Colloidal nanothermometers based on neodymium doped alkaline-earth fluorides in the first and second biological windows
Introduction
Nanomaterials activated with lanthanide ions are finding increasing importance in many technological fields, including biomedicine, in particular for in-vitro and in-vivo optical imaging [1], [2] controlled drug or payload delivery [3], photodynamic therapy [4] and for photothermal therapy (hyperthermia) for cancer treatment [5], [6]. In the context of photothermal therapy (in-situ conversion of light into heat), a continuous and local monitoring of the temperature of the treated tissues is crucial so as to obtain a sufficient temperature to kill cancer cells without harming healthy tissues in the vicinity.
Luminescent nanothermometers with high photostability and thermal sensitivity are being investigated for in-vivo temperature monitoring [7], [8], [9], [10]. Particularly, nanothermometers based on lanthanide doped nanoparticles (NPs) are increasing in popularity, due to the atypical 4f electronic energy level structure of the dopant lanthanide ions and their luminescence covering the entire optical spectral range. Since the population of close lying excited levels can depend on the temperature according to the Boltzmann distribution law, the lanthanide emission intensities generated by these coupled energy levels can change as a function of the temperature. In the case of lanthanides, emission bands are narrow and well-defined. Consequently, relative emission intensities of close energy states can be measured accurately, and only a short range of wavelengths needs to be recorded, two characteristics that facilitate their implementation in in-vivo situations. Nanothermometers based on the Yb3+ (sensitizer) and Er3+ (activator) dopant pair have been often proposed [11]. In these cases, the thermometer is based on the relative upconverted intensities of the Er3+ ions emission centred at 520 and 540 nm (following excitation at 980 nm) corresponding to transitions from the thermally coupled 2H11/2 and 2S3/2 excited states. In the case of the Yb3+, Tm3+ couple, upconverted emission bands around 800 nm, also excited at 980 nm with a laser, may undergo variations with temperature, as evidenced for the CaF2:Tm3+, Yb3+ host, due to thermal coupling of the Stark sublevels of the 3H4 state of Tm3+ ions [12].
A different alternative to pairs of lanthanide ions, in particular those excited with 980 nm, can be found in Nd3+ singly doped NPs, since the Nd3+ ion has recently been studied as an efficient emitter in the near infrared region (NIR) and particularly in the first (I-BW, 800–950 nm) and in the second (II-BW, 1000–1300 nm) biological windows [13], [14], [15]. These optical regions are interesting for in-vivo imaging as radiation absorption by biological tissues is very low, permitting a deeper penetration of the exciting and emitted radiations [16]. Moreover, the Nd3+ ion can be excited at 800 nm, in the I-BW where the absorption by biological tissues is approximately 25 times lower than for excitation at 980 nm, typically used to excite the Yb3+ ion in the formerly mentioned systems. Recent studies have also shown how the Nd3+ ion can find applications in optical temperature sensors by monitoring transitions among the two highest energy 4F3/2 Stark levels and the underlying 4I11/2 and 4I9/2 energy levels [17]. It is worth to remark that some Nd3+ transitions can be classified among the so-called hypersensitive transitions, i.e. transitions that exhibits a relatively strong sensitivity of the oscillator strength with respect to the local environment of the lanthanide ion [18], [19]. This behavior can be accounted for by particular high values of the U(2) and U(4) reduced matrix elements for hypersensitive transitions [20]. In particular, the 4I9/2 → 4G5/2 transition, located in the visible region around 17500 cm−1 has been recognised to be hypersensitive, as reported by Ansari et al. in a paper demonstrating the effect of the environment on hypersensitive transitions of Nd3+ complexes, that have been dissolved in different solvents [21]. Nonetheless, other Nd3+ bands show hypersensitivity, as illustrated below.
Inorganic fluorides, such as NaYF4, NaGdF4, LiYF4 or alkaline-earths fluorides (such as CaF2 [22], [23], [24], [25] and SrF2 [26], [27], [28], [29]) are known to be excellent materials to host lanthanide ions, in particular for upconversion luminescence [30]. In fact, they have low phonon energies that are important to reduce non-radiative relaxation processes of the excited states, improving the luminescence efficiency [31], [32]. Alkaline-earths fluorides have also demonstrated to be biocompatible [33], [34], a characteristic that is essential for possible use in biological fluids. In particular, lanthanide doped SrF2 NPs show strong luminescence in the optical region, and can be prepared by a facile hydrothermal method at low reaction temperatures (<200 °C) [35].
In this investigation, the target is to develop new Nd3+ based optical nanothermometers based on the SrF2 host and investigate their temperature dependent spectroscopic properties as optical nanothermometers in the biological windows. The thermal sensitivity was determined by a ratiometric technique, analyzing the ratio between the intensity of the emissions due to transitions among the 4F3/2 Stark levels and the 4I11/2 excited level or 4I9/2 ground state of the Nd3+ ion. Here, we also compare the spectroscopic properties of Nd3+ and Nd3+, Gd3+ codoped samples, in order to highlight the differences in the spectroscopic properties where Gd3+ ions were introduced in the crystalline host to produce NPs that can be useful as MRI contrast agents, as already observed for similar nanocrystalline compounds [33], [36].
Section snippets
Synthesis
Nd3+ doped SrF2 NPs (Nd3+/Sr2+ = 0.0309 nominal metal ratio) and Gd3+, Nd3+ codoped SrF2 (Nd3+/Sr2+ = 0.0385, Gd3+/Sr2+ = 0.244 nominal metal ratios) and were synthesized by a hydrothermal technique by Pedroni et al. [37]. Stoichiometric quantities of SrCl2·6H2O (Carlo Erba, >99%), GdCl3·6H2O (Aldrich, 99%), NdCl3·6H2O (Aldrich, 99.9%) were dissolved in 7 ml of deionized water in a 50 ml Teflon vessel. Then, 20 ml of a 1 M potassium citrate tribasic monohydrate (Aldrich, >99%) aqueous solution was added
Structural and ICP analysis
The obtained SrF2:Gd3+,Nd3+, and SrF2:Nd3+ NPs have a cubic phase (Space group n. 225, Fmm) as demonstrated by the XRPD patterns, shown in Fig. 1 and Fig. S1 (Supporting Information section), with no presence of other impurity phases. From the XRPD pattern for the SrF2: Gd3+,Nd3+ NPs, using the Debye-Scherrer formula for cubic structures, a lattice parameter of 5.762(1) Å is calculated for the NPs. This value of the lattice parameter is slightly smaller than for undoped SrF2 sample, that
Conclusions
Nd3+ or Nd3+,Gd3+ doped SrF2 NPs were investigated for possible use as nanothermometers. The synthesis is carried out using a facile hydrothermal technique, with citrate ions as hydrophilic capping agents. The prepared NPs are efficiently dispersed in water and in saline solutions, suggesting their possible use in biomedical applications. From spectroscopic investigations in the NIR region, in particular in the I-BW and II-BW, it was found that the NPs exhibit intense emission from the Nd3+
Acknowledgements
A. Speghini and P. Cortelletti thank University of Verona, Italy, for financial support in the framework of the project “Ricerca di Base 2015”. F. Vetrone acknowledges the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Fonds de recherche du Québec − Nature et technologies (FRQNT) for supporting his research.
Marco Pedroni received his PhD in Nanotechnology and Nanomaterials in Biomedical Applications from the University of Verona in 2012. Currently he is a post-doc at the Department of Biotechnology, University of Verona. His research interests focus on the development and characterization of inorganic luminescent nanomaterials.
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Marco Pedroni received his PhD in Nanotechnology and Nanomaterials in Biomedical Applications from the University of Verona in 2012. Currently he is a post-doc at the Department of Biotechnology, University of Verona. His research interests focus on the development and characterization of inorganic luminescent nanomaterials.
Paolo Cortelletti is a PhD student at the University of Verona, Italy. His current interests are on nanothermometry and upconversion properties of lanthanide doped fluoride nanomaterials.
Irene Xochilt Cantarelli received her PhD in Nanotechnology and Nanomaterials in Biomedical Applications from the University of Verona in 2015.
Nicola Pinna is Professor at the Institut für Chemie, Humboldt-Universität zu Berlin, Berlin, Germany. The actual research focuses on nanostructured materials, mainly dealing with the synthesis of nanomaterials by solution and gas phase routes, their characterization and the study of their physical properties.
Patrizia Canton is Patrizia Canton is an Associate Professor at Ca' Foscari University of Venice, Italy, