Materials Science and Engineering C 45 (2014) 635–643
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Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Near-infrared upconversion nanoparticles for bio-applications Qing Qing Dou, Hong Chen Guo, Enyi Ye ⁎ Institute of Materials Research and Engineering (IMRE), 3 Research Link, Singapore 117602, Singapore
a r t i c l e
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Article history: Received 24 January 2014 Accepted 21 March 2014 Available online 16 April 2014 Keywords: NIR upconversion Multi-modality Photodynamic therapy Photo activation
a b s t r a c t Upconversion nanoparticles (UCNs) attract intensive attentions in biomedical applications. They have shown great potential in bioimaging, biomolecule detection, drug delivery, photodynamic therapy and cellular molecules interactions. Due to the anti-Stokes optical property and NIR excitation, UCNs overcome the drawbacks encountered in conventional luminescent biomarkers. High signal to noise ratio, low cytotoxicity and stable high throughput results are obtained using UCNs as luminescent labels or light triggers in biomedical applications. In this review article, the reason for choosing UCNs as biomedical agents, the progress of the UCNs development and case studies of their biomedical applications will be discussed. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Fluorophores have been used for non-invasive detection of biological molecules and monitoring of real-time biological processes for several decades [1]. As a non-destructive method, fluorescence technique produce fast, sensitive and reproducible signal, and high resolution in samples with intrinsic color (e.g. blood). The optical bioimaging with fluorophores has become the state of the art with impacts on fundamental biomedical research and clinical practice. There are two main categories of fluorophores exploited for this purpose: one type converts short wavelength light to longer ones (downconversion), and another type converts longer wavelength to shorter (upconversion). This review focuses on the later one. Downconversion was studied earlier than upconversion. Organic dyes and quantum dots fall in this category. Most of organic fluorophores suffer from a common problem-photobleaching [2–4]. The track of the targets will be lost after the fluorescence bleaching, which lead to failure of the tasks. Quantum dots, feature with large molar extinction coefficient [5], higher quantum yield, narrow emission bandwidth [6], size-dependent tunable emission [7], composition tunable emission and higher photostability, seem to be a fantastic alternative to organic dyes [6,8, 9]. Unfortunately, quantum dots are usually composed with elements exhibiting intrinsic toxicity, such as Cd, Se etc. [10]. Their potential toxicity poses risks to health and environment, which became a concern and arouse debate to apply them in biological study [11,12]. Furthermore, both the organic fluorophores and quantum dots suffer from low signal-to-noise ratio. Downconversion luminescent materials are generally excited by UV and visible light, so the autofluorescence [13, 14] from the biological sample (such as mitochondria and lysosomes) ⁎ Corresponding author. E-mail address: [email protected] (E. Ye).
http://dx.doi.org/10.1016/j.msec.2014.03.056 0928-4931/© 2014 Elsevier B.V. All rights reserved.
is always present in the signal and thus decreases the sensitivity of the detection, leading to low signal-to-noise ratio. Moreover, the incident excitation light causes photodamage to living organisms. The second type, fluorescent upconversion nanoparticles (UCNs) overcomes most of the drawbacks of downconversion materials. UCNs exhibit antiStokes emission by emitting detectable photons of higher energy in the UV to a visible range upon near-infrared (NIR) irradiation. Coincidently, optical window in biological tissue falls in the NIR region [15], in which most biological molecules showing the lowest absorption of light. Therefore, the penetration depth of NIR is much deeper than UV or visible light, which enables deeper imaging or detection. As well the NIR light is much less toxic to biological system compared to UV light. Composed with inorganic crystals doped with lanthanide elements, the toxicity is much lower than quantum dots. UCNs' fluorescence originated from the energy transfer between different energy levels of lanthanide [16], so the upconversion fluorescence is much stable than organic dyes. Due to the aggregated sub-energy level of lanthanide, the emission bandwidth is very sharp and fluorescence lifetime is relatively long, up to several milliseconds [17]. The emission of the upconversion can be finely tuned by doping different lanthanide elements. The above mentioned superior properties over conventional downconversion labels render UCNs an ideal luminescent label for biological applications. In this review, we focus on the second type of fluorescent material-upconversion nanoparticles (UCNs). The development of UCNs and their applications in biomedical area will be discussed. 2. Luminescent upconversion process Development of upconversion nanoparticles (UCNs) is one of the hottest topics in recent years. The research interests on them aroused from their unique optical property—it converts low energy photons
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of long wavelength light to high energy photons to emit shorter wavelength light. Take Yb3 +/Er3 + and Yb3 +/Tm3 + absorber/emitter pair doped UCNs as an example; it will be more clearly to understand the upconversion procedure. In this process, Yb3 + absorbs energy near 980 nm as it has broad cross-section in this region [18–20]. As shown in Fig. 1, The absorber Yb3+ ions absorb NIR light, and then through lattice vibrations of the nanocrystalline matrix, the energy transfers to the emitter Er3+ or Tm3+ ions due to the energy overlap of the transition dipoles of the two elements [21,22]. Due to the complex energy level configuration of Er and Tm, the energy relaxes to different energy levels before it is released to ground state. Subsequently, wide span emissions ranging from UV, visible to NIR, corresponding to different energy levels, are generated when the energy is released to ground state. 3. Host matrix for upconversion It is essential to choose a proper matrix for upconversion process as it totally depends on the energy transfer between absorber and emitter within a suitable proximity. Different matrix provides different distance between the atoms in which the emitter and absorber are randomly and equally distributed. But the size or atom distance is not the only criteria for choosing the latticed. Considered in getting more effective luminescence, another requirement for the lattice is low lattice photon energy, which reduces non-radiative energy loss. The dynamics of the excited state of the rare earth ions and interactions between them, so the upconversion emissions were different in different crystal lattices even though with the same dopants [23,24]. Therefore, to search a proper crystal lattice is very essential to achieve high upconversion efficiency. So far, a lot of lattices have been explored to serve as the host matrix for upconversion process. The host used to incorporate the lanthanide absorbers and emitters can be classified into two main categories—amorphous and crystal. Amorphous material, most of them are glass, can host the lanthanide ions in the casting procedure. Germanate chalcohalide glass composed of GeO2–PbO–Nb2O5 glass [25,26] with different halide (Cl, Br, I) modifiers and Pr3 + dopant concentrations have been studied as an upconversion host. Calcium sodium aluminosilicate glass doped with Er3 + was also studied as an upconversion host material at room temperature and at 77 K [27]. Upconversion luminescence was also studied in Ho3 + doped ZnO–TeO2 glass [28], Er3 + doped SiO2–PbF2– ErF3 transparent glass ceramics [29] and amorphous Tm0.1La0.9P5O14 [30]. The requirements for the crystal lattice to be used for upconversion matrix are much higher than the amorphous material. It requires similar size lattice points and distance between them as well as similar charges. A series of crystals had been explored as upconversion host. One big
