Resonance Energy Transfer in Upconversion Nanoplatforms for

Dec 16, 2016 - incorporated with nanoparticles, such as quantum dots, gold nanoparticles, and upconversion nanoparticles, have been developed...
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Resonance Energy Transfer in Upconversion Nanoplatforms for Selective Biodetection Qianqian Su, Wei Feng, Dongpeng Yang, and Fuyou Li* Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers and Institute of Biomedicine Science, Fudan University, Shanghai 200433, China CONSPECTUS: Resonance energy transfer (RET) describes the process that energy is transferred from an excited donor to an acceptor molecule, leading to a reduction in the fluorescence emission intensity of the donor and an increase in that of the acceptor. By this technique, measurements with the good sensitivity can be made about distance within 1 to 10 nm under physiological conditions. For this reason, the RET technique has been widely used in polymer science, biochemistry, and structural biology. Recently, a number of RET systems incorporated with nanoparticles, such as quantum dots, gold nanoparticles, and upconversion nanoparticles, have been developed. These nanocrystals retain their optical superiority and can act as either a donor or a quencher, thereby enhancing the performance of RET systems and providing more opportunities in excitation wavelength selection. Notably, lanthanide-doped upconversion nanophosphors (UCNPs) have attracted considerable attention due to their inherent advantages of large anti-Stoke shifts, long luminescence lifetimes, and absence of autofluorescence under low energy near-infrared (NIR) light excitation. These nanoparticles are promising for the biodetection of various types of analytes. Undoubtedly, the developments of those applications usually rely on resonance energy transfer, which could be regarded as a flexible technology to mediate energy transfer from upconversion phosphor to acceptor for the design of luminescent functional nanoplatforms. Currently, researchers have developed many RET-based upconversion nanosystems (RET-UCNP) that respond to specific changes in the biological environments. Specifically, small organic molecules, biological molecules, metal−organic complexes, or inorganic nanoparticles were carefully selected and bound to the surface of upconversion nanoparticles for the preparation of RET-UCNP nanosystems. Benefiting from the advantage and versatility offered by this technology, the research of RET-based upconversion nanomaterials should have significant implications for advanced biomedical applications. It should be noted that energy transfer in a UCNP based nanosystem is most often related to resonance energy transfer but that reabsorption (and maybe other energy transfer processes) may also play an important role and that more studies regarding the fundamental aspects for energy transfer with UCNPs is necessary. In this Account, we present an overview of recent advances in RET-based upconversion nanocomposites for biodetection with a particular focus on our own work. We have designed a series of upconversion nanoplatforms with remarkably high versatility for different applications. The experience gained from our strategic design and experimental investigations will allow for the construction of next-generation luminescent nanoplatform with marked improvements in their performance. The key aspects of this Account include fundamental principles, design and preparation strategies, biodetection in vitro and in vivo, future opportunities, and challenges of RET-UCNP nanosystems.

1. INTRODUCTION

addition, the extent of RET can be easily predicted from the spectral properties of the donor and acceptor. Currently, there are several types of energy donors that have been employed, such as organic fluorophores, quantum dots, lanthanides, lanthanide complexes, and upconversion nanoparticles, which possess different optical properties.6−8 Luminescent lanthanides are one of the most prominent classes of dyes for energy transfer applications in biophysical research (e.g immunoassays).9 Luminescent lanthanides exhibit

Resonance energy transfer (RET) is an optical process describing nonradiative energy transfer between the lightsensitive donor−acceptor pairs.1 This process decreases the luminescent intensity of donor and consequently increases that of acceptor if the acceptor is emissive.1 The changes in luminescent intensity of donor and acceptor can be readily detected, offering extraordinary application versatility and agility in medical diagnostics, DNA analysis, and optical imaging.2−5 The incredible expansion in the applications of RET is related to the favorable distances for energy transfer. In © 2016 American Chemical Society

Received: July 22, 2016 Published: December 16, 2016 32

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Accounts of Chemical Research remarkable optical properties including sharp emission bandwidths and long luminescence lifetimes, while lanthanide-doped upconversion nanophosphors (UCNPs) possess the advantages of luminescent lanthanides and strong resistance to background interference under low-energy near-infrared (NIR) light excitation.10−16 Therefore, UCNPs with particular lanthanide ion dopants (e.g., Er3+, Tm3+, Ho3+, Tb3+) employed typically function as energy donors and can provide a tunable emission that is compatible with a variety of acceptors for RETbased biological/biomedical applications. Over the past decade, the development of upconversion nanoparticle research has increased the understanding of the nature of UCNPs and brought about many well-established synthesis methods and surface modification approaches, which provide substantially enhanced signals and biocompatibility for the design of RET-based upconversion nanosystems.17−24 However, the recent literature reviews mainly focus on organic molecule, polymer, or quantum dot-based resonance energy transfer.25−30 Here, we present an overview of the recent advances of RET-based upconversion nanoplatforms with a particular focus on our own work.

