3.3.1  Coprecipitation

The coprecipitation method is characterized by simple protocols, quite short reaction times, simple reaction conditions, and cheap experimental setups. In this procedure, the nucleation of the nanocrystals can be promoted using capping agents (such as polyvinylpyrrolidone (PVP) or polyethyleneimine (PEI)). In some cases, the nanoparticles (NPs) are directly generated without the need of postformation heat treatments, in others cases, annealing is necessary to obtain the desired phase.

3.3.2  Thermolysis

This synthetic approach is often used to form lanthanide-doped nanoparticles, since it provides high quality nanocrystals, with high control over dimension, monodispersity, and photoluminescence (PL) properties. It involves a heat treatment (~300°C) of lanthanide precursors, usually organometallic compounds (e.g., acetate or trifluoroacetate salts) that decompose in nonpolar high boiling organic solvents, such as oleylamine (OM), trioctylphosphine oxide (TOPO), or 1-octadecene (ODE). Surfactants with capping groups, for instance, oleic acid (OA), are in charge to control the nanoparticle size and to prevent their aggregation, due to long hydrocarbon chains. The main parameters affecting this synthetic approach are reaction temperature, metal precursors and their concentration, nature of the solvent, capping agent(s), and reaction time. By careful tuning of these experimental parameters, highly monodispersed nanoparticles with very good crystallinity have been produced using the thermolysis method. Besides these positive features, the thermolysis method presents some serious drawbacks. In particular, quite expensive procedures with demanding aspects such as high temperatures and air sensitive starting materials handling are involved. Moreover, the formation of highly toxic fluorinated by-products could limit the large-scale application of this synthetic approach in bio-related applications.

3.3.2.1  Fluorides

A substantial amount of literature has been published in the last 10 years reporting preparation of fluorides with the thermolysis method. One of the first reports was published by Yan et al. (Zhang et al. 2005), who synthesized LaF3 nanocrystals starting from La(CF₃COO)₃ salt, using OA as the capping agent and ODE as the high boiling noncoordinating solvent. This method was extended to other lanthanide-doped nanoparticles, for instance, for the preparation of the famous upconverter material, NaYF₄, by several groups (Abel et al. 2009; Boyer et al. 2006; G. Chen et al. 2010; Cuccia and Capobianco 2007; Yi and Chow 2006). Also, the group of Murray and co-workers (Ye et al. 2010), succeeded in the synthesis of NaYF₄:Yb, Er nanocrystals with a controlled size and morphology (spherical/nanorod): this approach definitely provided a way to high quality and monodipersed colloids. Also Yin et al. (Yu et al. 2010), synthesized monodisperse β-NaYF₄:Yb, Tm nanocrystals with controlled size (25–150 nm), composition, and shape (sphere, hexagonal prism, and hexagonal plate) by thermolysis of metal trifluoroacetates in hot solutions (300–330°C) containing OA, OM, and ODE.

Another interesting host for UC emission, NaGdF₄, was also prepared in nanocrystalline form using the thermolysis method (see Figure 3.2), by the group of Capobianco et al. (Boyer et al. 2007; Naccache et al. 2009). Other groups (Cichos et al. 2014; Johnson et al. 2011; Liu et al. 2010; Z.-L. Wang et al. 2010; Zhou et al. 2010) have investigated this host, also for its interesting magnetic resonance imaging (MRI) properties.

A general synthesis of high quality cubic and hexagonal NaREF₄(RE: Pr to Lu, Y) nanocrystals (nanopolyhedra, nanorods, nanoplates, and nanospheres) and NaYF₄:Yb, Er/Tm nanocrystals (nanopolyhedra and nanoplates) via the co-thermolysis of Na(CF₃COO) and RE(CF₃COO)₃ in OA/OM/1-ODE was reported (Mai et al. 2006). By tuning the ratio of Na/RE, solvent composition, reaction temperature and time, control of the phase, shape, and size of the nanocrystals has been achieved. Interesting hosts for UC nanomaterials have demonstrated to be the alkaline earth fluorides (D. Chen et al. 2010; Quan et al. 2008). Uniform alkaline earth metal fluoride MF₂(M = Mg, Ca, and Sr) nanomaterials with various shapes (tetragonal MgF₂ nanoneedles; cubic CaF₂ nanoplates and nanopolyhedra; cubic SrF₂ nanoplates and nanowires) have been synthesized from the thermolysis of alkaline earth metal trifluoroacetate in hot surfactant solutions, with OA, OM, and ODE (Du et al. 2009). The MF₂ nanocrystals were formed by the controlled fluorination of the M–O bond into the M–F bond at the nucleation stage and subsequent growth process. In these cases, the growth of shape-selective MF₂ nanocrystals was likely due to the template direction of micellar structures formed by self-assembly of capping ligands and the so-called “Ostwald ripening” process.