category is oxide, such as Y2O3 [31–33], ZrO2 [34–36], and TiO2 [37]. Bright white upconversion emission was also observed from Yb3 +, Er3+, and Tm3+ codoped Gd2O3 nanotubes [38–40]. Perovskite oxides were also employed as host, such as Pr3+ doped Bi4Ge3O12 [41], Er3+ doped YAlO3 [42], GdAlO3 [43], Ti2+ and Er3+ co-doped LiNbO3 [44], Yb3+ and Tm3 + co-doped GdAlO3 [43], Ho3 + doped LiTaO3 [45] and BaTiO3:Er3+ [37,46,47]. Other crystals composed with both oxygen and lanthanide ions were also used as host materials for upconversion processes, such as LiGd(MoO4)2, Y3Sc2Ga3O12, Gd3Ga5O12 [43], TmP5O14 and Tm0.1La0.9P5O14 [30], LuPO4:Yb3+,Tm3+ [48], La2(MoO4)3:Yb3+,Tm3+ [49], Tm3+/Yb3+/ Er3+ codoped Lu3Ga5O12 [50,51], La2O2S [52] and YbPO4:Er3+ [48,53] were also reported for upconversion. Halide compounds crystals were also reported for upconversion study. For example, Gd3+ doped Cs2NaGdCl6 [54], Er3 + doped RbGd2Br7 [55], Tm3 + doped Cs3Yb2Cl9 [56] and BaLu 2 F 8 doped with Er 3 + [57]. Transition metal ions (Zr4 + and Ti4 + [58,59], Re4 + and Mo3 + [60]) have similar ionic size to lanthanide ions, they were also reported to be used to generate NIR to visible upconversion luminescence. Capobianco's group made a lot of efforts to make upconversion nanoparticles with relatively new crystal lattice. For example, CaS: Eu2 +/Dy3+ emit strong red light upon NIR excitation [61]. They also found that GdVO4 doped with Er3 + and Yb3 + have two strong emissions peaks near 525 and 550 nm while a relatively weak red peak centered at 660 nm [62]. Similarly, the similar host lattice doped with different ions GdVO4:Tm3+/Yb3+/Ho3+/Li+ could harvest white emission in total [63]. Recently, they studied NaxScF3 + x crystal– monoclinic phase Na3ScF6 and hexagonal phase Na3ScF6 nanocrystals [64], as an upconversion material. Among all the crystal host, LaF3 [65–68] and NaYF4 [69–72] (including Li+ substitution LiYF4 [73,74]) are the most studied. Even though some host matrixes have similar size lattice points to hold the lanthanide ions, dopants easily cause defects such as interstitial anion and cation vacancies in the crystal. Considering neutrality in the crystal, the dopant concentrations have to be stringently limited. Thus, the luminescence is not high in these materials. Fluorides bear lower phonon energies (350 cm−1) than oxides (500 cm−1) and lower than heavy halides (300 cm−1) [16]; it is more stable than halides. Lattice with low phonon energy suffers less nonradiative energy loss in upconverted energy states. Theoretically, halides are more suitable to be used for host matrix [75]. Practically, it was found that the hexagonal phase Yb3+/Er3+ (or Yb3+/Tm3+) codoped NaYF4 nanocrystal was the most efficient infrared-to-visible upconversion luminescent materials [76–78]. For biological purpose, the toxicity of the host lattice is a key consideration point, which adds more limitations to choose the host. 4. Efforts on improving upconversion efficiency
Fig. 1. Energy diagram of Yb3+, Er3+ and Tm3+ and the energy transfer between them. The dashed–dotted, dashed, dotted, and full arrows represent photon excitation, energy transfer, multiphonon relaxation, and emission processes, respectively. Only visible and NIR emissions are shown here [16].
As a promising material used for biomedical applications, considerable efforts have been draw to improve the luminescent efficiency of UCNs. The upconversion was firstly studied in bulk material [79–81], and then researchers tried to make it into nanoscale with top-down or bottom-up methods. The small host leads to serious luminescence decrease due to the existence of a relative larger surface (larger surface to volume ratio). Especially for the upconversion process, the luminescence yield is affected in orders by any decreasing factors due to it is a multi-photon process: each photon process will be influenced by the same factor. To get repeatable and stable result, uniform size is highly required. Top-down methods cannot get as highly uniform sized nanoparticles as bottom-up methods, so intensive attention was on the latter. Hydrothermal synthesis is a typical bottom-up method for obtaining upconversion nanoparticles, but the size distribution of the nanoparticles was not satisfied [23,82]. After Zhang and Li developed a thermal decomposition method to obtain uniform sized NaYF4 nanocrystals with oleic acid as a shape control agent [70,71,83], uniform 30–50 nm-UCNs with ± 3 nm sized can be easily obtained and the
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morphology can be easily controlled as shown in Fig. 2a–d. Later on great efforts have been made to improve the quality of NaYF4 nanocrystals [69,72,84,85]. Other chemicals were also exploited to modify the shape of UCNs. Lin and Li [86] synthesized β-NaYF4:Ln3+ (Ln = Eu, Tb, Yb/Er, and Yb/Tm) hexagonal microprism crystals with sodium citrate as a shape modifier (Fig. 2e). The upconversion emission was then finely tuned by changing the absorber and emitter dopants' concentrations [87,88]. Take NaYF4:Yb3 +,Er3 +/Tm3 + as an example, as the similar energy level in lanthanide ions, the energy transfers between the absorber (Yb3 +) and emitter (Er3 + or Tm3 +) dopants. The deleterious cross relaxation between Yb3 + and Er3 + (or Tm3 +) [89] and cooperative interaction between Yb3+ [90] causes a decreased upconversion emission due to the absorbed energy loss. Thus the dopant concentration was limited to get a high yield luminescence. For some delicate applications, 30–50 nm nanoparticles were still quite large, thus hindered UCNs' applications. To solve the contradictory situation between size reluctant versus luminescence quenching, more challenges appeared and larger efforts are required. Prasas N. Prasad reported an approach [91] to synthesize 7–10 nm UCNs 43 times enhancement by increasing Yb3 + ions from 20% to 100% and corresponding decreased Y3 + content from 80% to 0% (Fig. 2f). A Bednarkiewicz demonstrated irreversible spatially confined infraredlaser-induced annealing of ultra-small ~ 8 nm NaYF4: 20% Yb3 +, 2% Er3+ under a 976 nm localized tightly focused beam from a continuous wave medium power laser diode excitation, where 2–3 order enhancement in luminescence yield was found. Moreover, efforts have been made in fine tuning the crystal structure, composition [73,74] and combinations to enhance the uminescent intensity of UCNs. One method to improve the upconversion luminescence was to coat a shell on the surface of a nanoparticle to minimize the surface defect [72,92–94]. This method improved the luminescence intensity to an extent, but the size increased at the meantime. This approach did not touch the structure of the nanocrystal but only repair the surface defects. Cappobianco el al. [95] reported a method to
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enhance the luminescence of UCNs by increasing the energy absorbance of the nanoparticles through an active shell (Fig. 3a). In detail, they coated an absorber doped layer on the surface of NaGdF4: Yb3 +,Er3 + core. With this method, the upconversion emission could reach 3 and 10 folds in the green and in the red to NaGdF4: Yb3 +,Er3 +/NaGdF4 core/shell, respectively; and 13 and 20 folds for the green and red emissions in the NaGdF4: Yb3+,Er3+ nanoparticles, respectively. The above methods were based on the hexagonal NaYF4 crystal matrix without changing the crystal structure or phase. Methods by fine adjusting the structure of the crystal were also exploited. For example, Zhang [73] tried to tune the upconversion efficiency by adjusting the absorber and emitter in NaYF4:Yb3 +,Er3 + nanocrystal distance with different sized alkali ions. Phase transition of nanocrystals was found with doping a different amount of Li and K. The energy transfer in between different energy levels in emitter lanthanide was also affected, which leads to the change of the intensity ratios between the blue, green, and red emission peaks. Liu et al. [93] tried to unveil the mechanism behind the process and tune the emission of UCNs (Fig. 3b). Recently, Liu [96] reported that lanthanide ions distributed in arrays of tetrad clusters KYb2F7:Er3+ orthorhombic crystallographic structure can greatly preserve the excitation energy within the sublattice domain by minimizing the migration of excitation energy to defects. Moreover, organic near-infrared dye as an absorbance antenna was attached on the β-NaYF4:Yb3+,Er3+ nanoparticles to enhance NIR absorbance to enhance the upconversion efficiency, reported by Jan C. Hummelen et al. [97] (Fig. 3c). Another advantage of this design was broadening of the absorption spectrum of the upconverter. It was reported that the dye-sensitized upconversion intensity got an enhancement by a factor of ~3300. 5. Biomedical applications of UCNs The unique property of anti-Stokes property of UCNs arouses great interest of biomedical applications. UCN needs NIR light as excitation
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Fig. 2. (a) TEM images of PVP/NaYF4: Yb,Er nanocrystals [70]. TEM images of (b) NaYF4:Yb, Er nanospheres (c) nanoellipses, and (d) nanoplates [71]. (a) β-NaYF4:Ln3+ (Ln = Eu, Tb, Yb/Er, and Yb/Tm) hexagonal microprisms [86]. (e) TEM images of NaYF4:2% Tm3+, 20% Yb3+ powders displaying uniformity of the particles (7–10 nm) with high UC efficiency [91].
