Nanocrystals: Soft Chemical

Review pubs.acs.org/CR

Recent Progress in Rare Earth Micro/Nanocrystals: Soft Chemical Synthesis, Luminescent Properties, and Biomedical Applications Shili Gai,†,‡ Chunxia Li,† Piaoping Yang,*,‡ and Jun Lin*,† †

State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China ‡ Key Laboratory of Superlight Materials and Surface Technology, Ministry of Education, Harbin Engineering University, Harbin, 150001, P. R. China 3.5.3. Ionic-Liquids-Based Synthesis 4. Hydrophilic Modification and Bioconjugation 4.1. Hydrophilic Modification 4.2. Bioconjugation 5. Toxicity 6. Bioimaging Applications 6.1. UCL Imaging 6.2. Tumor Targeting and Imaging 6.3. Multimodal Bioimaging 6.3.1. UCL/MRI Imaging 6.3.2. UCL/MRI/CT Imaging 6.3.3. UCL/MRI/PET Imaging 6.3.4. Others 7. Therapeutic Applications 7.1. Photodynamic Therapy (PDT) 7.2. Photothermal Therapy (PTT) 7.3. Drug and siRNA Delivery 8. Conclusion and Outlook Author Information Corresponding Authors Notes Biographies Acknowledgments Abbreviations Used References

CONTENTS 1. Introduction 2. Luminescent Properties of Lanthanide-Doped Materials 2.1. Down-Conversion Luminescence (DCL) 2.2. Up-Conversion Luminescence (UCL) 2.3. Multicolor Fine-Tuning 2.3.1. DC Multicolor Emissions 2.3.2. DC White Light Emissions 2.3.3. UC Multicolor Emissions 2.3.4. UC White Light Emissions 2.4. Luminescence Enhancement 2.4.1. Conventional Methods 2.4.2. Design of Core−Shell Structures 3. Soft Chemical Routes 3.1. Thermal Decomposition Method 3.1.1. Trifluoroacetate Precursor 3.1.2. Oleate, Acetylacetonate, Acetate, and Other Precursors 3.1.3. Methanol-Assisted Organic-Phase Synthetic Methods 3.2. Hydro/Solvothermal Method 3.2.1. Organic-Additive-Free Solvothermal Method 3.2.2. Hydrophilic-Ligand-Assisted Solvothermal Method 3.2.3. Hydrophobic-Ligand-Assisted Solvothermal Method 3.3. Coprecipitation Method 3.4. Pechini-Type Sol−Gel Process 3.4.1. Lanthanide-Doped Phosphor Film and Patterning 3.4.2. Lanthanide-Doped Phosphor Fiber by Electrospinning 3.5. Others 3.5.1. Microemulsion Method 3.5.2. Microwave-Assisted Method © 2013 American Chemical Society

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1. INTRODUCTION Luminescent materials, also called phosphors, are defined as solids that can absorb and convert certain types of energy into radiation of light.1 Among all kinds of phosphors, rare earth (RE) material is an important and attractive candidate. RE elements, which usually exist as trivalent cations, are composed of the 15 lanthanides (from lanthanum to lutetium), plus scandium and yttrium. With abundant f-orbital configurations, lanthanide (Ln) ions can exhibit sharp fluorescent emissions via intra-4f or 4f−5d transitions and thus are widely used as emitting species in many phosphors. In fact, due to the forbidden character of the 4f transitions, direct excitation of lanthanide ion (Ln3+) is a relatively inefficient process. From this point of view, a doping technique, which involves the incorporation of a low concentration of atoms or ions into host lattices to yield hybrid materials, is widely applied to synthesize Ln3+-doped inorganic materials with desirable luminescence

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Received: March 13, 2013 Published: December 18, 2013 2343

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Table 1. Typical Dopant−Host Combinations for Making Multicolored DC and UC Emissions activators Eu

sensitizers

D0→ F1 596 (w) 590 (m) 590 (s) 596 (w) 594 (w) 5 D4→7F6 489 (m) 490 (m) 486 (m) 487 (m) 488 (m) 5 D3→7F6 382 (s) 4 F9/2→6H15/2 485 (s) 486 (m) 485 (s) 477 (s) 4 G5/2→6H5/2 565 (s) 569 (m) 567 (m) 565 (s) 2 H11/2→4I15/2 523 (m) 521 (w) 521 (m) 520 (w) 521 (s→m) 5 S2, 5F4→5I8 549 (s) 540 (s) 550 (s) 542 (s) 545 (s) 1 D2→3F4 451 (w) 450 (w) 450 (w) 451 (w) − 5

YVO4 LaF3 NaYF4 Y2O3 Gd2O2S Tb3+

Ce3+ Ce3+ Ce3+

CeF3 Y2O3 LaF3 NaGdF4 YPO4 CaYAlO4

Dy3+ YVO4 Lu2O3 BaGdF5 GdF3 Sm3+ YVO4 Lu2O3 LaVO4 Gd2O3 Er3+ Yb3+ Yb3+ Yb3+ Yb3+ Yb3+

β-NaYF4 α-NaYF4 BaYF5 NaGdF4 YF3

Yb3+ Yb3+ Yb3+ Yb3+ Yb3+

β-NaYF4 BaYF5 Y2O3 NaYbF4 α-NaYF4

Ho3+

Tm3+ 3+

Yb Yb3+ Yb3+ Yb3+ Yb3+ a

major transitions and emissionsa (nm)

hosts

3+

α-NaYF4 β-NaYF4 NaLuF4 NaYbF4 LaF3

7

D0→7F2 619 (s) 614 (s) 614 (s) 610 (s) 615 (m) 5 D4→7F5 542 (s) 545 (s) 543 (s) 544 (s) 545 (s) 5 D3→7F5 414 (m) 4 F9/2→6H13/2 575 (s) 572 (s) 573 (s) 573 (s) 4 G5/2→6H7/2 604 (s) 606 (s) 605 (s) 608 (s) 4 S3/2→4I15/2 541 (s) 539 (s) 544 (m) 540 (s→m) 543 (m→w) 5 F5→5I8 649 (w→m) 650 (m) 650 (w) 645 (w) 644 (m→s) 1 G4→3H6 478 (m) 477 (s) 480 (m) 476 (s) 475 (m)

output colors

ref

D0→7F3

5

5

625 (w, s) 625 (s) 5 D4→7F4 582 (w) 585 (w) 587 (w) 583 (w) 584 (w) 5 D4→7F5 548 (m,w)

G5/2→6H9/2 649 (w) 655 (w) 648 (w) 651 (w) 4 F9/2→ 4I15/2 655 (m) 651 (m) 655 (s) 656 (m→s) 660 (w→s)

red red red red red

31 46 61 41 62

green green green green green

63 34 54 52 49

blue

64

green yellow blue blue

31 42 59 65

orange-red orange red-orange orange

66 42 67 68

green yellow red green → red green → yellow → red

69 70 71 72 73

green green green green green → yellow → orange

74 71 75 76 77

blue blue blue blue blue

78 79 15 76 80

4

G4→3F4 650 (w) 646 (w) 650 (w) − 650 (w) 1

H4→3H6 800 (s) (NIR) 800 (s) 800 (s) 800 (s) 800 (s) 3

s, m, and w refer to strong, moderate ,and weak emission intensities, respectively.

properties. In Ln3+-doped inorganic materials, the rigid host lattices provide a steady microenvironment for Ln3+ emitter. Some host materials or other codoping ions even possess a higher absorption coefficient than Ln3+ emitter, thus lead an efficient energy transfer to Ln3+ ions. Accordingly, Ln3+-doped inorganic materials can exhibit efficient luminescence emissions from the ultraviolet (UV), passing through the whole visible, to the mid-infrared light region upon excitation. Moreover, compared with lanthanide chelates, quantum dots (QDs), and organic dye molecules, Ln3+-doped inorganic materials hold all the advantages of a large Stokes shift, a sharp emission spectrum, a long lifetime, high chemical/photochemical stability, low toxicity, and reduced photobleaching.2−4 Enlightened by the factors described above, Ln3+-doped inorganic materials are attributed to be a promising phosphor for a wealth of applications in the fields of lasers, displays,

sensors, solar cells, electroluminescent devices, and biomedical research.5−16 Conventionally, powder phosphors are prepared by a solid reaction process, in which the solid precursor components (oxides and inorganic salts etc.) were directly mixed, ground, and then calcined at high temperature.17 Apparently, this process suffers from a waste of energy (>1000 °C, >10 h in general) and contamination of impurities, moreover, resulting in inhomogeneous composition and morphology for the final products. Thereby, a solid reaction process is especially unsuitable for Ln3+-doped inorganic materials with controllable morphologies. In contrast, many soft chemical routes, such as the thermal decomposition method, hydro-/solvothermal method, coprecipitation method, and sol−gel process, have shown powerful controllability in the preparation of highquality Ln3+-doped phosphors with tunable morphologies and 2344

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2.1. Down-Conversion Luminescence (DCL)

sizes (from nanometers to micrometers). These routes are based on solution-phase colloidal chemistry, in which the reactants (salts and additive molecules etc.) can be homogeneously mixed at molecular or ion level in solutions, allowing for the products to be precisely tuned in terms of size, shape, and composition on the nanometer scale. Additionally, the reaction temperatures are generally lower than 350 °C. Although some methods need a post-treatment of calcination to improve the crystallinity of the products, the temperature is moderate (600 °C) leading to the formation of RE oxides is necessary to drastically improve luminescence properties. It should be mentioned that the coprecipitation method favors the formation of hollow nano/microspheres using silica, carbon, polystyrene, or melamine formaldehyde (MF) spheres

as sacrificial templates; hence, hollow and Ln3+-doped LaF3, YVO4, and RE2O3 (RE = La, Gd, Lu, Y) have been synthesized.32,36,55,184,409−413 All in all, the morphologies of the products from the coprecipitation method are simple, coarse, and hard to control or fine-tune. Also, the luminescence of the products is always weak, and postannealing treatment is required to promote luminescent intensity. After annealing, capping reagents such as EDTA will be carbonized, which reduces the hydrophilicity of the products. Therefore, applications in biological fields will be limited because further surface modifications are often required to improve the hydrophilicity. However, the coprecipitation method is of significant importance in industrial applications as a consequence of its high yield, low cost, environmental benignancy, and synthetic convenience. 3.4. Pechini-Type Sol−Gel Process