Figure 3.2   (a) Excitation and emission spectra of NaGdF4: 15% Ce3+, 5% Tb3+ nanoparticles (1 wt% solution in hexane). (b) 1 wt% solution (hexane) of NaGdF4: 10% Ce3+, 5% Tb3+ nanoparticles under (i) ambient and (ii) 254 nm UV light. 1 wt% solutions of (iii) NaGdF4: 15% Ce3+, 5% Tb3+ and (iv) NaGdF4: 20% Ce3+, 5% Tb3+ nanoparticles (hexane) under 254 nm UV light. (c) TEM image of NaGdF4: 20% Ce3+, 5% Tb3+. (d) Emission spectra of 1 wt% solutions (hexane) of NaGdF4:Ce3+, Tb3+ core and NaGdF4:Ce3+ 20%, Tb3+ 5%/NaYF4 core/shell NPs. (e) 1 wt% solution (hexane) of aged NaGdF4: 20% Ce3+, 5%Tb3+ nanoparticles under (i) ambient and (ii) 254 nm UV light and NaGdF4: 20% Ce3+, 5% Tb3+/NaYF4 nanoparticles under (iii) ambient and (iv) 254 nm UV light. (f) TEM image of NaGdF4: 20% Ce3+, 5% Tb3+/NaYF4 sample. (Reprinted with permission from Boyer, J. C., J. Gagnon, L. A. Cuccia, and J. A. Capobianco. 2007. Synthesis, characterization, and spectroscopy of NaGdF4: Ce3+, Tb3+/NaYF4 core/shell nanoparticles. Chem. Mater. 19 (14):3358–3360. Copyright 2007 American Chemical Society.)

3.3.3  Solvo(hydro)thermal

The hydro-solvothermal strategy requires relatively low temperatures (usually <250°C) taking advantage of experimental setups involving an autoclave reactor. Despite the mild conditions, the method allows one to obtain nanoparticles with a good level of crystallinity, with good control over dimension and morphology by fine tuning the experimental temperature and reaction time, the nature of the solvent and the surfactant and their molar ratios. As an important advantage with respect to the thermolysis method, it produces a lower amount of toxic by-product. Organic solvents as alcohols or amines are used in the presence of surfactant additives such as OA, EDTA, CTAB, or PEI: nonetheless, water is frequently used as well.

3.3.3.2  Oxides

Hydrothermal synthesis (water, pH = 13, 24 h at 180°C), followed by calcination (800°C) was also used by Qu and coworkers (Z. Liu et al. 2013) to form sesquioxides nanoparticles. In particular, they reported about the synthesis of multimodal PEGylated Gd₂O₃:Yb³⁺, Er³⁺ nanorods (PEG-UCNPs) for in vivo UCL, T₁-enhanced magnetic resonance, and x-ray computed tomography imaging. PEGylation was introduced using a trialkoxysilane-PEG, conferring long blood circulation time, stability in vivo and noncytotoxic character, as indicated by small-animal experiments. With two different ligands—OA and aminohexanoic acid (AA)—Li and coworkers (Cao et al. 2011) succeeded in the hydrothermal synthesis of high quality water-soluble UC nanocrystals bearing appropriate functional groups using a one-step synthetic strategy. The OA/AA molar ratio allowed to optimize water dispersibility and provided amino groups for conjugation to folic acid (FA) for targeted bioimaging (Figure 3.3).

An interesting approach for the synthesis of cubic Er₂O₃ nanostructures with high yield and controlled size and shape has been developed via a solvothermal reaction of erbium nitrate in water/ethanol/decanoic acid media (Nguyen et al. 2010). The cubic Er₂O₃ phase was obtained at a temperature lower than 200°C and by tuning experimental parameters (such as the reaction temperature, the concentration of decanoic acid, and erbium precursor), different sizes and a variety of sheaves and brooms can be obtained. Furthermore, a change of the solvent (anhydrous ethanol instead of water/ethanol) had a strong influence on the particle size. Interestingly, at high precursor concentrations, nanorods were formed due to anisotropic growth. It was found that the UCL properties depend on the particle size of the products.