Figure 1. Schematic illustration of upconversion nanoparticle donor (UC-Ln3+) and organic dye acceptor energy-level diagrams and their spectra. Resonance energy transfer can occur if there is overlap between the UCNP emission and acceptor absorption spectrum.

2. RESONANCE ENERGY TRANSFER

the orientation factor k2 is limited to values between 1/3 and 4/ 3.32 More importantly, photon upconversion that converts low energy excitation wavelengths to high energy emission provides an excellent platform for bioapplications with minimized autofluoresence interference and large tissue penetration depths.33 It should be noted that the RET-UCNP system involves multiple donor−acceptor interactions, which becomes more complicated to reveal the energy transfer mechanism if more possibilities are taken into account. Another important point concerns the extremely low quantum yields of UCNPs, which make RET rather inefficient. On the other hand, it is probably the quantum yield of the emitting lanthanide ions (and not the one of the entire nanoparticle) that needs to be taken into account for FRET. But then, these quantum yields (and also the ones of UCNPs) are quite hard to determine. However, there is no doubt that emitter ions close to the nanoparticle surface can efficiently participate in a RET process; thus appropriate nanoparticle size and rational nanostructure design are typically required.

2.1. Basic Principle of Resonance Energy Transfer

Resonance energy transfer, usually known as Förster resonance energy transfer (FRET), was proposed and elucidated by Theodor Förster with experimental evidence in the late 1940s. The conclusion of the theory is described by the following equations:2 E FRET = R 06 =

R 06 6

R0 + r

6

=1−

IDA τ = 1 − DA , ID τD

9(ln 10)κ 2 ΦDJ 128π 5n 4NA

where EFRET is the FRET efficiency, R0 is the Förster distance at which the probability of the excited donor to fluoresce equals that of transfer of energy to its acceptor, r is the donor− acceptor distance, ID and IDA are the relative fluorescence intensity of the donor in the absence and presence of acceptor, τD and τDA are the excited-state lifetime of the donor in the absence of and presence of acceptor, κ2 is the orientation factor, ΦD is the quantum yield of the donor fluorescence in the absence of acceptor, n is the index of refraction, and J is the overlap integral between the donor and acceptor.

2.3. Choices of the Energy Acceptor

According to Fö rster’s theory, to fabricate an efficient upconversion resonance energy transfer process, three primary factors should be considered: (1) the extent of spectral overlap of the emission and absorption spectra of the donor and acceptor (Figure 1b); (2) the distance between the donor and corresponding acceptor; (3) the quantum yield of the donor and the absorption cross-section of the acceptor.34 Therefore, the acceptor can be a luminophore (e.g., organic dye, fluorescent protein, heavy metal complex, aromatic polymer nanosphere, or quantum dot) or a nonluminescent quencher (e.g., gold nanoparticles).35−37 It should be noted that the emission from lanthanide is not fluorescence, thus the energy transfer process is usually called luminescence resonance energy transfer (LRET) when using UCNPs as the energy donors, distinguishing the process from resonance energy transfer using organic fluorophores or QDs as the energy donors.8

2.2. Upconversion Nanoparticle as the Energy Donor

Upconversion nanoparticles show great promise as energy donor in FRET process due to unique optical properties, which can be ascribed to the electron transitions within this 4fn configuration.31 First, the arrangements of electrons within the 4fn configuration are substantially diverse, resulting in a fairly large number of energetic states (Figure 1a). From this, many different acceptors are available for matching the emission wavelength of lanthanides due to the multiple emission bands over a broad spectral range. Second, the well-shielded 4f orbital (by the completely filled 5s2 and 5p6 subshells) offers the lanthanide-doped materials narrow emission bands and high optical stability. A very comfortable aspect of most lanthanide-based donors is the unpolarized emission caused by the multiple transition dipole moments. They act as randomized donors and therefore