The sol−gel process, which is a typical soft chemical route for the fabrication of Ln3+-doped NCs, basically involves the synthesis of an inorganic and/or organic network by a chemical reaction in solution at low temperatures, followed by the transition from solution to colloidal sol then to a multiphasic gel form. To generate pure phase and high crystallinity multicomponent NCs with efficient luminescence, calcination at high temperatures is necessary. Prasad and co-workers developed an emulsion-based sol−gel process, which was named the sol−emulsion−gel method, to prepare Er3+-doped ZrO2, TiO2, and BaTiO3 NPs.414,415 However, the metal alkoxides and various organic/inorganic solvents used in this technique usually suffer from high cost, toxicity, unavailability, and fast hydrolysis rate. Our laboratory devoted itself to another Pechini-type sol−gel process, which associated with the following materials and procedures: first, simple metal salts (nitrates, chlorides, acetates, etc.) are dissolved in aqueous solution as precursors. Then a hydroxycarboxylic acid such as citric acid or salicylic acid is used as chelating ligands to form stable metal complexes, and their polyesterification with a polyhydroxy alcohol such as PEG or EG forms homogeneous polymeric resin gels on molecular level. The polymeric resin gels reduce the segregation of particular metal ions and ensure the homogeneity of the composition. Final calcination of the gels at high temperatures (500−1000 °C) generates pure phase multicomponent NCs, such as LaOCl:Ln (Ln = Dy and/or Tb), CaInO4:Eu, LaAlO3:Ln (Ln = Tm, Tb), LaGaO3:Ln (Ln = Sm and/or Tb), and CaYAlO4:Ln (Ln = Eu and/or Tb) NPs.64,105,106,416,417 Because of the high annealing temperatures, all the samples are composed of aggregated NPs with irregular spherical morphology and wide size distribution, such as LaAlO3:Ln (Ln = Tm, Tb) NPs with sizes ranging from 40 to 80 nm and CaInO4:Eu from 200 to 400 nm in size. Although the sol−gel process is not suitable for the preparation of high-quality NPs, in the past few years, our group has extended the application of the sol−gel process to combine with other techniques, and we have designed and synthesized Ln3+-doped optical materials in the forms of core− shell structure powder, thin film, patterning, and fiber. For core−shell structure powders, the Pechini-type sol−gel process is quite simple, just stirring core particles in the corresponding sol precursor solutions of the shells. All kinds of core−shell structured samples with different particle sizes from 300 nm to 1.2 μm (depending on the sizes of cores and layers of the shells) have been prepared, such as SiO2@Y2O3:Eu, 2365

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Figure 12. (a) Schematic diagram of the experimental μTM process used for patterning YVO4:Eu. Optical images of the patterned YVO4:Eu precursor gel films fabricated by (b1) μTM and (b2) after calcination at 700 °C; (b3) the corresponding luminescent image under 254-nm UV light excitation. (c) Schematic diagram of the electrospinning process. (d) SEM images of the as-formed 1D LaOCl:Eu fibers. Reprinted with permission from refs 30 (copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA), 107 (copyright 2010 Wiley-VCH Verlag GmbH & Co. KGaA), and 437 (copyright 2009 IOP Publishing Ltd.).

phosphors deposited on desired substrates by the simple Pechini-type sol−gel process, and patterning of the phosphor films has been realized by soft lithography techniques, including microcontact printing (μCP), microtransfer molding (μTM), and micromolding in capillaries (MIMIC). As early as 2002, we reported YVO4:Ln (Ln = Eu, Dy, Sm, Er) and LaPO4:Ln (Ln = Eu, Ce, Tb) phosphor films by dip-coating the corresponding phosphor sol on silica glass substrates at a constant speed (e.g., 0.2 cm/s) and then achieving their patterning in lines (5−60 μm) by MIMIC technique.424,425 Later, we reported the ordered arrays of luminescent YVO4:Eu, GdVO4:Ln (Ln = Eu, Dy, Sm), and CaWO4:Ln (Ln = Tb, Eu) thin films with square (side length about 20 μm) and dot (diameter about 10 μm) patterns by μCP and μTM techniques.30,426,427 As a typical example, Figure 12a illustrates the process for fabricating YVO4:Eu patterned arrays by the μTM technique, and the optical images are given in Figure 12b. In our process of μTM, the YVO4:Eu sol precursor (consisting of inorganic salts, citric acid, PEG, water, and ethanol) is employed as ink and deposited into a poly(dimethylsiloxane) (PDMS) mold by a

SiO2@YVO4:Eu, SiO2@LaPO4:Ce,Tb, SiO2@YBO3:Eu, SiO2@ CaWO4:Ln (Ln = Eu, Tb), and SiO2@CaMoO4:Tb spherical nano/microparticles.29,418−422 The thickness of the phosphor shells could be easily tailored by varying the number of deposition cycles (usually 30−100 nm for a deposition cycle). All the core−shell phosphors have perfect spherical shape with narrow size distribution, nonagglomeration, and smooth surface, even after being coated four times. 3.4.1. Lanthanide-Doped Phosphor Film and Patterning. For thin-film phosphors, the uniform thickness combined with smoother surface morphology and smaller grain size make it possible to define a smaller pixel spot size to achieve a higher resolution in the application of display screens. The patterning technologies of phosphor screens have a great effect on the resolution.423 Furthermore, high-resolution phosphor patterning has attracted much attention for its application in display fields such as cathode-ray tube (CRT) devices, flat-panel display devices, and FEDs. Therefore, a facile and precise screening process for high-resolution display devices is desirable. Our group has developed many kinds of thin-film 2366

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3.5.1. Microemulsion Method. The fabrication of NPs by the microemulsion method has been shown to be a convenient route to monodisperse particles in a certain range of sizes. Microemulsion is an isotropic, transparent, thermodynamically stable media composed of water phase, surfactant, and oil phase. The traditional microemulsion method used for the synthesis of NCs has always been inverse micelle (water-in-oil) systems, which consist of nanosized water droplets surrounded by a surfactant monolayer and dispersed in an oil-rich continuous phase. The small water droplets in the inverse micelle system possess the capacity to dissolve reactants, and constant exchange of the aqueous phase occurs among micelles due to the Brownian motion and frequent collisions. Thus, when inverse microemulsions containing different reactants are mixed, the nanosized water droplets inside these spherical micelles offer ideal nanoreactors for the formation of NPs, and their growth is limited by the micelle size. Several water− surfactant−oil inverse micelle systems, such as water−CTAB− cyclohexane, water−CTAB−pentanol, water−CO520−cyclohexane (CO520 = polyoxyethylene(5) isooctylphenyl ether), and water−AOT−n-heptane [AOT = sodium bis(2-ethylhexyl) sulfosuccinate], have been used as nanoreactors to prepare Ln3+-doped YF3, α/β-NaYF4, Y2O3, CeF3, ErF3, and LaPO4 UC and DC NCs.44,438−444 However, the yield is low, and the quality of the as-obtained NCs is not ideal. Recently, Li and co-workers designed a new approach for the synthesis of NCs by using a normal oil-in-water microemulsion system, in which the continuous phase is water.445 They proved that the mechanism of the normal microemulsion method is quite different from that of the inverse micelle system. In this hexane−linoleic acid−water system, the reaction occurs at the water−oil interface, and the generated NCs are passivated by linoleic acid ions, such as YF3, PrF3, NdF3, HoPO4, and CePO4 NCs with sizes in the range of 1.5−5 nm. It is worth noting that compared with traditional reverse-microemulsion methods, the method has high yield and productivity, owing to the large solubility of the source materials in the water phase. 3.5.2. Microwave-Assisted Method. In the past 3 years, the microwave-assisted method, which can shorten chemical reaction times from hours to minutes, has aroused considerable attention. This high-speed synthesis effect is coming from the efficient in-core volumetric heating with the help of microwave radiation, causing heating directly inside the sample.446,447 Compared to conventional heating for chemical reactions, the microwave dielectric heating brings the advantages of a fast heating rate and uniform heating without thermal gradients, superheating of the solvents, and selective heating properties.448−451 Hence, the energy-efficient microwave-assisted method has blossomed into a useful and rapid pathway for the synthesis of nanosized inorganic materials. Using EG as solvent, Zhang and co-workers synthesized hydrophilic BaYF5:Ce,Tb and MF2:Ln (M = Ca, Sr, Ba; Ln = Ce, Tb, Gd) NCs by microwave heating with a short timespan of 10 min.56,452 We and other groups prepared CePO4:Tb nanorods, Ln3+-doped NaGdF4 UC NPs, and NaYF4:Yb,Ln (Ln = Er, Tm, Ho) NCs/microcrystals by a similar microwave-assisted method in 10 min to 3 h.72,133,453 3.5.3. Ionic-Liquids-Based Synthesis. Ionic liquids, which are nonvolatile, nonflammable, and thermally stable organic salts, have been described as “green solvents” to replace conventional organic solvents in many chemical processes owing to their exceptional features, such as low melting point below 100 °C, relatively low viscosity, wide electrochemical

spin-coating process. Then the mold is brought into contact with the quartz substrate. After being baked to form a gel and the mold carefully peeled away, YVO4:Eu gel from the stamp is transferred to the substrate, resulting in a pattern on the substrate. Finally, the patterned YVO4:Eu films are produced by the postannealing process. Another attempt was made by combining the Pechini-type sol−gel process and inkjet printing for patterning YVO4:Eu thin film phosphor in dots and lines (both the diameter of the dots and the width of the lines are in the range of 30−40 μm) on ITO-coated glass (glass slide with indium−tin oxide films), in which the dot and line patterns on the substrate were realized by moving the computer-controlled horizontal translation stage.428 3.4.2. Lanthanide-Doped Phosphor Fiber by Electrospinning. Since was first developed in the 1930s, the electrospinning technique has been applied to form uniform fibers with diameters ranging from tens of nanometers up to micrometers for a variety of materials, such as organic, inorganic, and hybrid compounds.429−432 The basic setup for the electrospinning technique is shown in Figure 12c. In brief, electrospinning is a technique that uses the strong electrostatic force produced by a high static voltage, and the high static voltage is applied to a precursor solution placed into a syringe container with a millimeter diameter nozzle. Under employed electrical force, the precursor solution is ejected from the nozzle. After the solvents are evaporated during the course of jet spraying, 1D samples are collected on a grounded collector.433 We have reported quite a few 1D fiber-, belt-, and tubelike Ln3+-doped inorganic materials by combining the methods of the sol−gel process and electrospinning technique, in which the precursor solution was a sol consisting of polymer (mainly PVP), citric acid, and inorganic salts in water−ethanol solution. In addition, PVP was used to control the viscosity of the precursor sol and served as a template to generate 1D structures. After electrospinning, precursor solutions containing inorganic materials formed a continuous gel network within the polymer matrix, resulting in the formation of inorganic−PVP composite fibers. After an appropriate annealing at an elevated temperature in air, the organic PVP was removed so that pure inorganic fibers were obtained. Accordingly, 1D LaOCl:Ln, Y(V,P)O4:Ln, CaMoO4:Ln, Tb2(WO4)3:Eu, CaWO4:Tb, and Lu2O3:Eu nanofibers, nanotubes, or microbelts have been synthesized.66,107,112,434−436 Figure 12d gives the typical shapes of the 1D products, which was influenced by the experimental conditions, such as molar ratio of metal ions to water, volume ratio of water to ethanol, amount of PVP, spinning rate, and voltage. To sum up, the sol−gel process has intrinsic limitations in the synthesis of NPs, due to the irregular spherical morphology, wide size distribution, and considerable aggregation of the products. However, the sol−gel process can combine with the soft lithography technique and electrospinning technique easily; therefore, it is suitable to produce all the Ln3+-doped inorganic materials in other forms of thin film, patterned, and fibers. 3.5. Others

In addition to those widely used methods, there are some special ones, such as the microemulsion method, microwaveassisted method, and ionic-liquids-based synthesis, which possess attractive advantages and have been employed to produce RE nano/microcrystals. Although some works were reported, the exploration of these methods has just begun and thus will be the subject of a future paper. 2367