Figure 3.3   Scheme of hydrothermal reaction for preparing amino-functionalized UCNPs assisted with binary cooperative ligands: hydrophilic 6-AA and hydrophobic oleate. (Reprinted from Biomaterials, 32 (11), Cao, T. Y., Y. Yang, Y. A. Gao, J. Zhou, Z. Q. Li, and F. Y. Li, High-quality water-soluble and surface-functionalized upconversion nanocrystals as luminescent probes for bioimaging, 2959–2968, Copyright 2011, with permission from Elsevier.)

3.3.4  Sol–Gel

The sol–gel technique has been considered by some groups in the past years to prepare oxide-based UC nanomaterials and it is characterized by hydrolysis and polycondensation of metal alkoxide (or halide)-based precursors. On the other hand, in order to improve the crystallinity of the nanosized materials, a further heat treatment at relatively high temperatures is often carried out. Due to this treatment, the obtained nanoparticles present considerable aggregation, and well-dispersed water solutions are therefore hard to prepare, making their application in the biomedical field difficult. Nonetheless, these NPs can be considered for other applications not requiring very homogeneous dispersions.

An interesting upconverting material is lanthanide-doped ZrO₂. De la Rosa et al. prepared Er³⁺-doped zirconium oxide using the sol–gel process (De la Rosa-Cruz et al. 2003), followed by an annealing treatment at 1000°C for 10 h. It was found that the crystallite sizes presented dependence from the Er³⁺ concentration in the host, ranging from 28 to 46 nm. UC in the green and red regions were observed with NIR excitation and the intensity of the UC emission bands varied with the Er³⁺concentration in the host. Moreover, Prasad et al. investigated an interesting modification of the sol–gel technique to generate Er³⁺-doped ZrO₂ nanoparticles, considering a sol–emulsion–gel technique that used reverse micelles formed in emulsions as reactors for the growth of the nanocrystals (Patra et al. 2002). The authors also studied the effects of the Er³⁺ concentration and different codopants (e.g., Yb³⁺ and Y³⁺) in the ZrO₂ host on the UC emission. Green and red UC emission at 550 and 670 nm were observed from these oxide nanocrystals upon excitation at 980 nm, the total UC in the green and red regions decreases with increasing concentration of Er³⁺ ions in the host, while it increased with the presence of Y³⁺ and Yb³⁺ ions.

Other binary oxides as TiO₂ have revealed to be interesting as hosts for UC emission. Luo et al. (2011) prepared Er³⁺-doped anatase TiO₂ nanoparticles via a sol–gel solvothermal method. From emission and excitation spectra as a function on the temperature in the 10–300 K range, a crystal-field (CF) analysis for the Er³⁺ ions assuming a C_2v site symmetry revealed a relatively large CF strength (549 cm⁻¹). The UC intensity in Yb³⁺, Er³⁺ codoped nanoparticles was about five times higher than for Er³⁺ singly doped counterparts, due to efficient Yb³⁺ sensitization and energy transfer UC (ETU).

Patra et al. (2003b) investigated the effects of the Er³⁺ concentration, crystal size and phase, and different processing temperatures on the UC emission for Er³⁺-doped BaTiO₃ and TiO₂ nanocrystals, using a sol–emulsion–gel technique. Using the same experimental setup conditions, and the same Er³⁺ concentration, the observed UC intensity was higher for BaTiO₃ than for the TiO₂ host. For the TiO₂ host, the highest UC intensity was observed for samples heat treated at 800°C, where both the anatase and rutile phases were present. From an analysis of UC spectra and power studies, it was confirmed that UC emission was produced by excited-state absorption (ESA) processes.

The preparation of Ho³⁺, Yb³⁺-doped titanate nanotubes was carried out by Pedroni et al. (2012) via a two-step procedure: a first sol–gel process to produce the lanthanide-doped titania and a second hydrothermal treatment in alkaline conditions on the obtained doped titania powders to form the titanate nanotubes. A treatment at various temperatures was carried out with the aim of determining the different structural and optical properties of the nanotubes. It was found that on increasing the heat treatment the nanotube UC was stronger, due to reduction of hydroxyl groups and water on the surface of the nanotubes, resulting in changes in the interlayer distances.