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Fig. 3. Principal concept of the dye-sensitized nanoparticle. Antenna dyes (green) absorb NIR solar energy (red wavy arrows) and transfer it (brown arrows) to the nanoparticle core (in yellow), where upconversion occurs. Upconversion denotes a nonlinear (on the incident radiation intensity) process in which the energies of two NIR quanta are summed to emit a quantum of higher energy in the green-yellow region (green-yellow wavy arrow).
where the biological samples have minimum absorption, so tissue penetration depth is deeper than the conventional fluorescent agents. As most of the biological samples do not show upconversion property, the auto-fluorescence background is absent. UCNs emission depends on the energy transfer between different energy levels of lanthanides ions, thus the luminescence is stable without bleaching as most of organic dyes. The above advantages promise biomedical applications of UCN with high sensitivity and high selectivity. When compared with another type of hot inorganic fluorescent material-quantum dots, UCNs show superior advantages in biological toxicity as UCNs are usually composed with less toxic lanthanides elements. UCN have found potential applications in many different fields [98,99], mainly in several categories: bioimaging, bio-detection, therapy and auxiliary for molecule interaction study. 5.1. Bioimaging and detection Most of the luminescent material will find their application in imaging in vitro and in vivo, so do UCNs [100–102]. UCNs have the advantages over other fluorescent material used as imaging agent, such as minimum auto-fluorescence background and non-blinking and nonbleaching stable luminescence. Similarly, UCNs also find their applications in the detection of specific molecule in biomedical research with the luminescence as detection signal. Zhang and Dou [103] demonstrated the capability of the designed multicolor UCN in multiple detections in cellular level (Fig. 4). In this work, multicolor emission UCN was designed with proper dopants and different core–shell combinations. The multicolor UCNs were used to stain three different surface receptors on 3T3 cells, anti-BMPR2-UCNs-(A:Yb,Tm@B:Er@A:Yb3 +, Tm3 +), anti-PDGFR-UCNs-(A:Yb3+,Tm3+) and anti-α tubulin-UCNs-(A:Yb3+, Er3+@B:Tm3 + @A:Yb3 +,Tm3+), respectively. In the confocal images, the respective receptors were clearly viewed which confirm the feasibility of the UCN used in multiple detections in one assay at the same time. 5.2. Light sensitive gene activation in deep tissue Compared to bioimaging and detection, UCNs show more superiority in therapy and photo-active molecular in deep tissue. For imaging and detection, tissue is transparent to the NIR light, but the signal from the sample have to be collected after it comes out of the tissue. But one-way pathway (incident NIR to excite UCNs) is enough for therapy and molecule activation. Zhang's group explored the application of UCNs to be used as a remote control to activate biomolecules in deep tissue [104] (Fig. 5). Using UCNs for the remote activation purpose gains several advantages; they need NIR as a trigger, which is much less harmful than the shorter wavelength light. Moreover, the penetration
depth of NIR is much deeper than shorter wavelength UV or visible light, which enables deeper treatment in the tissue. In this work, the gene was caged in a mesoporous silica shell on the UCNs. The design not only protected the caged DNA/siRNA molecules from enzymatic environment but also minimized the toxicity of UCNs. The activation and knockdown of green fluorescent protein (GFP) was successfully achieved in tissue phantoms and in vivo with mice. It demonstrated the potential of using UCNs for the photo-controlled gene expression in deep solid tissue. 5.3. Photodynamic therapy and photothermal therapy Another attractive application of UCN is photodynamic therapy (PDT). The conventional PDT can only be applied in the superficial area, which is limited by the penetration depth of light source used for activation of photosensitizers. PDT with UCN minimizes the side effect of UV or visible PDT; the patient suffers less photo-damage upon the natural sunlight exposure. Zhang [105] used mesoporous-silica-coated UCNs to carry two types of photosensitizers for PDT (Fig. 6). Two peaks of multicolor-emission of the UCNs at a single excitation wavelength can simultaneously activate two photosensitizers to achieve an enhanced PDT. After injecting UCNs into melanoma tumors, in vivo studies also showed tumor growth inhibition in PDT-treated mice by direct injection of UCNs into melanoma tumors: tumor growth was suppressed. The inhibition of tumor was also observed in in vivo studies, after intravenous injection of UCNs conjugated with a tumor-targeting agent into tumor-bearing mice. It was the first in vivo PDT study with a UCN carried photosensitizer. This finding encourages further exploitations to develop a UCN platform for future noninvasive deep-cancer therapy. Besides photodynamic therapy, UCN could also be used in photothermal therapy while combined with photo-thermal agents. Scott A. Hilderbrand [106] developed NaYF4:Er3 +,Yb3 +@SiO2/Dye nanocomposites by incorporating carbocyanine dyes into the silica shell to utilize the dye to absorb NIR to enhance the efficiency of upconversion emission for optical imaging and photo-thermal treatment (Fig. 7). Carbocyanine dye was used as photothermal agents. Photothermal cell killing with the nano-composite was done under a 750 nm laser excitation, but the cell imaging was done with a 980 nm laser excitation. Cell imaging and photo-thermal cell killing was demonstrated with the nano-composite. 5.4. UCNs assisted multi-modality applications After proofing the feasibility of UCNs in imaging, delivery of active molecule and therapeutic applications, more and more study spread the UCNs in other biomedical applications. Multi-peak emissions of
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Fig. 4. (a) Schematic drawing of multiple detections. (b) UC emission from UCN tag from two types of surface receptor of 3T3 cells counterstained with DAPI. Color separated UC emission showing the position of BMPR2 receptor (red) and PDGF receptor (blue), and DAPI staining in pseudo color at the right bottom. (c) UCNs and DAPI merged image. (d) Color separated UC emission from BMPR2 surface receptors (red), PDGFR-α surface receptors (blue) and α-tubulin (green) and DAPI staining in pseudo color at the right bottom. (e) UCNs and DAPI merged image. Permission from Biomaterials [103]
UCNs enable them for multi-modality applications. Each of the peaks can be used for one function; as such the application potential of UCNs can be fully achieved. For instance, Su and Yeh [107] formulated upconversion nanoparticles (UCNs) as the NIR-triggered targeting and drug delivery vehicles to deliver drugs in vitro and in vivo for targeting, bioimaging, and chemotherapy at one time (Fig. 8). In detail, UCNs was coated with amino grouped silica with TEOS and APTES. And then the amine groups on the UCNs surfaces were partially conjugated with Nsuccinimidyl 3-(2-pyridyldithio)-propionate (SPDP), which contains a disulfide bond, the rest amine groups were PEGylated with the aid of NHS–EDC. The nanoparticles were then conjugated with DOX by thiolation followed by folic acid attachment, subsequently modifed with cage 2-nitrobenzylamine hydrochloride (NBA). The target was achieved thru folic acid on UCNs to recognize the receptors overexpressed on cancer cell surfaces: the release of antitumor drug-
doxorubicin was dependent on the disulfide bond of SPDP on the UCNs that can be cleaved by lysosomal enzymes within the cells. The concept of in vitro and in vivo imaging and chemotherapeutic efficacy had been proved in this work. 5.5. Molecule interaction study As a high sensitivity luminescent agent in biological system, UCNs also show promising potential to study the interaction between biomolecules and assist to study the cellular response/activity. Wong et al. [108] synthesized a series of polymer-coated UCNPs (short for upconversion nanoparticles in this paper) with different surface charges (positive, neutral, and negative) with selected surface-mounted polymers to study the endocytic mechanism. PVP, PEI and PAA were chosen to obtain neutral UCNP-PVP, positively charged UCNP-PEI and
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Fig. 5. (a) Schematic illustration. Plasmid DNA and siRNA are caged with DMNPE and then uncaged by upconverted UV light from NIR-to-UV UCNs. Inset shows the penetration depth of UV and NIR light in the skin. (b) Loading of caged plasmid DNA/siRNA into the mesopores of UCNs. Permission from PNAS [104]
negatively charged UCNP-PAA, respectively. They found that positively charged UCNPs significantly enhanced cellular uptake in cervical carcinoma (HeLa), glioblastoma (U87MG), and breast carcinoma (MCF-7) cells (Fig. 9). They also revealed that these cationic UCNPs can be uptaken mainly via clathrin-coated vesicular endocytosis. The results could provide guidance for the research of the interaction between particle charge and cell internalization.