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Table 4. Representative Examples for Surface Modification, Bioconjugation, Toxicity, and Applications of RE NPs

a

Viability measured by CCK-8 activity assay. bBy MTS assays. cBy Cell Titer-Glo luminescent cell viability assay. Other viabilities were measured by MTT assays. mSiO2: mesoporous silica layer. C18PMH−PEG: PEG-grafted poly(maleic anhydride-alt-1-octadecene) amphiphilic polymer.

window, and adjustable solvent polarity.454−457 Moreover, ionic liquids possess superior capability for the dissolution and

stabilization of metal cations, which endows them with the possibility of acting as solvents, capping agents, or surfactants in 2368

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mercapto groups. For example, amino group modification can be easily achieved by hydrolysis of (3-aminopropyl)triethoxysilane (APTS) in the formation process of silica shells or post-treatment with ethanol solution of APTS after silica coating.15,19,253,387,467,468 In addition, silica coating can protect the RE NPs cores against the attack from the biological environment, reducing the toxicity and improving the stability of the RE NPs.81,469 All the groups of Li, Zhang, Shi, and Tan have proved that silica-coated RE NPs are photostable, monodisperse, and biocompatible and can be highly dispersed in aqueous solvents (see refs 15, 19, 203, 225, 226, 253, 467, 468). It is noted that silica coating is readily applicable to both hydrophobic and hydrophilic RE NPs via the water-in-oil (water−CO520−cyclohexane) reverse-microemulsion method 2 0 3 , 2 2 5 , 2 5 3 , 4 6 7 , 4 6 8 and conventional Stö b er method,139,387,470,471 respectively. Polymer coating also has been applied to achieve hydrophilic modification based on ligand attraction or electrostatic absorption. Yi et al. reported that OM-capped NaYF4:Yb,Er@ NaYF4 or YOF:Yb,Er@YOF NPs were rendered hydrophilic by an amphiphilic PAA coating, which arises from the hydrophobic interactions between octadecyl groups of OM and the octyl/ isopropyl groups of the modified PAA molecules by 25% octylamine and 40% isopropylamine.189,201 After that, the hydrophilic carboxyl groups of PAA extended outward, endowing NPs with water solubility. Hyeon and co-workers reported the coating of OA/TOP-capped RE NPs with PEG− phospholipids. After encapsulation, the NPs were dispersed in water without any detectable degradation or aggregation.156,204,472 Li and co-workers developed a layer-by-layer method to functionalize NaYF4:Yb/Er NPs with amino groups.356,357 The layer-by-layer method is based on the electrostatic attraction between the positively charged poly(allylamine hydrochloride) (PAH) and negatively charged poly(sodium 4-styrenesulfonate) (PSS), permitting the NPs to be coated with controllable shell thickness and uniform layers of diverse composition. Accordingly, a normal primer of three polyelectrolyte layers (PAH/PSS/PAH) can be formed. However, before the layer-by-layer modification, the NPs should be hydrophilic. Apart from the coating process, ligand engineering, which involves exchange, oxidation, or removal of the native hydrophobic ligand, is another effective approach to realize hydrophilic modification. Employing ligand exchange reaction, OA/OM-capped NPs were easily converted into hydrophilic ones by replacing the original hydrophobic ligands by various hydrophilic organic molecules. For instance, Yin and coworkers utilized PAA to displace OA ligands at an elevated temperature in glycol solvent, providing the NPs carboxylic acid groups with high water solubility.473 Yi and Chow changed the hydrophobic surface of OM-capped NaYF4:Yb,Er NPs to hydrophilic by replacing OM with a bipolar surfactant, PEG 600 diacid (HOOC−PEG−COOH).69 After ligand exchange, the NPs possessed carboxyl-functionalized surfaces, thereby remaining a clear colloid in deionized water, and no noticeable reduction in fluorescence intensity was observed. Later, Xing and co-workers extended the method to OA-capped NPs.474 In addition, a variety of other hydrophilic organic molecules also have been used in the ligand exchange process, including 3mercaptopropionic acid (3MA),117,234 6AA,475 poly(allylamine) (PAAm),473,476 AEP,330 hexanedioic acid (HDA),477 citrate, 18,90 poly(amidoamine) dendrimers (PAMAM), 246 PVP,196,478 meso-2,3-dimercaptosuccinic acid (DMSA),479 11-

inorganic synthesis. Therefore, ionic liquids have been proved to be an attractive reaction media for inorganic nanomaterials and extremely helpful for fluoride NPs. Because tetrafluoroborate ([BF4]−), hexafluoroborate ([BF6]−), and hexafluorophate ([PF6]−) counterions of ionic liquids are unstable, they will decompose thermally and hydrolyze slowly to release F− ions under appropriate conditions.458,459 Nuñez and Ocaña, and Chen’s group accomplished the synthesis of hydrophilic LnF3 (Ln = La−Nd, Sm, Eu, Tb, Er) NCs by a facile precipitation of RE nitrate/acetylacetonate/acetate in different ionic liquids, including 1-n-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF4]), 1-butyl-3-methylimidazolium hexafluorophate ([Bmim][PF6]), 1-octyl-3-methylimidazolium hexafluorophosphate ([Omim][PF6]), and 1-octyl-3-methylimidazolium tetrafluoroborate ([Omim][BF4]).460,461 In these systems, the ionic liquids acted as solvent and template, as well as a fluorine source. The groups of Kong and Xu reported the synthesis of NaYF4:Yb,Er/Tm NPs by the solvothermal process, in which [Bmim][BF4] was applied as solvent/ cosolvent, reaction agent, and template.462−464 Recently, a new microwave-assisted ionic liquid protocol has been used to produce NaYF4 and REF3 (RE = La−Lu, Y) NCs with morphologies of nanodisks, nanoclusters, and elongated NPs.51,465,466 This method is a novel green chemosynthesis that combines the advantages of microwave heating and the excellent microwave-absorbing ability of ionic liquids, resulting in a significantly short reaction time (5−20 min) and highly crystallized products.

4. HYDROPHILIC MODIFICATION AND BIOCONJUGATION Nowadays, the promising and extensively studied applications of RE NPs are bioimaging and therapy. To be successfully used in these fields, RE NPs need to possess good dispersibility in aqueous solution. Moreover, the presence of some functional groups (amine, thiol, and carboxyl groups) on the surface to allow further conjugation with biologically active molecules, such as FA, antibody, biotin, peptide, avidin, protein, and DNA, is always required and important, especially for targeted biological applications. Although assisted by water-soluble surfactants (Cit3−, EDTA, PEI, PAA, AEP, etc.), some watersoluble RE NPs have been reported by the one-step hydro/ solvothermal method (section 3.2). The bioapplication of these products is limited by large size. To date, commonly used highquality RE NPs in the biological field are less than 50 nm, being produced by the thermal decomposition method and hydrophobic due to the OA-capped surface. Therefore, surface hydrophilic modification is necessary, and a two-step hydrophilic modification is applied to convert the hydrophobic RE NPs into hydrophilic ones, including surface silanization, polymer coating, ligand exchange, ligand oxidation, and ligand-free processes. The representative strategies for surface modification and further bioconjugation of RE NPs are summarized in Table 4. 4.1. Hydrophilic Modification

Surface silanization is a widely used hydrophilic modification method, in which a thin silica shell is assembled onto the surface of RE NPs by hydrolysis and polycondensation of tetraethoxysilane (TEOS). The thickness of the silica shell can be precisely adjusted by controlling the concentration of TEOS. Silica is highly biocompatible and its silanol-containing surface can be modified with carboxyl groups, amino groups, or 2369

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about 295 and 190 μg/mL respectively,22 which are lower than those of iron oxide NPs (200 μg/mL to 20 mg/mL) but higher than those of Au NPs (10−100 μg/mL).492−499 Because both iron oxide NPs and Au NPs have already been proved to be nontoxic for human by the US FDA, we can see that RE NPs show a relatively low cytotoxicity. To further quantify the potential toxicity of RE NPs, an acute long-term toxicity evaluation was carried out in small animals through pathological analysis, including body weight measurement and observational, histological, hematological, and serum biochemical assays. The fluctuation in body weight is a useful indicator for studying the toxicity effects of the RE NPs. Li and co-workers reported that the mice intravenously injected with NaYF4:Yb,Tm−PAA NPs (15 mg/kg) survived for 115 days with small weight differences and without any apparent adverse effects to their health.273 Further, Jalil and Zhang proved that the organ (heart, liver, spleen, lung, and kidney) weights were consistent among all the animals exposed to NaYF4:Yb,Er@ SiO2 NPs (10 mg/kg) by intravenous administration from 10 min to 7 days of sacrifice.81 These two groups also collected the health status and behavior of all the treated animals, including eating patterns, fur colors, and overall movements, and eventually, normal behaviors were observed. Histological assessment was conducted to determine the tissue damage, inflammation, or lesions from toxic exposure caused by RE NPs. Li and co-workers reported the histological changes of viscera (heart, liver, kidney, spleen, and lung) tissue in mice following the injection of NaYF4 :Yb,Tm−PAA, NaLuF4:Yb,Tm@SiO2−Gd−DTPA (DTPA = diethylene triamine pentacetate acid) and NaLuF 4 :Yb,Gd,Er/Tm-DTPA NPs,15,21,273 and no noticeable tissue damage was detected. In addition, there were no inflammatory infiltrates after the injection of NaYF4:Yb,Tm−PAA NPs. Although inflammation was visible in liver and lung tissues following the injection of NaLuF4:Yb,Tm@SiO2−Gd−DTPA NPs, long-term toxicity studies monitoring the behavior and physical signs of mice being injected with 3 mg/day NPs in succession for 1 week revealed that the treated mice did not show any obvious signs of toxicity. Meanwhile, Shi and co-workers demonstrated the neglectable organ tissue damages in mice after intravenous injection of NaYbF4:Tm−PEG NPs.276 Hematological assay of NaYF4:Yb,Tm−PAA NPs was conducted by Li and coworkers.273 Blood smears indicated that the number and shape of red blood cells, platelets, and white blood cells were normal, exhibiting no significant toxicity in the test mice. Hyeon and co-workers examined the long blood circulation half-life of 21.6 min for NaYF4:Yb,Er@NaGdF4@PEG− phospholipids−Ce6 (Ce6 = chlorin e6) NPs in mice, which would be beneficial for colloidal stability and imaging or diagnosis applications of the NPs.204 An established serum biochemistry assay was employed by Li and co-workers to evaluate the influence of NaYF4:Yb,Tm−PAA NPs on hepatic injury and kidney functions.273 Both the hepatic indicators (total bilirubin, alanine aminotransferase, and aspartate aminotransferase) and kidney indicators (creatinine and urea) were similar for the mice injected with NPs and the control ones, which suggested no overt toxicity of the NPs in mice at long exposure time up to 115 days. Besides, in biodistribution studies, the groups of Li and Shi revealed rapid accumulation of RE NPs in the liver and spleen in a short time owing to the reticuloendothelial system (RES).273,276 Then liver uptake decreased, whereas an increase in spleen accumulation was detected. After 14−30 days, the

aminoundecanoic acid (ADA),307 and phosphate-derived molecules.38 Li and co-workers developed a simple and versatile ligand oxidation strategy, in which the OA ligands on the surface were directly oxidized into azelaic acids (AA, HOOC(CH2)7COOH) with Lemieux−von Rudloff reagent.480 It is well-known that Lemieux−von Rudloff reagent only selectively oxidizes monounsaturated carbon−carbon double bonds to produce carboxylic groups. Therefore, the oxidation strategy is limited to the ligands containing unsaturated carbon−carbon bonds. Capobianco and co-workers developed a novel ligand-free approach, in which the removal of the oleate ligands from the surface is achieved through a facile stirring treatment of the OA-capped NPs in HCl solution.39 The ligand-free NPs are fit for direct conjugation with electronegative groups such as −SH, −COOH, −NH2, and −OH. 4.2. Bioconjugation

