) within the utilized ranges of time gating and integration windows (see the SI). The average number of individual experiments was typically five per construct (with W′9−10′ and W′18−10′ getting more repeats). Control samples were run with each measurement series. Two different fluorescence lifetime setups were required due to the difference in time scales. In-house detection setups were utilized that were similar to those previously reported.16,20,36 For extended details, please see the SI.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpclett.7b00584. Details of DNA strands, expanded materials, methods, and analysis, Tb−Cy3 and Cy3−QD FRET determinations (steady-state and lifetime), time-gated data sets, and some additional discussion (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

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ORCID

MATERIALS AND METHODS Quantum Dots and Fluorophores. CdSe/CdS/ZnS core/shell/ shell QDs emitting at 608 nm with ∼8.2 nm diameters coated with zwitterionic compact ligand CL4 were prepared as reported previously.21,29 Lumi4 reagent is an isophthalamide cage structure for Tb3+ commercially available from Lumiphore, Inc.42 Cy3-maleimide was obtained from GE Healthcare. DNA. Labeled and unlabeled DNA strands were obtained from Integrated DNA Technologies and Eurofins Operon. The DNA sequences and a list of relevant properties can be found in the SI. Labeling was done either by the vendor or in-house through maleimide or NHS-ester chemistry. The His6-modified DNA was obtained from Biosynthesis. All in-house labeled DNAs were purified by HPLC. Construct Formation. The structures were formed by combining all DNA strands (see Figure 1), annealing them at 50 °C for 10 min, then decreasing 1 °C per minute down to 12 °C, and then adding the QD and allowing them to conjugate for 60−90 min at 20 °C. The constructs were at 5−20 nM of QD with either 6 or 12 DNA wires per QD in 1×TA (Trisacetate) buffer with 12.5 mM Mg2+. The use of multiple DNA wires per QD does not change the EFRET; it only increases the probability that the system is initially excited.1,13,40 For further analysis, see the SI. Fluorescence Measurements. Fluorescence spectra were collected on a Tecan Infinite M1000 multifunction plate reader with time-gating capabilities. Samples were prepared in 96 well Corning flat-black microtiter plates at 100 μL volume with QD concentrations between 5 and 20 nM. Measurements were done at 20 °C. For direct QD and Cy3 excitation without time gating, 350 and 515 nm excitation was used, respectively. Timegated measurements were realized at 340 nm excitation with a time delay of 25−50 μs, with the most common setting at ∼35 μs. Collection times varied from 250 to 1000 μs, with between 20 and 100 excitation flashes per measurement. Importantly,

Sebastián A. Díaz: 0000-0002-5568-0512 Niko Hildebrandt: 0000-0001-8767-9623 Igor L. Medintz: 0000-0002-8902-4687 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge ONR, the NRL NSI, and LUCI grants in support of the VBFF program through the OSD and Lumiphore, Inc. for the gift of Lumi4-Tb reagents. S.A.D. acknowledges an ASEE postdoctoral fellowship through NRL. N.H. acknowledges the Institut Universitaire de France (IUF) for financial support. X.Q. acknowledges the China Scholarship Council for her fellowship.

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