2.4. Tuning Upconversion Emission

Over the past decade, significant progress has occurred in upconversion emissions tuning. The visible emission of Er3+ (green 4S3/2,2H11/2 → 4I15/2; red 4F9/2 → 4I15/2) has been 33

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have showed that only the surface-near lanthanide emitters are expected to transfer energy to QDs via nonradiative interaction, whereas the center-near emitters may also transfer energy to QDs via radiative interaction (reabsorption).46 From another perspective, the introduction of an inner filter effect could tune the emission of nanomaterials by using a high absorption efficiency chromophore for multiplexed encoding.47

extensively used in the fabrication of RET-UCNPs. In addition, the near-infrared emission of Tm3+ at around 800 nm (3H4 → 3 H6) has also successfully served as the detection signal or constant reference signal for biological applications.8,38 The combination of Er3+ and Tm3+ provides more possibilities in RET studies, guaranteeing a better overlap of the donor emission with the absorption of the acceptor, the existence of a constant reference signal enabling the design of ratiometric codes, and output signal with a deep penetration depth (Figure 2). Recently, the fabrication of core−shell nanostructures could

3. FABRICATION OF RET-UCNP NANOPLATFORMS A variety of chemical techniques, including physical adsorption, covalent coupling reaction, and coordination reaction, have been developed to fabricate RET-UCNP nanoplatforms. Here, we emphasize some of the most successful or promising strategies to date for the construction of these nanoplatforms (Figure 3).

Figure 2. Upconversion emission spectra of NaYF4:Yb/Er/Tm nanoparticles under excitation of a 980 nm laser.

enable upconverted emission through a variety of lanthanide activators by eliminating deleterious cross-relaxation.35,39 However, the applications of LRET studies of the upconverted emission from Tb3+, Eu3+, Dy3+, and Sm3+ have been rarely explored.

Figure 3. Generic strategies for the fabrication of RET-UCNP nanoplatforms.

(1) Physical adsorption involves the utilization of hydrophobic attraction, van der Waals force, electrostatic force, or other noncovalent interactions. For example, poly(maleic anhydride-alt-1-octadecene)−poly(ethylene glycol) (P-PEG) modified nanoparticles could encapsulate the hydrophobic acceptors into the hydrophobic domain of the amphiphilic polymers. The hydrophilic part of the amphiphilic polymer permits their dispersion in aqueous solution and further biofuctionalization.48,49 (2) Covalent coupling reaction involves modifying the surface of upconversion nanoparticles and then covalent bonding with acceptor molecules containing reactive functional groups. For example, we could oxidize the unsaturated carbon−carbon double bond of the ligand via Lemieux−von Rudloff reagent or covalent bonding with other functional groups (i.e., NH2).50,51 The resulting hydrophilic ligand bears a pendant carboxylic acid that provides a reactive functional group for further bioconjugation for detection or binding to a broad range of biotinylated proteins, antibodies, or DNAs. (3) Coordination reaction involves displacement of an original hydrophobic ligand, oleic acid or oleylamine, by a chromophoric complex or organic fluorescent dyes that have stronger coordination ability toward lanthanide ions. This technique is particularly suitable for those acceptors with carboxylic and phosphoric acid groups for coordination reaction though a one-step ligand exchange method.52,53 An alternative effective method for the

2.5. Tuning Upconversion Excitation Wavelength

Although promising results on upconversion emission tuning and enhancing have been achieved, there are still a variety of challenges that may restrict the widespread use of RET-UCNP in practical applications. One key challenge is the excitation light requirement near 980 nm, leading to significant cell death and tissue damage caused by local overheating issues and unreliable results in biodetections. To overcome this problem, Sun and Yan’s, Liu’s, and Wang’s groups reported three different nanostructure designs based on Nd3+-doped upconversion nanoparticles, which can greatly minimize the tissue overheating effect by diminishing water absorption under 808 nm excitation.40−43 Alternatively, recent study done by Haase and Piehler demonstrated that heating of the sample due to water absorption at 980 nm can be avoided by shortening the illumination times (e.g., 50 ms).44 2.6. Inner Filter Effect