After hydrophilic modification of RE NPs, further conjugation of biomolecules, mainly including FA, biotin, peptide, antibody, protein, avidin, and DNA, paves the way for potential bioapplications, especially for the special targeted imaging or therapy. As mentioned in section 4.1, most of the RE NPs produced from the two-step hydrophilic modification are functionalized with special groups (−COOH and −NH2), which are essential for linking of these biomolecules by chemical conjugation. For instance, PAA, AA, HDA, PEG 600 diacid, citrate, DMSA, TGA (thioglycolic acid), and 3MAmodified RE NPs, which are carboxyl-terminated, would facilitate the covalent coupling of amine-containing biomolecules, such as antibody (anti-claudin 4),117 protein (streptavidin),401,480 FA-ethylenediamine,392 FA-chitosan,479 and singlestranded DNA.481 The carboxylic acid groups on the NPs usually need to be activated with cross-linkers before the combination process. Amino-terminated NPs modified with all kinds of ligands, including ADA, PAAm, AEP, 6AA, PEI, diamino PEG, PAH, and PAMAM can react with biological molecules containing −COOH or −SH groups from the molecules themselves or postmodification, such as FA,362,384,439,467,482 biotin,325,330,357,483 avidin,484 antibody (e.g., anti-Her2, anti-CEAcam8/CD67, and rabbit anti-goat IgG),201,468,485,486 peptide [e.g., chlorotoxin, thiolated cyclo(Arg-Gly-Asp-Phe-Lys(mpa)), cyclo(RGDy(ε-acetylthiol)K)],366,487,488 and 3′-propylthiolterminated DNA.356

5. TOXICITY Prior to bioscience and medicine applications, potential toxicity investigation of RE NPs is vital to the future design of safe bioimaging and therapy agents. Cytotoxicity is a rapid, standardized, and sensitive test to assess the toxicity of RE NPs, mainly including MTT (methyl thiazolyl tetrazolium), MTS [(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, sodium salts], and CCK8 (cell counting kit) mitochondrial metabolic activity assays. In cytotoxicity tests, a series of concentrations of NPs was incubated with cells for a certain range of times. Then the viability of cells is measured to calculate the cytotoxic effect. As the examples show in Table 4, the RE NPs exhibit high cell viability, even with high concentrations, thereby low cytotoxicity is displayed. Another important cytotoxicity index, halfmaximal inhibitory concentration (IC50), has been measured by Li and co-workers. They reported that the IC50 values of NaYF4:Yb,Tm@FexOy NPs for KB cells after 24 and 48 h were 2370

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Figure 13. Classification and simple introduction of bioapplications of RE NPs.

NPs were nearly undetectable. Zhang’s group reported that RE NPs were mostly cleared from the body of mice by 7 days postinjection, while the initial accumulation was occurred in lung and heart.81,362 The facile excretion would decrease the possibility of long-term toxicity. All the in vivo toxicity results indicated that RE NPs did not show any evident toxic effects when injected in mice intravenously. Thereby, RE NPs have potential applications in the biomedical field. However, the toxicity investigations are still in their preliminary stages, and further toxicology studies including distribution, excretion, metabolism, pharmacokinetics, and pharmacodynamics in larger animals and deeper tissues should be the subject of future papers before clinical use in human.

cells by endocytosis and macrophages, respectively. The endocytic pathway is dependent on the size and shape of the NPs.500 For example, it had been proved that endocytosis of spherical NPs is easier and faster than that of rod-shaped or fiberlike NPs.506 Therefore, the morphology of NPs plays a key role in biochemistry, and the careful study of the synthesis method is desired. At present, RE NPs have been considered to be ideal for biomedical application, including bioimaging and therapy, as illustrated in Figure 13, especially the NPs smaller than 100 nm, such as the examples in Table 4. As for bioimaging, molecular imaging techniques, including magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET), and optical imaging, are powerful tools for biomedical research and clinical diagnostics. To improve the qualities of the imaging techniques, making use of imaging agents is necessary. RE-based NCs have cast new light on imaging probes, although DC NPs, such as Dy2O3:Tb, Gd2O3:Tb, GdS:Eu, and KGdF4:Ln (Ln = Eu, Tb, Dy), have been used for MRI and optical imaging.253,254,507,508 The use of high-energy UV excitation light is associated with several significant disadvantages, such as photodamage to living organisms and low light excitation penetration depths. Thus, the research on DC RE NPs has not received a wealth of attention. Differently, UCL imaging, which relates to the NIR excitation light, possesses high excitation penetration depth in biological tissues and negligible photodamage to living organisms. Therefore, UC NPs are widely used and intensively studied as bioimaging agents for tracing of cancer position and detection of therapy processes in all kinds of molecular imaging techniques. Moreover, assisted by multifunctional RE NPs, the molecular imaging techniques have been further combined with each other for multimodal biomedical imaging. In this section, we are going to introduce the applications of RE NPs for bioimaging. The classification and simple introduction have been shown in Figure 13. Typical applications and correspond-

6. BIOIMAGING APPLICATIONS In section 3, great efforts have been devoted to discuss the morphology tuning of RE NPs by soft chemical routes, because the morphology of NPs is a critical parameter that dictates their application in biochemistry, which has been studied carefully with iron oxide, Au NPs, and QDs.492,500−503 First, the morphology regarding size and shape holds tremendous influence on luminescent properties (sections 2.3 and 2.4). Second, size- and shape-dependent toxicity of NPs brings an adverse effect on vertebrates, and larger ones can be easily cleared by RES.500,502 Third, NPs can have enhanced blood circulation time due to the slow excretion by liver, long halflives during circulation, and bioavailability within the body.504,505 Moreover, they can reach very deep sites that other contrast agents or drugs cannot usually arrive at and can cross some biological barriers, including the gastrointestinal barrier and blood−brain barrier. Because of this, RE NPs is critical for accurate detection/visualization of tumor cells at very early stages and the subsequent therapeutic planning of disease. Fourth, NPs usually can be absorbed and cleared in 2371

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Figure 14. Time-dependent in vivo UCL imaging of subcutaneous U87MG tumor (left hind leg, indicated by short arrows) and MCF-7 tumor (right hind leg, indicated by long arrows) borne by athymic nude mice after intravenous injection of NaYF4:Yb,Er,Tm−PEG−RGD over a 24 h period. All images were acquired under the same instrumental conditions (power ≈ 80 mW/cm2 and temperature ≈ 21.5 °C on the surface of the mouse). Adapted from ref 487. Copyright 2009 American Chemical Society.

absorption and autofluorescence in this region. Li and coworkers have demonstrated that when Tm-doped UC NPs were injected into mice, the strong NIR UCL signal at 800 nm was detected, while visible UCL signals at 500−700 nm can hardly be collected under the same condition.22,509 Liu and coworkers reported the visible emitting of 5−7 mm tissue depth for NaYF4:Yb,Er NPs in mice,510 however, could be easily increased to 1.5 cm NIR emitting when Tm-doped NPs were used according to Li’s report. 489 Additionally, when NaLuF4:Gd,Yb,Tm (7.8 nm) or NaLuF4:Yb,Tm (24 nm) NPs were employed for UCL imaging in vivo of fur-rich mice, even for a black mouse and a large animal (rabbit) with serious signal-to-noise ratio, high-contrast NIR UCL imaging of the whole body with a penetration depth of ∼2 cm was achieved.90,489

ing surface modification, bioconjugation, cytotoxicity, and experiment conditions have been summarized in Table 4. 6.1. UCL Imaging

UCL bioimaging is based on the following two kinds of UCL emissions: one is the visible light (red, green or blue) emissions from Er/Ho/Tm-doped UC NPs. Cell pigmentation has strong absorption bands within the spectrum range of 400−700 nm. It is accepted that NIR-to-visible UCL bioimaging was restricted by the limited penetration depth of visible light, only a few millimeters of tissue in vivo. Recently, along with the development of methods to enhance the UCL intensity (section 2.4), the penetration depth has been increased to 1 cm. For instance, Zhang and co-workers first reported a visible UCL imaging with a penetration depth of 1 cm using NaYF4:Yb,Er NPs as luminescent probes in nude mice.362 Later, Zhao and co-workers reported a strong red UCL from GdF3:Yb,Er,Li@SiO2 NPs in white fur-rich Kunming mice, and the penetration depth was about 1 cm.139 Liu and co-workers injected polymer-modified NaYF4:Yb,Er and KMnF3:Yb,Er NPs into pork muscle tissue at varied depths (0−1 cm), and the imaging can be observed at about 0.5 cm depth for NaYF4:Yb,Er NPs, while 1 cm depth is seen for KMnF3:Yb,Er NPs, which have a very strong red emission.140 The other kind of UCL emission used in bioimaging is the excellent NIR-to-NIR UCL from Tm-doped NPs centered at 800 nm (Table 1). Compared with NIR-to-vis UCL, NIR-toNIR UCL shows higher penetration depth, even several centimeters, as reported by Li and co-workers.90,489 NIR (700−1000 nm) is located within the so-called “optical transmission window” of biological tissues, and the optical transmission window is considered as tissue transparency, because water, biological cells, and tissues have minimal

6.2. Tumor Targeting and Imaging

Tumor targeting is required for improving imaging and treatment efficacy. Assisted with this technique, imaging and therapy agents will accumulate in the diseased area to minimize the collateral damage to surrounding healthy tissues, which is especially important for cancer therapy to selectively kill cancer cells. Among various targeting techniques, molecular targeting, which lies in the specific recognition between the biomolecule couples of targeting agent and receptor, such as FA−FR (folate receptor), antibody−antigen, antibody−protein, and antibody− peptide, has gained significant interest. Furthermore, the attachment of biomlecules to imaging agent supplies high targeting efficiency and low toxicity for molecular targeting.16,123,363,511 For example, Li and co-workers designed a targeted imaging system based on RGD peptide and αvβ3 integrin receptor.487 As shown in Figure 14, when NaYF4:Yb,Er,Tm−PEG−RGD NPs were injected into athymic 2372