6. Perspectives and conclusion The past decade has witnessed tremendous efforts in the developments and exploration of bio-applications of upconversion nanoparticles. As reviewed in this article, selection of suitable host matrix for efficient upconversion process, efforts to improve the upconversion efficiency, applications of upconversion nanoparticles for bioimaging,
Fig. 6. Targeted in vivo PDT of a subcutaneous tumor model injected with FA-PEG-UCNs. (a) Schematic diagram showing UCN-based targeted PDT in a mouse model of melanoma intravenously injected with UCNs surface modified with folic acid (FA) and PEG moieties. Scale bar, 10 mm. (b) Change in tumor size as a function of time after treatment to assess the effectiveness of UCN-based mediated targeted PDT in tumor-bearing mice intravenously injected with FA-PEG-UCNs. Values are means ± s.e.m. (n = 7 mice per group). *P b 0.05 compared to control group 3 by Kruskal–Wallis ANOVA. Permission from Nature Medicine [105]
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Fig. 7. Application of UNP@SiO2/Dye nano-composites (blue dots and green dots) for optical imaging and photo-thermal therapy (cell disruption). Permission from Theranostics [106]
detection, photodynamic therapy, photo-activate of gene in deep tissue, NIR triggered drug release, as well as upconversion nanoparticles assisted studies on inter/intra cellular interactions have been discussed. Considerable progress has been made in the preparation of upconversion nanoparticles, especially in the control of the size, shape, composition and phase of the nanoparticles. As a result, it was found that the hexagonal phase NaYF4 nanoparticles so far is the most efficient host matrix for NIR-to-UV/Vis upconversion process. However, the luminescent quantum yield of upconversion nanoparticles is still far to be satisfied [109], thus limiting the use of these nanoprobes in most of the potential biomedical applications. To meet the needs, further development of upconversion nanoparticles is still needed; for example, smaller nanoparticles with uniform size distribution and stronger tunable fluorescence are highly desired. More efforts are required for
this purpose, such as to discover better host matrix, and to unveil the mechanism behind the process. Currently, most upconversion nanoparticles are excited by 980 nm lasers, where water also has strong absorbance; consequentially the 980 nm excitation heats up water and thus resulting in unnecessary tissue heating. Development of UCNs excited by NIR at other wavelength would be an ideal option to reduce the tissue heating without sacrificing the tissue penetration. Nowadays, researchers turned their attentions to other wavelength excitation for UCNs, for example 800 nm [110–113]. To enhance the targeting abilities and biocompatibilities, surface functionalization and bioconjugation strategies need to be optimized as well. Despite the challenges mentioned above, upconversion nanoparticles are indeed promising materials for bio-applications due to their unique optical properties. For bio-imaging, almost no interference from auto-
Fig. 8. Illustration of photocaged UCNPs following NIR laser activation to remove cage molecules and subsequent targeting of cancer cell. Permission from ACS Nano [107]
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Fig. 9. Top row: Multiphoton confocal fluorescent images at 980 nm of HeLa cells following 24 h incubation with 50 μg/mL UCNP–PEI (+) (left panel), UCNP–PVP (0) (middle panel), and UCNP–PAA (−) (right panel). Bottom row, from left to right: Bright field live-cell image of HeLa cells; UCNP-PEI (FITC-labeled) uptake through clathrin-mediated endocytosis; HeLa cells transfected with RFP-tagged clathrin for 24 h; Overlay image of the middle left and middle right images.
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Contents lists available at ScienceDirect
Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Near-infrared upconversion nanoparticles for bio-applications Qing Qing Dou, Hong Chen Guo, Enyi Ye ⁎ Institute of Materials Research and Engineering (IMRE), 3 Research Link, Singapore 117602, Singapore
a r t i c l e
i n f o
Article history: Received 24 January 2014 Accepted 21 March 2014 Available online 16 April 2014 Keywords: NIR upconversion Multi-modality Photodynamic therapy Photo activation
a b s t r a c t Upconversion nanoparticles (UCNs) attract intensive attentions in biomedical applications. They have shown great potential in bioimaging, biomolecule detection, drug delivery, photodynamic therapy and cellular molecules interactions. Due to the anti-Stokes optical property and NIR excitation, UCNs overcome the drawbacks encountered in conventional luminescent biomarkers. High signal to noise ratio, low cytotoxicity and stable high throughput results are obtained using UCNs as luminescent labels or light triggers in biomedical applications. In this review article, the reason for choosing UCNs as biomedical agents, the progress of the UCNs development and case studies of their biomedical applications will be discussed. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Fluorophores have been used for non-invasive detection of biological molecules and monitoring of real-time biological processes for several decades [1]. As a non-destructive method, fluorescence technique produce fast, sensitive and reproducible signal, and high resolution in samples with intrinsic color (e.g. blood). The optical bioimaging with fluorophores has become the state of the art with impacts on fundamental biomedical research and clinical practice. There are two main categories of fluorophores exploited for this purpose: one type converts short wavelength light to longer ones (downconversion), and another type converts longer wavelength to shorter (upconversion). This review focuses on the later one. Downconversion was studied earlier than upconversion. Organic dyes and quantum dots fall in this category. Most of organic fluorophores suffer from a common problem-photobleaching [2–4]. The track of the targets will be lost after the fluorescence bleaching, which lead to failure of the tasks. Quantum dots, feature with large molar extinction coefficient [5], higher quantum yield, narrow emission bandwidth [6], size-dependent tunable emission [7], composition tunable emission and higher photostability, seem to be a fantastic alternative to organic dyes [6,8, 9]. Unfortunately, quantum dots are usually composed with elements exhibiting intrinsic toxicity, such as Cd, Se etc. [10]. Their potential toxicity poses risks to health and environment, which became a concern and arouse debate to apply them in biological study [11,12]. Furthermore, both the organic fluorophores and quantum dots suffer from low signal-to-noise ratio. Downconversion luminescent materials are generally excited by UV and visible light, so the autofluorescence [13, 14] from the biological sample (such as mitochondria and lysosomes) ⁎ Corresponding author. E-mail address: [email protected] (E. Ye).