Inner filter effect takes place when the emission intensity decreases as a result of the acceptor absorption in the emission region. For UCNP based energy transfer systems, the upconversion luminescence of the donor overlaps well with the strong absorption bands of the acceptor; therefore there are sufficient conditions for FRET or inner filter effect by the energy acceptor to take place. Bednarkiewicz and co-workers have demonstrated that the energy transfer mechanism of UCNP-QD double-nanosystem related to not only resonance energy transfer but also reabsorption.45 Soukka and co-workers 34

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Figure 4. Schematic illustration of typical examples for the construction of RET-UCNP for detection by the spectral overlap and distance manipulation routes. (a) Upon addition of the analyte, LRET process is suppressed and thus upconversion emission is recovered. (b) Upon addition of the analyte, the distance between the donor and acceptor is close enough for an effective energy transfer and upconversion luminescence is decreased.

construction of a RET-UCNP nanoplatform is the twostep strategy, which converts the hydrophobic UCNPs into ligand-free hydrophilic nanoparticles including methods such as pH adjustment, nitrosonium tetrafluoroborate (NOBF4) usage, or lanthanide cation-assisted ligand exchange54−56 and then treatment with appropriate bound acceptors.

4. RET-UCNP IN DETECTIONS Generally, the design for the detection of target species is based on the changes in emission intensity of one upconversion emission band or the intensity ratio of two emission bands.8 The changes in upconversion emission can be achieved via the following routes: (1) one is to change the spectral overlap between upconversion nanoparticles and the energy acceptors by alternation of the chemical or physical surroundings after the addition of the target species; the absorption spectrum of the acceptor shows a significant change in intensity or position of the absorption peaks in the presence of the target species (Figure 4a); (2) the other is to change the distance between upconversion nanoparticles and target species by functionalizing upconversion nanoparticles with responsive moiety, such as a chromophore, luminophore, or magnetic particles (Figure 4b). On the basis of these two approaches, a variety of upconversion LRET probes have been developed for the detection of different target species with excellent detection sensitivity and selectivity.

Figure 5. (a) Design strategy for CN− detection via the construction of upconversion nanosystem based on LRET mechanism. (b) UV/vis absorption of Ir1 with and without the treatment of CN−, and luminescence spectra of OM-UCNPs and OA-Ir1-UCNPs injected with and without CN−. UCNP denotes NaYF4:20%Yb,1.6%Er,0.4% Tm. Adapted with permission from ref 59. Copyright 2011 American Chemical Society.

4.1. Manipulating Spectral Overlap between Donor and Acceptor

from 400 to 600 nm was observed due to the reaction of CN− with the α,β-unsaturated carbonyl ligand, resulting in a weak spectral overlap, and the energy transfer process is largely suppressed. The detection limit of CN− reaches up to 0.18 μM in aqueous solution (DMF/H2O, 9:1, v/v). We then developed a hybrid nanostructure combining NaYF4:Yb,Ho nanoparticles, P-PEG, and CN− responsive chromophoric Ir(III) complex ([(ppy)2Ir(dmpp)]PF6, Ir2), leading to a good detection limit to CN− (37.6 μM) in pure water.49 4.1.2. Detection of Cysteine/Homocysteine. We fabricated a yolk−shell upconversion nanophosphor loaded with hydrophobic chemodosimeter 8-oxo-8H-acenaphtho[1,2-

For the fabrication of LRET-UCNP based probe, manipulating the spectral overlap between upconversion nanoparticles and energy acceptors is a straightforward method to detect ions (cyanide anion (CN−), nitrite (NO2−), copper ion (Cu2+), mercury ion (Hg2+)), small molecules (O2, glutathione), and pH value.57 4.1.1. Detection for Cyanide Anions (CN−). Our group developed a CN− responsive chromophoric Ir(III) complex (Ir1)-coated NaYF4:20%Yb,1.6%Er,0.4%Tm nanoparticle sensing system based on the spectral overlap strategy via coordination reaction (Figure 5).58 In the presence of CN−, a significant weak absorption of Ir1 + CN− in the visible region 35

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4.2. Manipulating the Distance between Donor and Acceptor

b]pyrrole-9-carbonitrile (ANP) for the detection of Cys/Hcy in aqueous solution (Figure 6).59 NaLuF4:20% Yb,1% Er, 0.5%