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nude mice simultaneously bearing a U87MG tumor (αvβ3 integrin overexpressing) on the left hind leg and a MCF-7 tumor (expressing low levels of integrin αvβ3) on the right hind leg, upon excitation with a 980 nm laser, an intense UCL signal was observed in the left hind leg, whereas no significant UCL signal was seen in the other leg. Moreover, the UCL signal was removed from the body (mainly in liver and spleen) to the left hind leg gradually in 24 h, which indicated the in vivo targetspecific imaging of tumors by RGD peptide−αvβ3 integrin recognition. FR is a single-chain glycoprotein and overexpressed on the membrane of many cancer cell lines, yet it is minimally distributed in normal tissues. Due to the high-affinity ligand between FA and FR, FA-linked imaging and therapeutic agents can be exploited to target FR-overexpressing tumor tissues, thereby avoiding uptake by most healthy tissues. Several groups investigated FA-conjugated NaYF4:Yb,Er and LaF3:Yb,Er NPs for targeted imaging of FR-positive KB cell lines and FRnegative MCF-7 cell lines.307,384,467,511 Confocal luminescence images showed a strong luminescence signal from FR-positive cell lines after 1 h of incubation with NP−FA (NP is the abbreviation of nanoparticle), with almost no luminescence from FR-negative cells. Li and co-workers evaluated the targeting ability of NaYF4:Yb,Er-FA to FR in vivo and ex vivo with mice bearing HeLa tumors. A significant UCL signal was observed in the tumor for NaYF4:Yb,Er−FA-injected mouse for 24 h, whereas no luminescence signal was observed in the tumor after injection of NaYF4:Yb,Er−NH2.439 All these facts suggested the specific and effective in vitro and in vivo targeting of FR utilizing NP−FA. By using antibody−antigen recognition, NaYF4:Yb,Er and NaYbF4:Er/Tm/Ho NPs were conjugated with rabbit antiCEA8. Then NP−anti-CEA8 was applied for time-efficient immunolabeling of HeLa cells, with respect to the immunoreaction that will take place between anti-CEA8 antibody and CEA8 antigen expressed on the surface of HeLa cells.126,387,464,486 Xu and co-workers proved the conjugation of CEA8 antibody and antigen by the strong UCL imaging of HeLa cells cultured with NP−anti-CEA8, while very weak fluorescence was seen with cells cultured with NP−NH2. Presently, other special recognitions between targeting agents and receptors, for example, anti-Her2 and Her2 protein,201 chlorotoxin (CTX) peptide and metalloproteinase 2 (MMP-2) endopeptidase,366 or anti-DENV2 (Dengue virus serotype 2) antibody and DENV2 envelope protein,363 also have been used for targeted cancer cell imaging and therapy. All the reports demonstrated that the conjugation of NPs with targeting agents selectively attached themselves onto corresponding receptorexpressed cancer cells, whereas NPs without targeting agent were not able to recognize the cancer cells. Accordingly, UCL NPs have been widely used as targeting imaging agents for cancer cells.

visualization method with high sensitivity (picomolar) and is often restricted by low spatial/planar resolution. Optical imaging, which provides the highest sensitivity (almost single molecule) and excellent planar resolution, is the only technique that can offer cellular/molecular-level information, whereas the penetration depth is low. To obtain more complementary and accurate information about the anatomical structure and physiological function for clinical diagnosis and prognosis, integration of the advantages of two or more imaging techniques in one nanoparticle to form multimodal bioimaging is highly desired. RE UC NPs, which are good optical imaging bioprobes themselves, are good choices to act as multimodal contrast agent and achieve multimodal bioimaging, such as UCL/MRI, UCL/MRI/CT, UCL/MRI/PET, UCL/CT, and MRI/CT. In the following, we will introduce the multimodal bioimaging applications of some typical examples. 6.3.1. UCL/MRI Imaging. MRI is a harmless medical diagnostic technique based on nuclear magnetic resonance together with the relaxation of proton spins in a magnetic field.512 Accordingly, MRI contrast agents should be magnetic materials. MRI contrast agent can be evaluated through longitudinal and transverse relaxivities (r1 and r2), which refer to the paramagnetic component of spin−lattice and spin−spin relaxation rates (1/T1 and 1/T2) per unit concentration of contrast agent, respectively. Compared to T2 contrast agents (e.g., iron oxide), the major advantage of T1 contrast agents is the positive imaging by signal enhancing with contrast agent concentration, which can maximize anatomical imaging with high spatial resolutions. MRI and UCL imaging are two complementary modalities that when integrated in one system will combine both the advantages of high spatial resolution and sensitivity, as a result enhancing the quality of bioimaging. Paramagnetic Gd3+ ions are widely used T1 MRI contrast agent owing to the existence of seven unpaired 4f electrons. By adding Gd3+ and Ln3+ (Ln3+ = Er3+, Ho3+, Tm3+) ions in one nanocrystal, the integration of UCL imaging and MRI has been achieved. Plus, the NCs overcome the leaching of Gd3+ ions in Gd3+−chelates contrast agents. Some Gd-based hosts, including NaGdF4, Gd2O3, GdF3, and BaGdF 5 NPs have been used as T 1 MRI contrast agent.196,392,400,513 When these Gd-based hosts were doped with Er3+, Ho3+, and/or Tm3+, dual-modal UCL/MRI contrast agents were formed.20,72,139 Li and co-workers reported that NaGdF4:Yb,Er,Tm−PAA NPs showed a high relaxivity of 5.6 s−1 mM−1 (the approximate value of the commercial Gd− DTPA agent is 5.77 s−1 mM−1) and, at the same time, displayed both NIR-to-vis and NIR-to-NIR UCL in mice.509 The pre- and postcontrast color mapping coronal MRI of the whole body in Figure 15 indicated a significant contrast enhancement in different organs, particularly in liver and spleen, confirming the accumulation of the NPs in them. Zhao and co-workers reported GdF3:Yb,Er,Li NPs as dual-modal UCL/MRI contrast agent (r1 = 2.986 s−1 mM−1),139 and Gd2O3:Yb,Er NPs exhibit good T1 MRI contrast with a relaxivity of 1.5 s−1 mM−1, as reported by Tan and co-workers.254 Gd-doped UC NPs, which possess intense UCL emissions and tunable relaxivities (0.14−2.27 s−1 mM−1), also have been used as UCL/MRI imaging contrast agents, such as NaYF4:Gd,Yb,Ln (Ln = Er and/or Tm, Er and Eu) and NaLuF4:Gd,Yb,Er/Tm NPs.18,19,21,117,511 Shi and co-workers reported an increased signal-to-noise ratio of 66.6% after the injection of NaYF4:Gd,Yb,Er,Tm@

6.3. Multimodal Bioimaging

Different molecular imaging techniques, including MRI, CT, PET, and optical imaging, have their own advantages and disadvantages with respect to spatial resolutions, penetration depths, and areas of application. MRI affords excellent spatial resolution (several tens of micrometers) and high penetration depth, while it suffers from insufficient sensitivity and low planar resolution. CT imaging offers exceptional anatomical information, albeit with a poor soft-tissue contrast, low planar resolution, and limited sensitivity. PET imaging can provide a 2373

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Figure 16. In vivo serial CT view images of rats after intravenous injection of (A) iobitridol solution (350 mg I/mL) and (B) Gd2O3:Yb,Er−PEG NPs solution (50 mg RE/mL) at timed intervals. Adapted from ref 20. Copyright 2013 Elsevier Ltd.

Figure 15. Color-mapped coronal images of (A) the whole body and (B, C) transversal cross-sectional images of the liver (L) and spleen (S) of mice at preinjection and at 40 min after intravenous injection of NaGdF4:Yb,Er,Tm−AA at 1.5 mg/kg. Adapted from ref 509. Copyright 2010 Elsevier Ltd.

clearance.514 Recently, some new types of CT contrast agents, such as RE elements with large atomic numbers, were developed due to their high X-ray absorption coefficient (e.g., Yb, 3.88 cm2 g−1; Gd, 3.11 cm2 g−1; and clinically used I, 1.94 cm2 g−1 at 100 keV). Therefore, Yb/Lu/Gd-based hosts, including NaYbF4, NaLuF4, Yb2O3, NaGdF4, GdF3, Gd2O3, and BaGdF5 NPs, have been functioning as promising CT contrast agents.20,276,392,515−517 In vivo investigations showed that the CT contrast efficacy of Yb/Lu/Gd-based NPs were much higher than that of clinical iobitridol at the same/lower concentration, as seen in the comparative examples shown in Figure 16 (for iobitridol contrast agents and Gd2O3:Yb,Er− PEG NPs). More important, some characteristic imaging cannot be obtained with iodinated contrast agents, even under larger dosages. In this year, radioelement (153Sm) doped RE NPs have been used for single photon emission computed tomography (SPECT) imaging by the group of Li.518,519 When 153Sm-doped NPs were injected into mice, the radioactivity signals were detected exclusively in liver and spleen, owing to the high sensitivity and tissue penetration depth of 153Sm emission. A combination of UCL/MRI/CT trimodal imaging yielded high sensitivity, spatial resolution, and 3D tissue detail. Remarkably, MRI has higher sensitivity to soft tissues than CT imaging, so RE-based NPs containing Gd, Yb/Lu/Gd, and Er/Tm/Ho elements have been developed as trimodal contrast agents having all the imaging elements of MRI, CT, and UCL imaging, respectively. Qu and co-workers designed Gd2O3:Yb,Er−PEG NPs for in vivo UCL/MRI/CT trimodal imaging.20 Once Gd2O3:Yb,Er−PEG NPs were injected into mice, except for the strong T1 MRI and bright UCL imaging, as shown in Figure 16, a significant enhancement of the CT imaging signal of the liver and spleen could be observed at an early time (10 min) and then gradually increased in 2 h, while there is no soft tissue CT imaging preinjection. Moreover, although with a much lower dosage, the CT contrast efficacy of Gd2O3:Yb,Er−PEG NPs was much higher than iobitridol. Li and co-workers constructed other kinds of trimodal contrast agents based on NaLuF4 NPs, including NaLuF 4 :Gd,Yb,Tm and NaLuF 4 :Yb,Tm@SiO 2 −Gd− DTPA.15,21 Both of them offered excellent NIR-to-NIR UCL

SiO2−Au@PEG NPs in mice, demonstrating the feasibility of the Gd-doped NPs as MRI contrast agents in vivo.19 The positive-contrast applicability of NaYF4:Gd,Yb,Er/Tm NPs for MRI was studied by Li and co-workers, and anatomical image results indicated a significant contrast enhancement in spleen and liver areas after injection of the NPs in mice.18,511 Moreover, lymphatic MRI was examined by the enhanced uptake of NaLuF4:Gd,Yb,Er/Tm NPs in lymph node.21 Generally speaking, the relaxivity values of the Gd-doped NPs are lower than those of Gd-based hosts. Besides, the groups of van Veggel and Shi discovered that the amount of Gd3+ ions on the surface is the major contributor to the relaxivity enhancement.196,220 van Veggel and co-workers reported that the r1 values of Gd3+ ions increased from 3.0 to 7.2 s−1 mM−1 with the decreasing particle size of NaGdF4 NPs from 8.0 to 2.5 nm. Shi and co-workers first reported a nearly 100% loss of relaxivity for Gd3+ ions buried deeply within crystal lattices (>4 nm). Later, they reported a nearly 4-fold increase in the r1 value from 0.67 to 2.73 s−1 mM−1 for NaYF4:Yb,Er,Gd (about 18 nm in size) and NaYF4:Yb,Er@ NaGdF4 (about 26 nm) NPs, respectively; meanwhile, a 27-fold enhancement of UCL intensity was seen with the NaGdF4 coating.203 Therefore, Gd-based hosts with smaller size (larger surface area) and without doping on the surface are beneficial for T1 MRI. From this point of view, the optimized core−shell structure NPs, such as NaYF4:Yb,Er@NaGdF4, have been successfully designed to obtain high UCL intensity and large r1 value (usually 2.2−10.4 s−1 mM−1).203−205,220 6.3.2. UCL/MRI/CT Imaging. X-ray computed tomography (CT), another efficient diagnostic imaging methodology, is based on the differential X-ray absorption features of diverse tissues and commonly used to generate high-resolution threedimensional (3D) structure details. Motivated by this principle, CT imaging is inefficient for soft tissues due to the low density differences between them. Up to date, the clinically used CT contrast agents are iodinated compounds. As shown in Figure 16A, iodinated compounds suffered from short imaging time and potential renal toxicity due to their rapid kidney’s 2374