Er³⁺ and Yb³⁺, Er³⁺-doped Y₂O₃ core–shell particles were synthesized by Dorman et al. (2012) with a two-step process, where the cores were prepared by a molten salt technique and the shell was deposited with a sol–gel process. The authors succeeded inpreparing cores with sizes of 100–150 nm, and shell layers up to 12 nm thick, tunable by controlling the mass ratio between the lanthanide chlorides used as precursors and the core (Er³⁺-doped Y₂O₃) nanoparticles. A Y₂O₃ shell layer with optimal thickness of 8 nm induced a 53% increase in luminescence lifetimes and visible separation in Stark splitting. Optically active-shell layers, as Yb₂O₃ and Yb³⁺-doped yttria, also facilitated energy transfer between the lanthanide ions, and it was found that Yb₂O₃ is an interesting host for the shell and it produce an increased lifetime and low pump power needed for UC. Lu et al. (2008) investigated Tm³⁺, Yb³⁺-doped Y₂O₃ NPs synthesized with the Pechini sol–gel technique, and coated with SiO₂ or TiO₂ shells using the Stober method. Larger NPs have stronger UC emission than smaller NPs and the core–shell structures are useful to enhance the UCL.

Guo et al. (2004) have investigated the UC properties of other sesquioxides, such as Tm³⁺, Er³⁺, and Yb³⁺-doped cubic phase Gd₂O₃ nanoparticles, prepared by the sol–gel technique. UC emission upon 980 nm laser excitation has been observed in the blue, green, and red regions with a relevant increase of the red emission with respect to the green one.

Nanocrystalline lanthanide-doped Lu₃Ga₅O₁₂ garnets have been prepared using a sol–gel technique and subsequent heat treatment at 900°C for 16 h in air, by Venkatramu et al. (2010). The aggregated nanomaterials showed an average particle size of 40 nm. These materials show higher luminescence intensities compared to that found for similarly doped sesquioxides (e.g., Y₂O₃) but also for other nanocrystalline garnets, as Gd₃Ga₅O₁₂ and Y₃Al₅O₁₂.

An interesting investigation on films composed by nanocrystalline lanthanide-doped YVO₄ nanoparticles was carried out by Yu et al. The films were prepared with a combined use of a Pechini sol–gel process and soft lithography (Yu et al. 2002). From x-ray diffraction analysis, it was found that the films began to crystallize at 400°C and the crystallinity was found to increase on increasing of the annealing temperatures. Starting from nonpatterned phosphor films, mainly consisting of grains with an average size of 90 nm, crystalline films of different thicknesses were obtained. Quite interestingly, the Sm³⁺-doped YVO₄ films also showed UCL upon laser excitation at 940 nm. In particular, anti-Stokes emissions from the ⁴G_5/2 excited state to the lower lying ⁶H_5/2, ⁶H_7/2, and ⁶H_9/2 states have been observed. As the ⁶F_11/2 level of Sm³⁺ has a very short lifetime, ESA transitions starting from the ⁶F_11/2 energy level have a low probability and the authors proposed that the most probable UC mechanisms could be an energy transfer between Sm³⁺ ions.

3.3.5  Combustion

Combustion synthesis includes controlled explosion reactions and one important advantage of this technique is that the reaction products can be generated in few minutes. Usually, these reactions involve highly exothermic processes that are started by a heat source, to reach temperatures up to 3000°C in the form of a self-sustained combustion propagating through the materials. This technique is most usually considered to synthesize oxide-based upconverting nanoparticles.

Upconverting lanthanide-doped sesquioxides (e.g., Y₂O₃, Lu₂O₃, and Gd₂O₃) prepared by the combustion (or propellant) technique have been investigated by Capobianco et al. in several papers published in the last decade. The first paper on upconverting Er³⁺-doped nanocrystalline Y₂O₃ appeared in the literature in the year 2000, describing the UC emission of the Er³⁺ ions under laser excitation at 815 nm (Capobianco et al. 2000). The sample was prepared by combustion synthesis, using glycine as a fuel. A further heat treatment at 500°C was needed to decompose the residual nitrate ions. The decay times for the Er³⁺ excited levels obtained for the nanocrystalline sample were found to be in general significantly longer than those observed for the bulk counterpart, due to increased multiphonon relaxation caused by CO₂ and water absorbed onto the surface of the nanosized sample. The same preparation technique was also used to prepare Ho³⁺-doped Y₂O₃ nanopowders, in order to compare the UC properties with those of the bulk counterpart.