An essential prerequisite to manipulate the distance may be the use of strong interaction between the energy donor and acceptor, including DNA−DNA interaction, antigen−antibody interaction, etc. 4.2.1. Biotin Detection. Soukka and co-workers first demonstrated that the combination of UCNPs and QDs in FRET through biotin−streptavidin interaction can be used for the detection of biotin in a large concentration range (ca. 1 nM to 1 μM) with detection limits down to approximately 5 nM. After biotin binding to streptavidin, the minimum distance between UCNP surface and QD center was estimated to be 6 nm. This short distance guaranteed efficient nonradiative energy transfer (with a FRET efficiency of ca. 7%).46 4.2.2. DNA Detection. Krull and co-workers have reported on the successful use of covalently immobilized UCNPs on paper as LRET donors for the optical detection of nucleic acid targets. Target oligonucleotide served to bridge probe oligonucleotide on the surface of UCNP and reporter oligonucleotide on the surface of QD. This LRET-based nucleic acid hybridization assay showed good performance for determination of HPRT1 target in 90% serum samples, with a limit of detection of 24 fmol.62 Our group designed a sensor system that operates within the predefined distance.50 As shown in Figure 8, we first prepared capture DNA-conjugated

Figure 6. Schematic representation of a turn-off luminescent probe for detection of cysteine/homocysteine. Yolk−shell structured NaLuF4:20%Yb,1%Er,0.5%Tm nanoparticles (YSUCNP) served as the energy donor and the chromophoric chemodosimeters served as the acceptor. Adapted with permission from ref 63. Copyright 2014 American Chemical Society.

Tm was prepared as the energy donor.. Ratiometric detection of Cys/Hcy was successfully achieved by using the UCL emission at 800 nm of Tm3+ as internal reference, and the detection limit of Cys reaches up to 28.5 μM. Note that chemodosimeter ANP solely can severed as an irreversible fluorescence turn-on sensor for Cys/Hcy; this yolk−shell nanostructure could be used as a reversible probe after removal of the loadings.60 4.1.3. Detection of Hg2+ Ions. Our group developed an absorption-shifting method by conjugating the chromophoric Ru(II) complex (N719) on the surface of NaYF4:Yb,Er,Tm nanophosphors through coordination reaction (Figure 7a).56

Figure 8. Schematic illustration of DNA sensor system by manipulating the distance between upconversion nanoparticles (NaYF4:20%Yb,2%Er) and target DNA. Adapted with permission from ref 50. Copyright 2008 American Chemical Society. Figure 7. (a) Schematic representation of upconversion nanosystem for Hg2+ ions detection. (b) UV/vis absorption spectra of N719 with and without Hg2+ treatment, and UCL spectrum of NaYF4:20% Yb,1.6%Er,0.4%Tm nanoparticles. Adapted with permission from ref 52. Copyright 2011 American Chemical Society.

UCNPs NaYF4:Yb,Er, making use of the specific interaction between streptavidin and biotin. We next labeled reporter DNA with a molecular fluorophore N,N,N′,N′-tetramethyl-6-carboxyrhodamine (TAMRA), whose absorption spectrum overlap with the green upconversion emission of NaYF4:Yb,Er. By measuring the luminescence intensity ratio (I580/I540 or I540/ I654), we can quantitatively detect the target oligonucleotide, and the detection limit reaches up to the nanomole per liter level.

The results demonstrated a decrease in the spectral overlap between the absorption band of N719 and the green upconversion emission of NaYF4:Yb,Er,Tm nanoparticles upon the addition of Hg2+ into the system (Figure 7b). The limit of detection of the NaYF4:Yb,Er,Tm−N719 system in water is about 1.95 ppb. Note that heavy metal ions such as Hg2+ are also able to quench the emission of UCNPs directly as demonstrated by Wolfbeis’s group.61

4.3. Upconversion Probes for the Detection of Intracellular Analytes

RET-UCNP technique is ideally suited to elucidate the spatiotemporal distributions and imbalances of constituent molecules or ions in living cells due to the incomparable 36

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Accounts of Chemical Research advantages as mentioned previously. Although conventional wide-field fluorescence microscopy allows for a faster image acquisition when taking RET images, it suffers from fluorophore emission originating above and below the focal plane to yield images with significant out-of-focus signal. We developed a three-dimensional visualization tool combined with a conventional confocal laser scanning microscopy and a 980 nm laser, upconversion laser scanning upconversion luminescence microscopy (LSUCLM), which shows its promise in long-term imaging with high sensitivity.58 Recently, we demonstrated the applicability of the OA capped Ir1-UCNPs for the detection of intracellular CN− via LRET technique (refer to section 4.1.1). As observed by LSUCLM, HeLa cells without treatment with CN− showed only a weak green upconversion emission after incubation with OA-Ir1-UCNPs (Figure 9a). By contrast, a significant enhance-