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Figure 17. (A) Schematic of mesoporous-silica-coated UC NPs coloaded with ZnPc and MC540 photosensitizers for PDT (not to scale). (B) Schematic diagram showing up-conversion nanoprticle-based targeted PDT in a mouse model of melanoma intravenously injected with UC NPs surface modified with FA and PEG moieties. Scale bar, 10 mm. (C) Targeted in vivo PDT of a subcutaneous tumor model injected with FA−PEG− UCNs−ZnPc−MC540. Representative gross photos of a mouse from each group 1−3 intravenously injected with FA−PEG−UCNs−ZnPc− MC540, unmodified UCNs−ZnPc−MC540, or PBS (phosphate-buffered saline) showing the change in tumor size (highlighted by dashed white circles) before (0 d) and 7 d after PDT treatment. Scale bars, 10 mm. Adapted from ref 25. Copyright 2012 Nature America, Inc.

emission, high r1 relaxivitiy, and strong X-ray attenuation in vivo. They also designed hollow Fe3O4@NaLuF4:Yb,Tm NPs, in which the superparamagnetic Fe3O4 core acted as MRI negative contrast agents with a r2 relaxivity value of 21.63 s−1 mM−1, and the NaLuF4:Yb,Tm shell was used for UCL/CT imaging.520 Shi and co-workers designed NaYF4:Gd,Yb,Er,Tm@SiO2−Au@PEG5000 NPs for UCL/ MRI/CT trimodal imaging.19 In this system, Au NPs have the following two functions: (1) CT contrast agent with high X-ray absorption coefficient, because of the large atomic number and electron density, and (2) UCL enhancement (3−4 times in this case) through the surface plasmon resonance effect. The intensified trimodal imaging signals for cancerous cells and lesions were clearly evidenced by local injection of the nanoprobes in mice. Later, the same group constructed a new nanocomposite of NaYF4:Yb,Er,Tm@NaGdF4@TaOx−PEG− silane (x ≈ 1) to realize high-performance UCL/MRI/CT trimodal imaging.521 First, the combination of Ta element (possessing a high X-ray attenuation coefficient) with RE elements provided a notable signal enhancement when the concentration of the nanocomposite was increased. Second, tantalum oxide is highly fluorescence transparent, and when was coated on the surface of phosphor, it does not reduce the luminescence intensity as most modification materials did. 6.3.3. UCL/MRI/PET Imaging. Positron emission tomography (PET) nuclear imaging, a clinical tool with detection sensitivity and low spatial resolution, was combined with MRI and UCL imaging by labeling UC NPs with fluorine-18 (18F). 18 F is the most widely used radionuclide. On the basis of the strong binding between 18F− and RE3+ ions, Li and co-workers developed a simple process to synthesis 18F-labeled RE NPs by sonication and centrifugation of a mixture of 18F− ions and RE NPs in water, such as the prepared samples of NaYF 4 :Yb,Er,Gd− 1 8 F−citrate, NaYF 4 :Yb,Er,Gd− 1 8 F−FA, Y2O3−18F−F127, and Gd(OH)3−18F−F127 NPs.18,511,522,523 The whole-body PET imaging of all the 18F-labeled RE NPs

was measured by a Siments Inveon small-animal micro-PET scanner, and the results indicated that intense radioactive signals were detected exclusively in liver and spleen in Kunming mice by the tail vein. Therefore, a new generation of UCL/ MRI/PET multimodality nanoprobes that integrate UCL (NaYF4:Yb,Er), magnetism (Gd3+), and radioactivity (18F) have been developed with NaYF4:Yb,Er,Gd−18F−citrate and NaYF4:Yb,Er,Gd−18F−FA NPs. Utilizing NaYF4:Yb,Er,Gd−18F−FA NPs, Li and co-workers realized targeted UCL/MRI/PET trimodal imaging, assisted by the molecular recognition of FA. 6.3.4. Others. Liu and co-workers synthesized NaYF4:Yb,Er−Fe3O4@polymer−dye nanocomposite for a new triple-modal UCL/DCL/MRI imaging by encapsulating NaYF4:Yb,Er NPs, Fe3O4 NPs, and squaraine dye into amphiphilic polymers.524 The nanocomposite showed strong UCL, DCL, and MRI (r2 = 86 s−1 mM−1) signals, even when injected into mice. The stability of the nanocomposite has been demonstrated by the UCL and DCL signal levels in collected organs, which were consistent with each other. Besides the representative multimodal bioimaging discussed above, there are some other patterns, such as UCL/PET,523 UCL/CT,276,517 MRI/CT,392 UCL/SPECT,519,525 and CT/SPECT.518 Every dual-modal pattern contains two of the following components: 18 F, Gd/Fe, elements with high X-ray attenuation coefficient, 153 Sm, and Er3+/Tm3+/Ho3+ for PET, MRI, CT, SPECT, and UCL imaging, respectively. Reports indicated that the imaging signals can be detected in cells and mice easily, providing new platforms for the next generation of probes for sensitive bioimaging applications. To sum up, in vivo imaging techniques are powerful tools to monitor biological situations at a target site and visualize an abnormal state of the body. The synergistic combination of UCL imaging with other imaging techniques (MRI, CT, and PET) is critical for biological imaging and biomedical applications. First, UCL imaging is low cost, multicolor, and 2375

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NaYF4:Yb,Er NPs. In their reports, the amount of 1O2 produced by ZnPc was increased with the exposure time of the chemical method. Then, the therapy efficacy was assessed by cell viability. When the cells incubated with NaYF4:Yb,ErPEI-ZnPc or NaYF4:Yb,Er@mSiO2−ZnPc were exposed to a NIR laser, more cell death was induced compared with those treated with NaYF4:Yb,Er-PEI or NaYF4:Yb,Er@mSiO2 NPs, respectively. Later, the same group improved PDT drug with a dual-photosensitizer approach, in which ZnPc and MC540 (merocyanine 540) photosensitizers were loaded into NaYF4:Yb,Er@mSiO2 UC NPs simultaneously (denoted as UCNs− ZnPc−MC540).25 Compared to approaches using a single photosensitizer, UCNs−ZnPc−MC540 enhanced the generation of singlet oxygen and reduced cell viability. Slow tumor growth rate was achieved in vivo when tumor-bearing mice were injected with UCNs−ZnPc−MC540 and irradiated with a 980-nm laser, but not with NaYF4:Yb,Er@mSiO2 NPs or radiation alone. In addition, they further examined the targeted PDT efficacy by conjugation these new PDT drugs with FA and antibody.25,363,482 In vitro and in vivo results suggested that the PDT drugs modified with cancer-specific targeting agents possessed more significant antitumor effect than unmodified ones (Figure 17). Liu and co-workers reported another kind of NIR lightinduced PDT drug by loading Ce6 photosensitizer on NaYF4:Yb,Er@PEG UC NPs.23,24 The PDT drug showed a much deeper tissue penetration depth and thus improved the in vivo tumor growth inhibition efficacy. Other photosensitizer molecules, including MC540,471 meso-tetraphenylporphine (TPP),251,528 and (4-carboxyphenyl)porphine (TCPP),24 also have been selected and integrated with NaYF4:Yb,Er UC NPs to construct NIR-laser-triggered PDT drugs, because the emission bands of NaYF4:Yb,Er NPs well match the absorption peaks of these photosensitizers. The excellent cancer cell killing ability of all the NIR-light-induced PDT drugs have been confirmed by cancer cell viability in vitro and in vivo. In addition, NaYF4:Yb,Tm-based PDT drug, which would adsorb the blue emission from Tm3+ ions, has been prepared by incorporation of Ru(bpy)32+ in the silica layer of NaYF4:Yb,Tm@SiO2 NPs.529 Applying NaYF4:Yb,Er@NaGdF4 or NaYF4:Yb,Er,Gd NPs as energy transfer agents, the combination of MRI/UCL imaging and PDT was performed.203,204

easily accessed compared with nuclear, ultrasound, and magnetic resonance imaging. Second, it is a facile method to provide cellular/molecular-level resolution. Plus, UCL imaging agents have been functionalized with targeting agents (e.g., FA, antibody, and Fe3O4) to realize molecular/magnetic targeted imaging. Unfortunately, the targeted imaging has been focused on targeted UCL imaging and mainly tested in vitro. Only several reports involved the design of targeted multimodal imaging agents.16,511,526,527 Therefore, the concept still needs to be further investigated, especially in small animals, to realize accurate, local, and directional imaging of specific target structures in vivo.

7. THERAPEUTIC APPLICATIONS Research on cancer therapy is a crucial and worldwide issue since it causes millions of deaths annually. Due to the high mutation rates and genetic heterogeneities of viruses, the search for cancer therapies still continues and looks more complicated than in the past. Thus, lots of new materials and mechanisms have been explored for cancer therapy. As described above, RE NPs are excellent imaging tools to identify the locations and sizes of tumors. Therefore, when RE NPs were combined with therapeutic agents, multifunctional probes are synthesized for imaging-guided and tumor-targeted therapies. These multifunctional probes provide excellent imaging functionality, tumortargeting ability, and therapy efficiency, thereby resulting in the development of multifunctional diagnositic and therapeutic systems. To date, the combination has been applied to the therapy methods of photodynamic therapy (PDT), photothermal therapy (PTT), and delivery of chemotherapy drugs. The classification and simple therapeutic mechanism are shown in Figure 13. 7.1. Photodynamic Therapy (PDT)

PDT involves a vital component, a photosensitizer, which is a photosensitive molecule and works as a light-sensitive drug. When was exposed to light of appropriate wavelengths, the photosensitizer will be excited and transfer its energy to the surrounding molecular oxygen to generate a cytotoxic and reactive oxygen species, singlet oxygen (1O2), which can oxidize and kill cancer cells. Indeed, most photosensitizers are activated by visible light; thus, the efficacy of PDT in living tissue has been restricted by the low penetration depth of visible light. In view of this, a combination of photosensitizers and UC NPs to produce deep-cancer PDT was exploited by utilizing the resonance energy transfer from UC NPs to photosensitizers. In this combined system, the maximum absorption wavelength range of photosensitizer should locate in the spectral overlap between the emitted visible light of UC NPs. So, when the combined system was excited by a 980 nm NIR laser, UC NPs will convert NIR light to visible light, which further activates the photosensitizer to release 1O2, as depicted in Figure 17a. Shi and co-workers showed direct evidence of the energy transfer from UC NPs to the photosensitizer MB (methylene blue) by UCL spectra, in which a remarkable red-light quenching in the spectra of NaYF4:Er,Yb,Gd@SiO2−MB was found.203 Zhang and co-workers designed NIR light-triggered PDT drugs by attaching photosensitizer ZnPc (zinc phthalocyanine) to NaYF4:Yb,Er-PEI UC NPs or incorporating ZnPc into NaYF 4 :Yb,Er@mSiO 2 UC NPs (mSiO 2 = mesoporous silica).9,225,363,482 Note that the absorption peak of ZnPc (∼670 nm) overlaps within the red emission peak of