An interesting analysis about the morphological structure of lanthanide-doped Lu₂O₃ powders obtained by propellant synthesis has been carried out by Polizzi et al. (2004). The samples showed a very porous, open morphology with fractal scaling properties. The building blocks of the fractal aggregates are lanthanide-doped cubic Lu₂O₃ crystalline particles with 60–90 nm of average size, which exhibit changes in the lattice parameter proportional to the lanthanide ionic radius. A similar morphological structure was also found for nanocrystalline Y₂O₃ prepared with the same combustion method (Polizzi et al. 2001).

The spectroscopic properties of Er³⁺, Yb³⁺-doped Gd₂O₃ nanoparticles prepared by combustion synthesis have been investigated by Singh et al. (2008, 2009), the samples were prepared using urea as the fuel. The solution containing the precursors was heated at 60°C to evaporate water, becoming a gel and this gel was transferred to a furnace and maintained at 500°C until the auto-ignition started and a voluminous structure formed. Changes in the color and the intensity of the UC emission were observed and attributed to the monoclinic to cubic structural transformation in the Gd₂O₃ nanoparticles due to a postsynthesis heat treatment of the sample at 600°C and 900°C. The upconverting Gd₂O₃ nanopowders were found to be also useful for optical thermometry, by considering the Er³⁺ UC emission in the green region from the two thermally coupled excited states ²H_11/2 and ⁴S_3/2 of Er³⁺, centered at wavelengths of 523 and 548 nm. In the 300–900 K temperature range, the maximum sensitivity derived from the fluorescence intensity ratio technique of the green UC emission is approximately 0.0039 K⁻¹.

Garnets hosts were also considered as hosts for upconverter nanomaterials. Capobianco et al. investigated Er³⁺-doped and Tm³⁺ and Yb³⁺ codoped Gd₃Ga₅O₁₂ (GGG) prepared by the combustion synthesis using glycine as the fuel. This garnet host resulted to be much less prone to incorporate water and CO₂ on the particle surface with respect to sesquioxides, with great benefit to the lanthanide emission properties, increased by a less pronounced nonradiative decay due to water phonons. NIR to visible UC of the nanocrystalline Er³⁺-doped Gd₃Ga₅O₁₂ was studied following excitation of the ⁴I_9/2 exited state upon 800 nm laser excitation (Vetrone et al. 2003). It was found that if the Er³⁺ doping is low (around 1%) ESA was the predominant mechanism responsible for populating the upper emitting states. However, as the Er³⁺ concentration was increased to 5%, the decay times for the UC emissions were lengthened and deviated from exponentiality, suggesting the presence of ETU. The 1% each Tm³⁺ and Yb³⁺ codoped Gd₃Ga₅O₁₂ nanostructured sample showed strong UC emission in the UV (¹D₂ → ³H₆), blue (¹D₂ → ³F₄), blue-green (¹G₄ → ³H₆), red (¹G₄ → ³F₄), and NIR (¹G₄ → ³H₅/³H₄ → ³H₆) regions upon excitation of the Yb³⁺ ions with a 980 nm laser radiation (Pandozzi et al. 2005). Due to subsequent energy transfers from the Yb³⁺ ion to the Tm³⁺ ions (energy transfer efficiency about 0.576).

3.3.6  Ionic Liquids

Ionic liquids (ILs) are considered nowadays interesting materials for preparation of inorganic materials as a “green” alternative to the conventional solvents (Lorbeer et al. 2010, 2011). They have unique properties, as thermal and chemical stability, a wide electrochemical window. Moreover, ILs can act as capping agents or surfactants in the inorganic synthesis. Although ILs are very useful for nanoparticles preparation, a certain amount of agglomeration of the prepared nanoparticles is one of the main drawbacks of the technique.