Figure 10. (a) Schematic illustration of Nd3+-sensitized upconversion nanosystem for ClO− detection. (b) In vivo detection of ClO− in a mouse model with arthritis disease. Adapted with permission from ref 43. Copyright 2015 Royal Society of Chemistry.

reaction between hCy3 and NaClO. Using the ratiometric upconversion emission I540/I654 as the detection signal, hCy3UCNP:Nd3+ was successfully used for sensing ClO− with a low detection limit of 27 ppb. More importantly, this nanoprobe was used for the detection of ClO− in a mouse model of arthritis (Figure 10b). Although the penetration depth of green light is relatively limited, it still can be used for in vivo detection by virtue of high resistance to autofluorescence interference capability of upconversion nanoparticles. 4.4.2. In Vivo Imaging of MeHg+. The penetration depth of light in tissue is strongly wavelength dependent. The maximum value is found for red and near-infrared wavelengths. Green illumination penetrates only 0.3 to 0.8 mm below the skin, while light in the NIR region penetrates a few millimeters.64,65 Therefore, we first developed a P-PEG coated NaYF4:Yb,Er,Tm upconversion nanoparticle based sensing system using 800 nm NIR emission as detection signal. Hydrophobic heptamethine cyanine dye hCy7 acted as the MeHg+-responsive dye for the detection of MeHg+ in vivo (Figure 11a).48 By tracing the signal change at 800 nm, this sensing system could be utilized for monitoring the excess of MeHg+ in the liver of a mouse (Figure 11b).

Figure 9. Upconversion luminescent and ratiometric UCL (green-tored) images obtained for HeLa cells without (top, a−c) and with the treatment of CN− (bottom, d−f) after incubation with OA-Ir1UCNPs. UCNP denotes NaYF4:20%Yb,1.6%Er,0.4%Tm. Adapted with permission from ref 59. Copyright 2011 American Chemical Society.

ment in green upconversion intensity was observed after CN− treatment in the growth medium (Figure 9d). The clear difference in ratiometric images of control and treated samples indicates that this RET-UCNP based probe could be effectively used for monitoring intracellular CN− ions.59 In the case of Hg2+ detection, we observed a 2.5-fold enhancement of upconversion emission in the green channel after further incubation with Hg2+ ions and N719-UCNPs for only 15 min, demonstrating that LRET nanosystems are capable of monitoring Hg2+ variation in living cells.56 In addition to metal ions, RET-UCNP technique could enable the detection of small biological molecules (i.e., cysteine/homocysteine) in vitro.63

4.5. RET-UCNP for Real Time Monitoring

The resonance energy transfer technique offers the unique advantage of monitoring analyte molecule dynamics in vitro. To achieve this function, we could make proper use of the changes in the distance between the energy donor and acceptor. Our group developed a ratiometric design (Figure 12) for analyte release kinetics monitoring in living cells, using mesoporous silica-coated NaYF4:Yb,Er nanocomposites as analyte carrier (NaYF4:Yb,Er@mSiO2).66 The linear relation between the green-to-red emission intensity ratio and the percentage of DOX released was found. Therefore, this ratiometric design based on LRET may offer an accurate and reliable platform for localized fluorophore delivery monitoring in living samples, avoiding dosing errors and the influence of the internal microenvironment.

4.4. Upconversion Probes for in Vivo Detection

The promising sensing capability of upconversion nanoparticles based on resonance energy transfer mechanism can also be introduced into animals for analyte monitoring in vivo. 4.4.1. In Vivo Imaging of Hypochlorite (ClO−). We utilized NaYF 4 :30%Yb,1%Nd,0.5%Er@NaYF 4 :20%Nd (UCNP:Nd3+) upconversion nanoparticles with ClO−-responsive cyanine dye hCy3 for the detection of ClO− in living samples by utilizing LRET and inner filter mechanism.43 hCy3 was encapsulated into the hydrophobic nanodomain made by oleic acid and P-PEG (Figure 10a). The change of the absorbance of hCy3 is attributed to the selective oxidation