7.2. Photothermal Therapy (PTT)

In PTT, a photoabsorber is employed to absorb and transform optical irradiation into heat. Then the elevated temperature induces denaturation of intracellular protein or disruption of membrane, leading to thermal ablation of cancer cells. Compared to chemotherapy or surgery, PTT is less invasive and hence has attracted increased attention in cancer treatment. Previously, noble metal materials, such as gold and silver nanorods, nanocages, and nanoshells, have served as photothermal therapeutic agents due to their strong optical absorption in the NIR region.530,531 Recently, Liu and co-workers designed NaYF4:Yb,Er@ Fe3O4@Au−PEG multifunctional NPs for MRI/UCL imaging-guided and magnetically targeted photothermal cancer therapy.532 To test the magnetically targeted PTT effect, mice bearing tumors were intravenously injected with NaYF4:Yb,Er@Fe3O4@Au−PEG NPs. On the one hand, UCL imaging showed a several-fold increase signal for the tumor once attached on a magnet, and the T2-weighted MRI signals decreased by 62.1% (while 18.7% without magnet) before and 2376

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Figure 18. (A) Schematic illustration of the preparation of UCNP@P−Pt/RhB NPs and possible cellular pathways for cisplatin and UCNP@P−Pt/ RhB NPs. (B) TEM images of UCNP@P−Pt/RhB NPs in HeLa cells (i, ii) after 6 h of incubation with 200 μg/mL UCNP@P−Pt/RhB and tumor tissues (iii, iv) from the mouse treated with 250 mg/kg of UCNP@P−Pt (3.75 mg/kg equivalent cisplatin) for 24 h. (C) Cumulative DOX release from NaYF4−PEI as a function of release time in the release media of PBS buffer with different pH values. (D) Confocal laser scanning microscopy images of HeLa cells incubated with NaYF4−PEI−DOX for 1 h (a−c) and 6 h (d−f), as well as DOX-loaded NaYF4−PEI−FA for 1 h (g−i) and 6 h (j−l) at 37 °C, respectively. Each series can be classified to the nuclei of cells (being dyed in blue by Hoechst 33324 for visualization), DOX-loaded nanocarriers, and a merge of the two channels of both above, respectively. Adapted from refs 537 (copyright 2013 Elsevier Ltd.) and 538 (copyright 2013 Wiley-VCH Verlag GmbH & Co. KgaA).

structures exhibit sustained drug release profiles in the release media of buffer, just like the trend shown in Figure 18C. When cells were incubated with them, the red fluorescence distributed inside cells arising from DOX can be observed and increased with time (e.g., Figure 18D), indicating that the DOX-loaded hollow structures can pass through the cytomembrane, assemble in cells, and release drug to induce significant cell apoptosis and death. Normally, the anticancer efficacy of the drug-loaded systems is close to that of free drugs when the concentrations of them are high, which has been explained by the fact that small DOX molecules diffuse into cells rapidly, while drug-loaded systems are transported into cells by an endocytosis mechanism (illustrated in Figure 18A), and the endocytosis mechanism has been proved by our recent research. We synthesized UCNP@P−Pt/RhB nanocomposites, where P−Pt is short for the copolymer mPEG-b-PCL-b-PLL/ Pt(IV) and UCNP denote NaYF4:Yb,Er.538 In the bio-TEM images, the NPs inside the nucleus (Figure 18Biii,iv) provided direct evidence that they can pass through the cytomembrane, escape from lysosomal, assemble in cytoplasm, and then pass through the nuclear pores and enter the nucleus. Moreover, the therapeutic effect can be enhanced obviously when the hollow structures are modified with targeting molecules (Figure 18D), because more drug-loaded systems can be uptaken, contributing to the targeting recognition. Therefore, compared with free drugs, one attractive advantage of using drug carriers is the targeted drug delivery for selective destruction of cancer cells. More important, the luminescence emission intensity of every DOX-loaded carrier increases with the cumulative release of DOX, reaching a maximum when the DOX release is over. The reason for the weakened luminescence can be attributed to the organic groups in DOX, which yield high-energy vibrations to quench the UCL emissions. The relationship between the emission intensity and drug release extent allows the delivery process and therapy efficiency to be monitored and tracked.

after NPs injection, proving the excellent magnetic tumortargeting effect. On the other hand, when 808 nm NIR laser irradiation is applied, the surface temperature of tumors was increased to ∼50 °C under the magnetic field, while it was ∼38 °C for irradiated tumors on uninjected mice. After the magnetically targeted PTT, all the tumors disappear, suggesting an outstanding therapeutic efficacy with 100% of tumor elimination. Moreover, a unique molecular/magnetic dualtargeting cancer PTT agent, which may offer more selective and localized therapy, was allowed by conjugation of NaYF4:Yb,Er@Fe3O4@Au−PEG NPs with FA molecules.16 Besides, Song and co-workers synthesized NaYF4:Yb,Er@Ag NPs, which can achieve UCL bioimaging and PTT with the same 980 nm NIR laser simultaneously.490 Upon treatment with 980 nm NIR light from 8 to 20 min, the viability of HepG2 cells incubated with NaYF4:Yb,Er@Ag NPs was decreased from 65.05% to 4.62%, implying an efficient PTT ability. 7.3. Drug and siRNA Delivery

A drug delivery system, which can deliver chemotherapy drugs to the targeted cells or tissues in a controlled manner by drug carriers, is another efficient therapy mode. An ideal drug delivery system, especially nanoengineered ones, can slip selectively into virus tissue and protect the drug from biological degradation before reaching their destination.533−535 Our group pioneeringly exploited RE3+-doped inorganic NPs for drug delivery, mainly including hollow RE NPs/microparticles and RE NPs functionalized mesoporous silica composites. Hollow RE NPs/microparticles, such as hollow CaF2:Ce,Tb−PAA,168 GdVO4:Yb,Er/Tm/Ho−PAA,536 NaYF4:Yb,Er−PEI,537 and Yb(OH)CO3@YbPO4:Er,318 can store drug molecules inside their hollow interiors. We have evaluated the drug loading and controlled release behaviors of them by using doxorubicin hydrochloride (DOX), a widely used anticancer drug, as a model drug. All the DOX-loaded hollow 2377

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tracked. Additionally, a stimuli-responsive drug delivery system is going to be constructed with RE NPs functionalized with silica materials. Shi and co-workers constructed a NIR-triggered anticancer drug delivery system by modifying the channels of NaYF 4 :Yb,Tm@NaYF 4 @mSiO 2 NPs with azobenzene groups.557 Upon 980 nm light irradiation, the visible light and UV light emitted by NaYF4:Yb,Tm@NaYF4 core induce the continuous photoisomerization of azobenzene groups, which acts as an impeller and expels drug molecules out of the pores. We reported rattle-type Gd2O3:Eu@mSiO2 NPs for stimuli-responsive drug delivery with thermosensitive poly(Nisopropyl acrylamide) (PNIPAM) as controlled switch.558 The multifunctional carriers exhibit a remarkable positive temperature-sensitive on−off modulation for indomethacin release, i.e., rapid drug release rate at an increased temperature (“on” phase) and completely stopping at a decreased temperature (“off” phase), realizing the controlled drug delivery and therapy. Assisted by cisplatin, which is an anticancer drug as well as a radiosensitizer, Shi and co-workers also synthesized hollow NaYF4:Yb,Er@NaGdF4@mSiO2−FA NPs for chemo/radiotherapy and UCL/MRI dual-mode imaging.526 They proved that the tumor growth in mice treated with radiation and NaYF4:Yb,Er@NaGdF4@mSiO2−cisplatin was effectively inhibited in 1 week, while other groups treated with cisplatin or NaYF4:Yb,Er@NaGdF4@mSiO2−cisplatin did not show significant inhibited effect. And after half a month, the chemo/ radiotherapy efficiency in mice was more obvious. With further conjugation of FA for targeting, the new system showed the most effective chemo/radiotherapy via active targeting effects. More details about the silica composite carriers have been summarized in our previous review.559 Small-interfering RNA (siRNA), synthetic double-stranded RNA consisting of 21−23 nucleotides, is especially attractive as an anticancer therapeutic agent in gene therapy, since in the RNA interference process, siRNA induces efficient sequencespecific silencing of gene expression.560,561 However, the clinical application of therapeutic siRNA has been very challenging due to the fast degradation, immune response, and poor cellular uptake of siRNA in biological tissues. Fortunately, packaging siRNA within NPs overcomes the impediments. Zhang and co-workers investigated the delivery behavior and therapy effect of siRNA by using the carrier NaYF4:Yb,Er@SiO2−anti-Her2 NPs.468 When cells were incubated with NaYF4:Yb,Er@SiO2−anti-Her2−siRNA, first, UCL was observed in SK-BR-3 cells (Her2 receptors overexpressed) but not in MCF-7 cells (low level of Her2 receptors expressed), suggesting that only cells with Her2 receptors were transfected by the NPs and siRNA was delivered into them. Second, luciferase gene expression in transfected SKBR-3 cells was down-regulated by 45.5%, while it was not silenced in transfected MCF-7 cells. The exogenous gene expression assays proved the targeted delivery behavior and gene silencing effect of siRNA with NaYF4:Yb,Er@SiO2−antiHer2 carrier. In addition, siRNA delivery behavior in cells also has been presented through fluorescence resonance energy transfer efficiency between NaYF4:Yb,Er@SiO2 donor and BOBO-3 dye stained siRNA acceptor.562 Liu’s group presented a light-induced siRNA release system, in which NaYF4:Yb,Tm@mSiO2 was functionalized with photosensitive onitrobenzyl linkers and then adsorbed anionic siRNA through electrostatic attractions.563 After excitation with NIR light, the linker could be cleaved by the emitted UV light, and siRNA was