In the past few years, some papers have appeared in the literature to prepare upconverting nanomaterials using the ILs technique, succeeding also to generate various nanocrystal sizes and morphologies. Eu³⁺-doped GdF₃ nanoparticles have been prepared by the ILs technique by Lorbeer et al. (2010) with a microwave reaction starting from the lanthanide acetates. Fast and efficient synthesis of small, uniform, oxygen-free lanthanide nanofluorides with excellent luminescence has been achieved and a quantum efficiency of up to 145% was determined. Moreover, the same group succeeded in preparing pure, oxygen-free hexagonal EuF₃ nanoparticles by reacting europium acetate hydrate with PF₆ and BF₄ ILs at 120°C using microwave synthesis, with reaction times as short as 30 s (Lorbeer et al. 2011). Extremely small particles (<15 nm) were obtained and the morphology varied from nearly spherical and cuboid to rodlike crystallites forming larger clusters. Very interestingly, the size and shape varied in different ILs. Lanthanide-doped YF₃ nanoparticles were prepared by Nuñez and coworkers using BmimBF₄ as the fluoride source (Nuñez and Ocaña 2007). In most cases, highly uniform NPs were obtained and their size could be varied in the nanometer range by adjusting the nature and concentration of the starting lanthanide precursors. Zhang et al. (2008) have synthesized a series of lanthanide fluoride nanocrystals in three ILs (i.e., OmimPF₆, OmimBF₄, and BmimPF₆), utilizing the partial hydrolysis of PF₆⁻ and BF₄⁻ to introduce a fluoride source. Lanthanum fluoride nanocrystals can be obtained in a large amount (products up to 0.15 g per 10 mL solvents) with the ILs technique. Interestingly, in these “all-in-one” systems, the ILs acted as solvents, reaction agents, and templates. Regarding different upconverting fluorides, water-soluble and pure hexagonal-phase Yb³⁺ or Er³⁺ and Tm³⁺-doped NaYF₄ nanoparticles were successfully obtained by Liu et al. (2009) with use of a IL, BmimBF₄, which acts as solvent, template, and also fluorine source. One interesting advantage of the obtained nanocrystals is that the ILs overlayer on their surface renders them directly dispersed in water.

Spherical NaYF₄ nanoclusters have been synthesized using an IL (1-butyl-3-methylimidazolium tetrafluoroborate) based technique using a microwave reaction system. The nanoclusters have diameters ranging from 200 to 430 nm and are formed by the self-assembly of smaller NaYF₄ nanoparticles. Quite interestingly, the size of the nanoclusters could be easily controlled by variations of the precursor amounts. It was demonstrated that the ILs have key roles as solvents for the reaction, absorbents of microwave radiation, and the main fluorine sources for the NaYF₄ generation. The obtained nanoclusters exhibit excellent UC properties.

An interesting approach combining more synthetic techniques was introduced by He et al. (2011) to prepare lanthanide-doped upconverting NaGdF₄ nanocrystals with various crystalline structures. This approach used an OA/IL two-phase system that combined the advantages of the thermal decomposition and ILs techniques, exploiting the two-phase approach in the OA- and IL-phase through a one-step controllable reaction.

Figure 3.4   (a) Representation showing dopant ions in KGdF4 host and the crystal defects for the core-only nanoparticles. (b) Schematization of the core–shell nanoparticles. (c) TEM image of the KGdF4:Tm3+, Yb3+ core-only nanoparticles. (d, e) TEM images of the KGdF4:Tm3+, [email protected] core–shell nanoparticles showing an increase in the particles size. (f) TEM size distributions for the KGdF4:Tm3+, Yb3+ core-only nanoparticles and (g) the KGdF4:Tm3+, [email protected] core–shell nanoparticles. (Wong, H.-T., F. Vetrone, R. Naccache, H. L. W. Chan, J. Hao, and J. A. Capobianco. 2011. Water dispersible ultra-small multifunctional KGdF4:Tm3+, Yb3+ nanoparticles with near-infrared to near-infrared upconversion. J. Mater. Chem. 21 (41):16589–16596. Reproduced by permission of The Royal Society of Chemistry.)