http://dx.doi.org/10.1016/j.msec.2014.03.056 0928-4931/© 2014 Elsevier B.V. All rights reserved.
is always present in the signal and thus decreases the sensitivity of the detection, leading to low signal-to-noise ratio. Moreover, the incident excitation light causes photodamage to living organisms. The second type, fluorescent upconversion nanoparticles (UCNs) overcomes most of the drawbacks of downconversion materials. UCNs exhibit antiStokes emission by emitting detectable photons of higher energy in the UV to a visible range upon near-infrared (NIR) irradiation. Coincidently, optical window in biological tissue falls in the NIR region [15], in which most biological molecules showing the lowest absorption of light. Therefore, the penetration depth of NIR is much deeper than UV or visible light, which enables deeper imaging or detection. As well the NIR light is much less toxic to biological system compared to UV light. Composed with inorganic crystals doped with lanthanide elements, the toxicity is much lower than quantum dots. UCNs' fluorescence originated from the energy transfer between different energy levels of lanthanide [16], so the upconversion fluorescence is much stable than organic dyes. Due to the aggregated sub-energy level of lanthanide, the emission bandwidth is very sharp and fluorescence lifetime is relatively long, up to several milliseconds [17]. The emission of the upconversion can be finely tuned by doping different lanthanide elements. The above mentioned superior properties over conventional downconversion labels render UCNs an ideal luminescent label for biological applications. In this review, we focus on the second type of fluorescent material-upconversion nanoparticles (UCNs). The development of UCNs and their applications in biomedical area will be discussed. 2. Luminescent upconversion process Development of upconversion nanoparticles (UCNs) is one of the hottest topics in recent years. The research interests on them aroused from their unique optical property—it converts low energy photons
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of long wavelength light to high energy photons to emit shorter wavelength light. Take Yb3 +/Er3 + and Yb3 +/Tm3 + absorber/emitter pair doped UCNs as an example; it will be more clearly to understand the upconversion procedure. In this process, Yb3 + absorbs energy near 980 nm as it has broad cross-section in this region [18–20]. As shown in Fig. 1, The absorber Yb3+ ions absorb NIR light, and then through lattice vibrations of the nanocrystalline matrix, the energy transfers to the emitter Er3+ or Tm3+ ions due to the energy overlap of the transition dipoles of the two elements [21,22]. Due to the complex energy level configuration of Er and Tm, the energy relaxes to different energy levels before it is released to ground state. Subsequently, wide span emissions ranging from UV, visible to NIR, corresponding to different energy levels, are generated when the energy is released to ground state. 3. Host matrix for upconversion It is essential to choose a proper matrix for upconversion process as it totally depends on the energy transfer between absorber and emitter within a suitable proximity. Different matrix provides different distance between the atoms in which the emitter and absorber are randomly and equally distributed. But the size or atom distance is not the only criteria for choosing the latticed. Considered in getting more effective luminescence, another requirement for the lattice is low lattice photon energy, which reduces non-radiative energy loss. The dynamics of the excited state of the rare earth ions and interactions between them, so the upconversion emissions were different in different crystal lattices even though with the same dopants [23,24]. Therefore, to search a proper crystal lattice is very essential to achieve high upconversion efficiency. So far, a lot of lattices have been explored to serve as the host matrix for upconversion process. The host used to incorporate the lanthanide absorbers and emitters can be classified into two main categories—amorphous and crystal. Amorphous material, most of them are glass, can host the lanthanide ions in the casting procedure. Germanate chalcohalide glass composed of GeO2–PbO–Nb2O5 glass [25,26] with different halide (Cl, Br, I) modifiers and Pr3 + dopant concentrations have been studied as an upconversion host. Calcium sodium aluminosilicate glass doped with Er3 + was also studied as an upconversion host material at room temperature and at 77 K [27]. Upconversion luminescence was also studied in Ho3 + doped ZnO–TeO2 glass [28], Er3 + doped SiO2–PbF2– ErF3 transparent glass ceramics [29] and amorphous Tm0.1La0.9P5O14 [30]. The requirements for the crystal lattice to be used for upconversion matrix are much higher than the amorphous material. It requires similar size lattice points and distance between them as well as similar charges. A series of crystals had been explored as upconversion host. One big
category is oxide, such as Y2O3 [31–33], ZrO2 [34–36], and TiO2 [37]. Bright white upconversion emission was also observed from Yb3 +, Er3+, and Tm3+ codoped Gd2O3 nanotubes [38–40]. Perovskite oxides were also employed as host, such as Pr3+ doped Bi4Ge3O12 [41], Er3+ doped YAlO3 [42], GdAlO3 [43], Ti2+ and Er3+ co-doped LiNbO3 [44], Yb3+ and Tm3 + co-doped GdAlO3 [43], Ho3 + doped LiTaO3 [45] and BaTiO3:Er3+ [37,46,47]. Other crystals composed with both oxygen and lanthanide ions were also used as host materials for upconversion processes, such as LiGd(MoO4)2, Y3Sc2Ga3O12, Gd3Ga5O12 [43], TmP5O14 and Tm0.1La0.9P5O14 [30], LuPO4:Yb3+,Tm3+ [48], La2(MoO4)3:Yb3+,Tm3+ [49], Tm3+/Yb3+/ Er3+ codoped Lu3Ga5O12 [50,51], La2O2S [52] and YbPO4:Er3+ [48,53] were also reported for upconversion. Halide compounds crystals were also reported for upconversion study. For example, Gd3+ doped Cs2NaGdCl6 [54], Er3 + doped RbGd2Br7 [55], Tm3 + doped Cs3Yb2Cl9 [56] and BaLu 2 F 8 doped with Er 3 + [57]. Transition metal ions (Zr4 + and Ti4 + [58,59], Re4 + and Mo3 + [60]) have similar ionic size to lanthanide ions, they were also reported to be used to generate NIR to visible upconversion luminescence. Capobianco's group made a lot of efforts to make upconversion nanoparticles with relatively new crystal lattice. For example, CaS: Eu2 +/Dy3+ emit strong red light upon NIR excitation [61]. They also found that GdVO4 doped with Er3 + and Yb3 + have two strong emissions peaks near 525 and 550 nm while a relatively weak red peak centered at 660 nm [62]. Similarly, the similar host lattice doped with different ions GdVO4:Tm3+/Yb3+/Ho3+/Li+ could harvest white emission in total [63]. Recently, they studied NaxScF3 + x crystal– monoclinic phase Na3ScF6 and hexagonal phase Na3ScF6 nanocrystals [64], as an upconversion material. Among all the crystal host, LaF3 [65–68] and NaYF4 [69–72] (including Li+ substitution LiYF4 [73,74]) are the most studied. Even though some host matrixes have similar size lattice points to hold the lanthanide ions, dopants easily cause defects such as interstitial anion and cation vacancies in the crystal. Considering neutrality in the crystal, the dopant concentrations have to be stringently limited. Thus, the luminescence is not high in these materials. Fluorides bear lower phonon energies (350 cm−1) than oxides (500 cm−1) and lower than heavy halides (300 cm−1) [16]; it is more stable than halides. Lattice with low phonon energy suffers less nonradiative energy loss in upconverted energy states. Theoretically, halides are more suitable to be used for host matrix [75]. Practically, it was found that the hexagonal phase Yb3+/Er3+ (or Yb3+/Tm3+) codoped NaYF4 nanocrystal was the most efficient infrared-to-visible upconversion luminescent materials [76–78]. For biological purpose, the toxicity of the host lattice is a key consideration point, which adds more limitations to choose the host. 4. Efforts on improving upconversion efficiency
Fig. 1. Energy diagram of Yb3+, Er3+ and Tm3+ and the energy transfer between them. The dashed–dotted, dashed, dotted, and full arrows represent photon excitation, energy transfer, multiphonon relaxation, and emission processes, respectively. Only visible and NIR emissions are shown here [16].