5. CONCLUSIONS The resonance energy transfer technique offers substantial flexibility in regulating the optical process between the upconversion nanoparticles and other matched optically active 37

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the nanosystems. Moreover, further designs and experiments of RET-UNCP probes are needed to detect the concentration of target analyte in vivo. Alongside this, the use of RET technology could be extended to develop multimodality nanosystems with synergistic action for diagnosis and treatment. Nevertheless, this technology will shape wider attention on the development trajectory of the research field in luminescent materials.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Fuyou Li: 0000-0001-8729-1979 Funding

This work was supported by State Key Basic Research Program of China (Grants 2015CB931800 and 2013CB733700), the National Science Foundation of China (Grants 21231004 and 21375024), and the China Postdoctoral Science Foundation (Grant 2015M571482) for financial support. Notes

The authors declare no competing financial interest. Biographies

Figure 11. (a) Schematic illustration of upconversion nanosystem for MeHg+ detection. (b) In vivo detection of MeHg+ in a mouse. Adapted with permission from ref 48. Copyright 2013 American Chemical Society.

Qianqian Su obtained her B.E. degree in Material Science and Engineering from Shandong University. She received her M.S. degree in Polymer Chemistry and Physics from Guangzhou Institute of Chemistry, Chinese Academy of Sciences, and completed her Ph.D. in the group of Prof. Liu Xiaogang at National University of Singapore. She is carrying out postdoctoral research work at Fudan University with Prof. Fuyou Li. Her current research focuses on the development of novel nanomaterials for bioapplications. Wei Feng received his B.S. degree in 2004 and Ph.D. degree in 2009 in Chemistry from Peking University. He then carried out postdoctoral research at Peking University with Prof. Chunhua Yan. He is currently an associate professor in the Department of Chemistry at Fudan University. His research interests involve the design and synthesis of luminescent nanomaterials. Dongpeng Yang is currently a Ph.D. student with research interests in functional nanomaterials. Fuyou Li received his B.S. degree in 1995 and Ph.D. degree in 2000 from Beijing Normal University. Then he became a postdoctoral fellow at Peking University for two years. He was as an associate professor at Peking University from 2002−2003 and Fudan University from 2003−2006. He has been working as a full Professor at Fudan University since 2006. His current research interests cover luminescent materials for sensing, bioimaging, and biomedicine.

Figure 12. (a) Schematic illustration of upconversion nanocarriers for DOX delivery monitoring and the linear relationship between the value of green-to-red ratio and DOX release percentage. (b) Confocal microscopic images of HeLa cells treated with NaYF4:Yb,Er@mSiO2− DOX using the ratio of green-to-red as signal in the course of DOX release time. UCLG and UCLR denote green and red upconversion emission, respectively. Adapted with permission from ref 66. Copyright 2015 American Chemical Society.



REFERENCES

(1) Medintz, I.; Hildebrandt, N. FRET-Förster Resonance Energy Transfer: from Theory to Applications; Wiley-VCH: Weinheim, Germany, 2014. (2) Wu, P. G.; Brand, L. Resonance Energy Transfer: Methods and Applications. Anal. Biochem. 1994, 218, 1−13. (3) Selvin, P. R. Fluorescence Resonance Energy Transfer. Methods Enzymol. 1995, 246, 300−334. (4) Bettinelli, M.; Carlos, L.; Liu, X. G. Lanthanide-Doped Upconversion Nanoparticles. Phys. Today 2015, 68, 38−44. (5) Zhou, B.; Shi, B. Y.; Jin, D. Y.; Liu, X. G. Controlling Upconversion Nanocrystals for Emerging Applications. Nat. Nanotechnol. 2015, 10, 924−936.

species. These RET-based upconversion nanomaterials may evolve into an extremely important class of nanoplatform with high designability and tunability for a broad range of bioapplications. However, the key challenges in the development of RET-UCNP nanosystems involve further enhancing the efficiency of energy transfer, deepening the tissue penetration depth, and fabricating nanoplatforms with broad band excitation. In addition, it is important to consider and distinguish RET, reabsorption, or both or even some other process of energy transfer when analyzing the optical data of 38

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DOI: 10.1021/acs.accounts.6b00382 Acc. Chem. Res. 2017, 50, 32−40