3.4.1  Silica-Shell Formation

Nanoparticles tailored for biological imaging applications need to provide stable suspension in water and buffered solutions, and often the possibility to introduce chemical functionalities for biomolecule targeting. Most of the “as-prepared” lanthanide-doped nanoparticles are capped with hydrophobic molecules such as oleate (Li et al. 2008) or OM (Chan et al. 2012), and for this reason, several approaches were developed to increase the polarity of the nanoparticle surface to obtain water dispersibility. An overview of these synthetic approaches has been recently reviewed in focused publications (Muhr et al. 2014; Sedlmeier and Gorris 2014). Silica encapsulation offers the possibility to endow lanthanide-doped nanocrystals with a surface material that is hydrophilic, transparent to radiation and photophysically inert, simple to functionalize, and intrinsically nontoxic (Arap et al. 2013; Bonacchi et al. 2011; Genovese et al. 2014). The shell usually does not affect the emission efficiency of the nanocrystals, and actually in some cases improves it. Beside this behavior, silica can be independently doped with other fluorophores or contrast agents (Qian et al. 2009), or drugs to develop multimodal imaging or theranostic tools: this possibility is fostered by mesoporous silica shells (Li et al. 2013; P. Yang et al. 2012), formed adding to the synthetic mixture surfactant agents like CTAB (Liu et al. 2012; Qian et al. 2009).

Figure 3.6   Schematization of the cation exchange process to form NaYF4:Yb, [email protected] core–shell nanoparticles. (Dong, C., A. Korinek, B. Blasiak, B. Tomanek, and F. C. J. M. van Veggel. 2012. Cation exchange: A facile method to make NaYF4:Yb3+, [email protected] [email protected] nanoparticles with a thin, tunable, and uniform shell. Chem. Mater. 24 (7):1297–1305. Reproduced by permission of The Royal Society of Chemistry.)

A few synthetic approaches are available to cover lanthanides-doped nanosystems: nanoparticles presenting hydrophobic capping agents are frequently coated using a reverse microemulsion approach (water-in-oil) (Jalil and Zhang 2008). Silica coating involves an increase of the nanoparticles average diameter, a process that may cause some loss of monodispersity of the starting material: for this reason, most of the reports adopt this approach, starting from very monodisperse OA-capped nanocrystals and using the microemulsion method for silica shell formation, that guarantees nanocrystals core confinement within the reverse micelles of the microemulsion (Li et al. 2008). Shell thickness can be varied mainly acting on the amount of tetrathoxysilane introduced in the microemulsion and/or on the surfactant-to-water ratio, the main parameter affecting the number of reverse micelles within the microemulsion.

In a recent example, Li et al. (Zhu et al. 2014) developed a NIR-to-NIR emitting imaging (Figure 3.7).

Lanthanide-doped core was synthesized by a solvothermal method (average diameter 20 nm), and during the silica coating step ethoxysilane functionalized PEG (PEG–siloxane) was added into the microemulsion to achieve PEGylation (final hydrodynamic diameter ~65 nm).

Hydrophilic nanocrystals are usually coated in water–alcohol mixtures using a Stöber approach (Stöber et al. 1968). With this strategy, Wolfbeis et al. (Mader et al. 2010) faced the coating of lanthanide-doped nanoparticles and microparticles with average diameters spanning from 50 nm to 15 µm. They adopted a click chemistry-based strategy to functionalize the surface of the nano- and microparticles with a few “click reagents” and alkyne-modified fluorescent dyes.

Figure 3.7   TEM images of (a) NaYF4:Yb, Tm UCNPs and (b) NaYF4:Yb3+, [email protected] nanoparticles modified with PEG (PEG-UCNPs), and room temperature UCL spectrum of PEG-UCNPs in water (5 mg/mL, λex = 980 nm). (Zhu, X., B. Da Silva, X. Zou, B. Shen, Y. Sun, W. Feng, and F. Li. 2014. Intra-arterial infusion of PEGylated upconversion nanophosphors to improve the initial uptake by tumors in vivo. RSC Adv. 4 (45):23580–23584. Reproduced by permission of The Royal Society of Chemistry.)

The silica modification quite often produces systems that are prone to aggregation processes and unspecific binding, and for this reason just the formation of an ultrathin silica shell of few nanometers (Li and Zhang 2006; F. Liu et al. 2013) or proper functionalization treatments (Bagwe et al. 2006) were developed.

Polymer-coated lanthanide-doped nanoparticles can also be coated by a silica shell, since some polymers such as PVP (Li and Zhang 2006) favor the condensation of a silica layer. This approach moves toward more direct coating protocols since PVP is often used as a stabilizing agents in many hydrothermal syntheses. Surface modification can be carried out during the growth of the silica shell or after its formation, and besides colloidal stabilization endow nanoparticles with moieties bearing –NH₂ (M. Wang et al. 2009), –COOH (F. Liu et al. 2013), –SH (Y. Yang et al. 2012), or functional groups for click chemistry (Mader et al. 2010).