As a promising material used for biomedical applications, considerable efforts have been draw to improve the luminescent efficiency of UCNs. The upconversion was firstly studied in bulk material [79–81], and then researchers tried to make it into nanoscale with top-down or bottom-up methods. The small host leads to serious luminescence decrease due to the existence of a relative larger surface (larger surface to volume ratio). Especially for the upconversion process, the luminescence yield is affected in orders by any decreasing factors due to it is a multi-photon process: each photon process will be influenced by the same factor. To get repeatable and stable result, uniform size is highly required. Top-down methods cannot get as highly uniform sized nanoparticles as bottom-up methods, so intensive attention was on the latter. Hydrothermal synthesis is a typical bottom-up method for obtaining upconversion nanoparticles, but the size distribution of the nanoparticles was not satisfied [23,82]. After Zhang and Li developed a thermal decomposition method to obtain uniform sized NaYF4 nanocrystals with oleic acid as a shape control agent [70,71,83], uniform 30–50 nm-UCNs with ± 3 nm sized can be easily obtained and the
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morphology can be easily controlled as shown in Fig. 2a–d. Later on great efforts have been made to improve the quality of NaYF4 nanocrystals [69,72,84,85]. Other chemicals were also exploited to modify the shape of UCNs. Lin and Li [86] synthesized β-NaYF4:Ln3+ (Ln = Eu, Tb, Yb/Er, and Yb/Tm) hexagonal microprism crystals with sodium citrate as a shape modifier (Fig. 2e). The upconversion emission was then finely tuned by changing the absorber and emitter dopants' concentrations [87,88]. Take NaYF4:Yb3 +,Er3 +/Tm3 + as an example, as the similar energy level in lanthanide ions, the energy transfers between the absorber (Yb3 +) and emitter (Er3 + or Tm3 +) dopants. The deleterious cross relaxation between Yb3 + and Er3 + (or Tm3 +) [89] and cooperative interaction between Yb3+ [90] causes a decreased upconversion emission due to the absorbed energy loss. Thus the dopant concentration was limited to get a high yield luminescence. For some delicate applications, 30–50 nm nanoparticles were still quite large, thus hindered UCNs' applications. To solve the contradictory situation between size reluctant versus luminescence quenching, more challenges appeared and larger efforts are required. Prasas N. Prasad reported an approach [91] to synthesize 7–10 nm UCNs 43 times enhancement by increasing Yb3 + ions from 20% to 100% and corresponding decreased Y3 + content from 80% to 0% (Fig. 2f). A Bednarkiewicz demonstrated irreversible spatially confined infraredlaser-induced annealing of ultra-small ~ 8 nm NaYF4: 20% Yb3 +, 2% Er3+ under a 976 nm localized tightly focused beam from a continuous wave medium power laser diode excitation, where 2–3 order enhancement in luminescence yield was found. Moreover, efforts have been made in fine tuning the crystal structure, composition [73,74] and combinations to enhance the uminescent intensity of UCNs. One method to improve the upconversion luminescence was to coat a shell on the surface of a nanoparticle to minimize the surface defect [72,92–94]. This method improved the luminescence intensity to an extent, but the size increased at the meantime. This approach did not touch the structure of the nanocrystal but only repair the surface defects. Cappobianco el al. [95] reported a method to
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enhance the luminescence of UCNs by increasing the energy absorbance of the nanoparticles through an active shell (Fig. 3a). In detail, they coated an absorber doped layer on the surface of NaGdF4: Yb3 +,Er3 + core. With this method, the upconversion emission could reach 3 and 10 folds in the green and in the red to NaGdF4: Yb3 +,Er3 +/NaGdF4 core/shell, respectively; and 13 and 20 folds for the green and red emissions in the NaGdF4: Yb3+,Er3+ nanoparticles, respectively. The above methods were based on the hexagonal NaYF4 crystal matrix without changing the crystal structure or phase. Methods by fine adjusting the structure of the crystal were also exploited. For example, Zhang [73] tried to tune the upconversion efficiency by adjusting the absorber and emitter in NaYF4:Yb3 +,Er3 + nanocrystal distance with different sized alkali ions. Phase transition of nanocrystals was found with doping a different amount of Li and K. The energy transfer in between different energy levels in emitter lanthanide was also affected, which leads to the change of the intensity ratios between the blue, green, and red emission peaks. Liu et al. [93] tried to unveil the mechanism behind the process and tune the emission of UCNs (Fig. 3b). Recently, Liu [96] reported that lanthanide ions distributed in arrays of tetrad clusters KYb2F7:Er3+ orthorhombic crystallographic structure can greatly preserve the excitation energy within the sublattice domain by minimizing the migration of excitation energy to defects. Moreover, organic near-infrared dye as an absorbance antenna was attached on the β-NaYF4:Yb3+,Er3+ nanoparticles to enhance NIR absorbance to enhance the upconversion efficiency, reported by Jan C. Hummelen et al. [97] (Fig. 3c). Another advantage of this design was broadening of the absorption spectrum of the upconverter. It was reported that the dye-sensitized upconversion intensity got an enhancement by a factor of ~3300. 5. Biomedical applications of UCNs The unique property of anti-Stokes property of UCNs arouses great interest of biomedical applications. UCN needs NIR light as excitation
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Fig. 2. (a) TEM images of PVP/NaYF4: Yb,Er nanocrystals [70]. TEM images of (b) NaYF4:Yb, Er nanospheres (c) nanoellipses, and (d) nanoplates [71]. (a) β-NaYF4:Ln3+ (Ln = Eu, Tb, Yb/Er, and Yb/Tm) hexagonal microprisms [86]. (e) TEM images of NaYF4:2% Tm3+, 20% Yb3+ powders displaying uniformity of the particles (7–10 nm) with high UC efficiency [91].
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Fig. 3. Principal concept of the dye-sensitized nanoparticle. Antenna dyes (green) absorb NIR solar energy (red wavy arrows) and transfer it (brown arrows) to the nanoparticle core (in yellow), where upconversion occurs. Upconversion denotes a nonlinear (on the incident radiation intensity) process in which the energies of two NIR quanta are summed to emit a quantum of higher energy in the green-yellow region (green-yellow wavy arrow).
where the biological samples have minimum absorption, so tissue penetration depth is deeper than the conventional fluorescent agents. As most of the biological samples do not show upconversion property, the auto-fluorescence background is absent. UCNs emission depends on the energy transfer between different energy levels of lanthanides ions, thus the luminescence is stable without bleaching as most of organic dyes. The above advantages promise biomedical applications of UCN with high sensitivity and high selectivity. When compared with another type of hot inorganic fluorescent material-quantum dots, UCNs show superior advantages in biological toxicity as UCNs are usually composed with less toxic lanthanides elements. UCN have found potential applications in many different fields [98,99], mainly in several categories: bioimaging, bio-detection, therapy and auxiliary for molecule interaction study. 5.1. Bioimaging and detection Most of the luminescent material will find their application in imaging in vitro and in vivo, so do UCNs [100–102]. UCNs have the advantages over other fluorescent material used as imaging agent, such as minimum auto-fluorescence background and non-blinking and nonbleaching stable luminescence. Similarly, UCNs also find their applications in the detection of specific molecule in biomedical research with the luminescence as detection signal. Zhang and Dou [103] demonstrated the capability of the designed multicolor UCN in multiple detections in cellular level (Fig. 4). In this work, multicolor emission UCN was designed with proper dopants and different core–shell combinations. The multicolor UCNs were used to stain three different surface receptors on 3T3 cells, anti-BMPR2-UCNs-(A:Yb,Tm@B:Er@A:Yb3 +, Tm3 +), anti-PDGFR-UCNs-(A:Yb3+,Tm3+) and anti-α tubulin-UCNs-(A:Yb3+, Er3+@B:Tm3 + @A:Yb3 +,Tm3+), respectively. In the confocal images, the respective receptors were clearly viewed which confirm the feasibility of the UCN used in multiple detections in one assay at the same time. 5.2. Light sensitive gene activation in deep tissue Compared to bioimaging and detection, UCNs show more superiority in therapy and photo-active molecular in deep tissue. For imaging and detection, tissue is transparent to the NIR light, but the signal from the sample have to be collected after it comes out of the tissue. But one-way pathway (incident NIR to excite UCNs) is enough for therapy and molecule activation. Zhang's group explored the application of UCNs to be used as a remote control to activate biomolecules in deep tissue [104] (Fig. 5). Using UCNs for the remote activation purpose gains several advantages; they need NIR as a trigger, which is much less harmful than the shorter wavelength light. Moreover, the penetration
depth of NIR is much deeper than shorter wavelength UV or visible light, which enables deeper treatment in the tissue. In this work, the gene was caged in a mesoporous silica shell on the UCNs. The design not only protected the caged DNA/siRNA molecules from enzymatic environment but also minimized the toxicity of UCNs. The activation and knockdown of green fluorescent protein (GFP) was successfully achieved in tissue phantoms and in vivo with mice. It demonstrated the potential of using UCNs for the photo-controlled gene expression in deep solid tissue. 5.3. Photodynamic therapy and photothermal therapy Another attractive application of UCN is photodynamic therapy (PDT). The conventional PDT can only be applied in the superficial area, which is limited by the penetration depth of light source used for activation of photosensitizers. PDT with UCN minimizes the side effect of UV or visible PDT; the patient suffers less photo-damage upon the natural sunlight exposure. Zhang [105] used mesoporous-silica-coated UCNs to carry two types of photosensitizers for PDT (Fig. 6). Two peaks of multicolor-emission of the UCNs at a single excitation wavelength can simultaneously activate two photosensitizers to achieve an enhanced PDT. After injecting UCNs into melanoma tumors, in vivo studies also showed tumor growth inhibition in PDT-treated mice by direct injection of UCNs into melanoma tumors: tumor growth was suppressed. The inhibition of tumor was also observed in in vivo studies, after intravenous injection of UCNs conjugated with a tumor-targeting agent into tumor-bearing mice. It was the first in vivo PDT study with a UCN carried photosensitizer. This finding encourages further exploitations to develop a UCN platform for future noninvasive deep-cancer therapy. Besides photodynamic therapy, UCN could also be used in photothermal therapy while combined with photo-thermal agents. Scott A. Hilderbrand [106] developed NaYF4:Er3 +,Yb3 +@SiO2/Dye nanocomposites by incorporating carbocyanine dyes into the silica shell to utilize the dye to absorb NIR to enhance the efficiency of upconversion emission for optical imaging and photo-thermal treatment (Fig. 7). Carbocyanine dye was used as photothermal agents. Photothermal cell killing with the nano-composite was done under a 750 nm laser excitation, but the cell imaging was done with a 980 nm laser excitation. Cell imaging and photo-thermal cell killing was demonstrated with the nano-composite. 5.4. UCNs assisted multi-modality applications After proofing the feasibility of UCNs in imaging, delivery of active molecule and therapeutic applications, more and more study spread the UCNs in other biomedical applications. Multi-peak emissions of
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Fig. 4. (a) Schematic drawing of multiple detections. (b) UC emission from UCN tag from two types of surface receptor of 3T3 cells counterstained with DAPI. Color separated UC emission showing the position of BMPR2 receptor (red) and PDGF receptor (blue), and DAPI staining in pseudo color at the right bottom. (c) UCNs and DAPI merged image. (d) Color separated UC emission from BMPR2 surface receptors (red), PDGFR-α surface receptors (blue) and α-tubulin (green) and DAPI staining in pseudo color at the right bottom. (e) UCNs and DAPI merged image. Permission from Biomaterials [103]
UCNs enable them for multi-modality applications. Each of the peaks can be used for one function; as such the application potential of UCNs can be fully achieved. For instance, Su and Yeh [107] formulated upconversion nanoparticles (UCNs) as the NIR-triggered targeting and drug delivery vehicles to deliver drugs in vitro and in vivo for targeting, bioimaging, and chemotherapy at one time (Fig. 8). In detail, UCNs was coated with amino grouped silica with TEOS and APTES. And then the amine groups on the UCNs surfaces were partially conjugated with Nsuccinimidyl 3-(2-pyridyldithio)-propionate (SPDP), which contains a disulfide bond, the rest amine groups were PEGylated with the aid of NHS–EDC. The nanoparticles were then conjugated with DOX by thiolation followed by folic acid attachment, subsequently modifed with cage 2-nitrobenzylamine hydrochloride (NBA). The target was achieved thru folic acid on UCNs to recognize the receptors overexpressed on cancer cell surfaces: the release of antitumor drug-
doxorubicin was dependent on the disulfide bond of SPDP on the UCNs that can be cleaved by lysosomal enzymes within the cells. The concept of in vitro and in vivo imaging and chemotherapeutic efficacy had been proved in this work. 5.5. Molecule interaction study As a high sensitivity luminescent agent in biological system, UCNs also show promising potential to study the interaction between biomolecules and assist to study the cellular response/activity. Wong et al. [108] synthesized a series of polymer-coated UCNPs (short for upconversion nanoparticles in this paper) with different surface charges (positive, neutral, and negative) with selected surface-mounted polymers to study the endocytic mechanism. PVP, PEI and PAA were chosen to obtain neutral UCNP-PVP, positively charged UCNP-PEI and
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Fig. 5. (a) Schematic illustration. Plasmid DNA and siRNA are caged with DMNPE and then uncaged by upconverted UV light from NIR-to-UV UCNs. Inset shows the penetration depth of UV and NIR light in the skin. (b) Loading of caged plasmid DNA/siRNA into the mesopores of UCNs. Permission from PNAS [104]
negatively charged UCNP-PAA, respectively. They found that positively charged UCNPs significantly enhanced cellular uptake in cervical carcinoma (HeLa), glioblastoma (U87MG), and breast carcinoma (MCF-7) cells (Fig. 9). They also revealed that these cationic UCNPs can be uptaken mainly via clathrin-coated vesicular endocytosis. The results could provide guidance for the research of the interaction between particle charge and cell internalization.