By combination of RE luminescence property and effective targeting drug delivery ability, a new chemotherapeutics of imaging-guided and targeted drug delivery system has been developed. NaYF4 :Yb,Er@polymer−PEG−FA and NaYF4:Yb,Er−Fe3O4@polymer multifunctional nanocomposites have been applied for imaging-guided and targeted drug delivery by Liu and co-workers.24,524 Taking advantage of the strong UCL signals in cells, NaYF4:Yb,Er@polymer−PEG− FA−DOX system exhibited greater cytotoxicity to FR-positive KB cells than free DOX and NaYF4:Yb,Er@polymer−PEG− DOX system under the same condition. They also observed that cells near the magnet were mostly killed by the NaYF4:Yb,Er−Fe3O4@polymer−DOX therapy agent, while those far from the magnet largely survived. Shi and co-workers prepared an active MRI/UCL imaging-guided and nucleartargeted therapy system by conjugation of NaYF4:Yb,Er@ NaGdF4−PEG with TAT peptide.527 On the one hand, in vitro dual MRI/UCL imaging was performed on Hela cells. On the other hand, after loading of DOX, confocal laser scanning microscopy images showed that TAT peptide encouraged drug delivery to cell nuclei directly and efficiently. So, when cells were incubated with NaYF4:Yb,Er@NaGdF4−PEG−TAT− DOX, the cell viability can be decreased to 32% due to the effect of nuclear targeting, while it is as high as 77% and 74% for free DOX and NaYF4:Yb,Er@NaGdF4−PEG−DOX with an equivalent concentration of 500 mg/mL. All the results supported that targeted delivery of anticancer drugs is beneficial to enhance the therapeutic efficacy, and the UCL property enables the therapy efficiency to be monitored and tracked. Also these two groups studied the delivery behaviors and luminescence properties of these drug carrier systems with or without targeting modification in cells with a fluorescence microscope. The results indicated that the luminescence intensities of the UC NPs increased with the incubation time, even as long as 48 h, demonstrating that the UC NPs will not be biodegraded in cancer cells and the UCL is stable enough to be detected. In recent years, amorphous silica, which is an FDA-approved food additive, has been considered to be an excellent candidate as a drug carrier, especially mesoporous silica with its unique advantages, including large surface area, high pore volume, uniform and tunable pore size, nontoxic nature, and good biocompatibility.539−544 Accordingly, RE NPs functionalized with mesoporous silica composites have been employed for drug delivery. There are two basic structures for the composite systems. One is the embedded structures, in which RE NCs, such as YVO4:Ln (Ln = Eu, Dy, Sm, Er) and CaWO4:Tb, can be embedded into channels of the well-known MCM-41, MCM-48, and SBA-15 mesoporous silica particles.545−549 The other one is the core−shell structures, in which RE NPs can be used as cores and incorporated inside the mesoporous silica shells, including Y2O3:Eu@mSiO2, CeF3:Tb@SiO2@mSiO2, Gd 2 O 3 :Eu/Er@SiO 2 @mSiO 2 , and NaYF 4 :Yb,Er@SiO 2 @ mSiO2 composites.550−554 Compared with hollow RE particles, these composite delivery systems exhibit both the luminescence properties of RE materials and the notable advantages of silica, such as much larger surface area for drug loading, more mild drug delivery rate, and better biocompatibility. Our group designed core−shell structured Fe 3 O 4 @SiO 2 @mSiO 2 @ YVO4:Eu and Fe3O4@SiO2@mSiO2@ NaYF4:Yb,Er multifunctional nanocomposites.555,556 Both of them exhibit bright luminescence emission and high magnetization, allowing the drug release and therapy process to be targeted, monitored, and 2378

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released synchronously. The light-induced siRNA release process is effective in living cells. As described above, the combination of diagnosis and therapy by UC NPs is an attractive and active area. First, the diagnosis is based on NIR excitation light, which will expand the applicability to almost any tissue, contributing to high penetration depth and negligible photodamage. Second, therapies assisted by UC NPs can be triggered by NIR irradiation and tracked by their luminescence, so the therapeutic agents can be targeted to the diseased area and then start to kill the cancers by the NIR-induced therapies, which will protect the healthy tissues from damage. However, the therapy effectiveness in animal tumor models and, subsequently, in larger animals and deeper tissues has rarely been reported, especially for the therapy mode of chemotherapy drug delivery. Therefore, further investigations are still needed to replenish this lack of data.

pharmacodynamics in larger animals and deeper tissues should be continued in the future.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

8. CONCLUSION AND OUTLOOK In this review, we highlight the recent progress on RE inorganic nano/microcrystals. First, RE luminescence tuning was focused on, including luminescence enhancement and multicolor emission by regulating the sorts and levels of doping ions, particle size, phase, host, introducing non-RE3+ ions or metal NPs, and so on. Subsequently, several soft chemical routes for the controlled synthesis of RE nano/microcrystals were reviewed. Although a rich variety of high-quality products with tailored architectures were achieved through the facile adjustment of reaction parameters, current control strategies depend strongly on experimental trial-and-error approaches. Concurrently, most of the synthetic mechanisms are collections of hypotheses owing to the lack of effective measurement technique and supporting data. Therefore, development of a new monitoring technique is of great urgency to reveal the mechanism of the reaction process. Moreover, a better understanding of the synthetic methodology will promote the systematic design of synthetic strategies and then direct us to produce nano/microcrystals with predesigned structures. Beyond the points concluded above, ligands were employed to control the morphologies of products, usually attached on the surface. To realize biomedicine applications in organism, surface hydrophilic modification and bioconjugation are critical. As described above, many new interesting fruits have been established. Nevertheless, surface modifications always lead to the decrease of luminescence intensity. And it is still a challenge to modify the NPs so as to improve their biocompatibility and luminescent intensity synchronously. Finally, multifunctional NPs have been synthesized by combining UC NPs with other imaging agents and therapy agents. So far, multifunctional UC NPs show their potential in multimodal bioimaging (UCL/MRI, UCL/MRI/CT, UCL/ MRI/PET, etc.) as well as imaging-guided therapy (PDT, PTT, and drug delivery). Despite the fact that the studies of cytotoxicity levels, biodistributions, and excretion routes of the multifunctional UC NPs have been carried out in cell and small animal models, the investigations are still in their early stages of in vitro testing or preliminary animal studies and require concerted effort for efficacy and safety. On the one hand, precise evaluations of imaging and therapy efficacy in vitro and in vivo should be performed. On the other hand, prior to the clinical use in human, further toxicology studies including distribution, excretion, metabolism, pharmacokinetics, and

Shili Gai was born in Jilin, China, in 1986. She received her B.S. and Ph.D. degrees from Harbin Engineering University (Harbin, China) in 2009 and 2013, respectively. Her research focuses on rare earth luminescence materials and multifunctional composite materials, including the study of the controllable synthesis, physical chemical properties, and biomedical applications.

Chunxia Li was born in Shandong, China, in 1977. She received her B.S. (2002) and M.S. (2005) in Chemistry from Northeast Normal University (Changchun, China) and her Ph.D. (2008) from the Changchun Institute of Applied Chemistry (Changchun, China). After graduation, she became an Assistant Professor in Prof. Jun Lin’s group and was promoted to Associate Professor in 2012. Her current research interests include the controllable synthesis of rare earth luminescence nanomaterials and their bioapplication. 2379

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AOT APTS [BF4]− [BF6]− [Bmim][BF4]

sodium bis(2-ethylhexyl) sulfosuccinate (3-aminopropyl)triethoxysilane tetrafluoroborate hexafluoroborate 1-n-butyl-3-methylimidazolium tetrafluoroborate [Bmim][PF6] 1-butyl-3-methylimidazolium hexafluorophate bpy 2,2′-pyridine Ce6 chlorin e6 CCK-8 cell counting kit CIE Commission Internationale de L’Eclairage Cit3− citrate Copt optimal dopant concentration CO520 polyoxyethylene(5)isooctylphenyl ether CRT cathode-ray tube CT X-ray computed tomography CTAB cetyltrimethylammonuim bromide CTX chlorotoxin DC down-conversion DCL down-conversion luminescence ddtc diethyl dithiocarbamate DEG diethylene glycol DENV2 Dengue virus serotype 2 DMSA meso-2,3-dimercaptosuccinic acid DOX doxorubicin hydrochloride DTPA diethylene triamine pentacetate acid EDTA ethylenediaminetetraacetic acid EG ethylene glycol ESA excited state absorption ETU energy transfer up-conversion FA folic acid FDA Food and Drug Administration FEDs field emission displays HDA hexanedioic acid HEEDA N-(2-hydroxyethyl)ethylenediamine IC50 half-maximal inhibitory concentration ITO-coated glass glass slide with indium−tin oxide films LEDs light-emitting diodes lg β chelating constant LSS liquid−solid solution MB methylene blue MC540 merocyanine 540 MF melamine formaldehyde MFNPs NaYF4:Yb,Er@Fe3O4@Au−PEG multifunctional NPs MIMIC micromolding in capillaries MMP-2 peptide and metalloproteinase 2 MRI magnetic resonance imaging MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, sodium salt MTT methyl thiazolyl tetrazolium Mn+ metal ions Na2EDTA ethylenediamine tetraacetic acid disodium NCs nanocrystals NIR near-infrared NP nanoparticle NPs nanoparticles OA oleic acid ODE octadecene OM oleylamine

Piaoping Yang is currently a Professor of Chemistry in the College of Material Science and Chemical Engineering at Harbin Engineering University (Harbin, China). He received his B.S. degree at Nankai University (Tianjin, China) and his Ph.D. degree at Jilin University (Changchun, China). After graduation, he joined Prof. Jun Lin’s group for postdoctoral research. His research mainly focuses on the fabrication and biomedical applications of rare earth based functional materials.

Jun Lin was born in Changchun, China, in 1966. He received B.S. and M.S. degrees in Inorganic Chemistry from Jilin University (Changchun, China) in 1989 and 1992, respectively, and a Ph.D. in Inorganic Chemistry from the Changchun Institute of Applied Chemistry (CIAC) (Changchun, China) in 1995. Then he went to City University of Hong Kong (1996), Institute of New Materials (Saarbrücken, Germany, 1997), Virginia Commonwealth University (Richmond, VA, 1998), and University of New Orleans (New Orleans, LA, 1999) working as a postdoctor. He came back to China in 2000 and since then has been a Professor at CIAC. His research interests include bulk and nanostructrued luminescent materials and multifunctional composite materials together with their applications in display, lightening, and biomedical fields.

ACKNOWLEDGMENTS This project is financially supported by the National Natural Science Foundation of China (NSFC 51332008, 21271053, 21221061), National Basic Research Program of China (2010CB327704, 2014CB643803), and the national High Technology Program of China (2011AA03A407). ABBREVIATIONS USED AA azelaic acids ADA 11-aminoundecanoic acid AEP 2-aminoethyl dihydrogen phosphate 2380

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Review

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1-octyl-3-methylimidazolium hexafluorophosphate 1-octyl-3-methylimidazolium tetrafluoroborate poly(acrylic acid) poly(allylamine) poly(allylamine hydrochloride) poly(amidoamine) dendrimers phosphate-buffered saline poly(dimethylsiloxane) photodynamic therapy HOOC−PEG−COOH poly(ethylene imine) positron emission tomography hexafluorophate 1,10-phenanthroline photoluminescence poly(N-isopropylacrylamide) phosphino-poly(acrylic acid) poly(sodium 4-styrenesulfonate) photothermal therapy polyvinyl pyrrolidone quantum dots quantum yield rare earth rare earth acetate rare earth acetylacetonate rare earth oleate reticuloendothelial system longitudinal relaxivities transverse relaxivities scanning electron microscopy small-interfering RNA single photon emission computed tomography single-source precursor (4-carboxyphenyl)porphine transmission electron microscopy tetraethoxysilane thioglycolic acid trioctylphosphine trioctylphosphine oxide meso-tetraphenylporphine up-conversion up-conversion luminescence ultraviolet zinc phthalocyanine microcontact printing microtransfer molding energy difference one-dimensional spin−lattice relaxation rates spin−spin relaxation rates fluorine-18 three-dimensional 3-mercaptopropionic acid 6-aminohexanoic acid

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