6. Perspectives and conclusion The past decade has witnessed tremendous efforts in the developments and exploration of bio-applications of upconversion nanoparticles. As reviewed in this article, selection of suitable host matrix for efficient upconversion process, efforts to improve the upconversion efficiency, applications of upconversion nanoparticles for bioimaging,
Fig. 6. Targeted in vivo PDT of a subcutaneous tumor model injected with FA-PEG-UCNs. (a) Schematic diagram showing UCN-based targeted PDT in a mouse model of melanoma intravenously injected with UCNs surface modified with folic acid (FA) and PEG moieties. Scale bar, 10 mm. (b) Change in tumor size as a function of time after treatment to assess the effectiveness of UCN-based mediated targeted PDT in tumor-bearing mice intravenously injected with FA-PEG-UCNs. Values are means ± s.e.m. (n = 7 mice per group). *P b 0.05 compared to control group 3 by Kruskal–Wallis ANOVA. Permission from Nature Medicine [105]
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Fig. 7. Application of UNP@SiO2/Dye nano-composites (blue dots and green dots) for optical imaging and photo-thermal therapy (cell disruption). Permission from Theranostics [106]
detection, photodynamic therapy, photo-activate of gene in deep tissue, NIR triggered drug release, as well as upconversion nanoparticles assisted studies on inter/intra cellular interactions have been discussed. Considerable progress has been made in the preparation of upconversion nanoparticles, especially in the control of the size, shape, composition and phase of the nanoparticles. As a result, it was found that the hexagonal phase NaYF4 nanoparticles so far is the most efficient host matrix for NIR-to-UV/Vis upconversion process. However, the luminescent quantum yield of upconversion nanoparticles is still far to be satisfied [109], thus limiting the use of these nanoprobes in most of the potential biomedical applications. To meet the needs, further development of upconversion nanoparticles is still needed; for example, smaller nanoparticles with uniform size distribution and stronger tunable fluorescence are highly desired. More efforts are required for
this purpose, such as to discover better host matrix, and to unveil the mechanism behind the process. Currently, most upconversion nanoparticles are excited by 980 nm lasers, where water also has strong absorbance; consequentially the 980 nm excitation heats up water and thus resulting in unnecessary tissue heating. Development of UCNs excited by NIR at other wavelength would be an ideal option to reduce the tissue heating without sacrificing the tissue penetration. Nowadays, researchers turned their attentions to other wavelength excitation for UCNs, for example 800 nm [110–113]. To enhance the targeting abilities and biocompatibilities, surface functionalization and bioconjugation strategies need to be optimized as well. Despite the challenges mentioned above, upconversion nanoparticles are indeed promising materials for bio-applications due to their unique optical properties. For bio-imaging, almost no interference from auto-
Fig. 8. Illustration of photocaged UCNPs following NIR laser activation to remove cage molecules and subsequent targeting of cancer cell. Permission from ACS Nano [107]
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Fig. 9. Top row: Multiphoton confocal fluorescent images at 980 nm of HeLa cells following 24 h incubation with 50 μg/mL UCNP–PEI (+) (left panel), UCNP–PVP (0) (middle panel), and UCNP–PAA (−) (right panel). Bottom row, from left to right: Bright field live-cell image of HeLa cells; UCNP-PEI (FITC-labeled) uptake through clathrin-mediated endocytosis; HeLa cells transfected with RFP-tagged clathrin for 24 h; Overlay image of the middle left and middle right images.
fluorescence makes them excellent probes for in vivo imaging featured with high sensitivity. For photodynamic therapy and other NIRtriggered applications with upconversion nanoparticles, NIR is advantaged over UV or visible light that are used in conventional methods. We do believe that with more efforts in the improvement of the upconversion efficiency together with more in-depth investigations, the biomedical applications of the upconversion nanoparticles will be surely further pushed forward. References [1] D. Evanko, Nat. Methods 2 (2005) 160–161. [2] D. Beer, J. Weber, Opt. Commun. 5 (1972) 307–309. [3] I.P. Kaminow, L.W. Stulz, E.A. Chandross, C.A. Pryde, Appl. Opt. 11 (1972) 1563–1567. [4] C. Eggeling, J. Widengren, R. Rigler, C. Seidel, Anal. Chem. 70 (1998) 2651–2659. [5] W.W. Yu, L. Qu, W. Guo, X. Peng, Chem. Mater. 15 (2003) 2854–2860. [6] U. Resch-Genger, M. Grabolle, S. Cavaliere-Jaricot, R. Nitschke, T. Nann, Nat. Methods 5 (2008) 763–775. [7] W.K. Leutwyler, S.L. Bürgi, H. Burgl, Science 271 (1996) 933. [8] W.C.W. Chan, D.J. Maxwell, X. Gao, R.E. Bailey, M. Han, S. Nie, Curr. Opin. Biotechnol. 13 (2002) 40–46. [9] X. Gao, Y. Cui, R.M. Levenson, L.W.K. Chung, S. Nie, Nat. Biotechnol. 22 (2004) 969–976. [10] R. Hardman, Environ. Health Perspect. 114 (2006) 165. [11] A. Shiohara, A. Hoshino, K.-i. Hanaki, K. Suzuki, K. Yamamoto, Microbiol. Immunol. 48 (2004) 669–675. [12] K.M. Tsoi, Q. Dai, B.A. Alman, W.C. Chan, Acc. Chem. Res. 46 (2012) 662–671. [13] J. Aubin, J. Histochem. Cytochem. 27 (1979) 36–43. [14] Y. Yuanlong, Y. Yanming, L. Fuming, L. Yufen, M. Paozhong, Lasers Surg. Med. 7 (1987) 528–532. [15] B.J. Tromberg, N. Shah, R. Lanning, A. Cerussi, J. Espinoza, T. Pham, L. Svaasand, J. Butler, Neoplasia 2 (2000) 26. [16] F. Auzel, Chem. Rev. 104 (2004) 139–174. [17] M. Pollnau, P.J. Hardman, W.A. Clarkson, D.C. Hanna, Opt. Commun. 147 (1998) 203–211. [18] J. Dong, M. Bass, Y. Mao, P. Deng, F. Gan, J. Opt. Soc. Am. B 20 (2003) 1975–1979. [19] L.D. DeLoach, S.A. Payne, L.L. Chase, L.K. Smith, W.L. Kway, W.F. Krupke, IEEE J. Quantum Electron. 29 (1993) 1179–1191. [20] M.J. Weber, J. Lynch, D.H. Blackburn, D. Cronin, IEEE J. Quantum Electron. 19 (1983) 1600–1608. [21] I.M. Batyaev, N.V. Danil'chuk, Y.A. Kabatskii, V.N. Shapovalov, S.M. Shilov, J. Appl. Spectrosc. 51 (1989) 1262–1264. [22] F. Auzel, G. Baldacchini, L. Laversenne, G. Boulon, Opt. Mater. 24 (2003) 103–109. [23] J.H. Zeng, J. Su, Z.H. Li, R.X. Yan, Y.D. Li, Adv. Mater. 17 (2005) 2119–2123. [24] L. Wang, R. Yan, Z. Huo, L. Wang, J. Zeng, J. Bao, X. Wang, Q. Peng, Y. Li, Angew. Chem. Int. Ed. 44 (2005) 6054–6057.
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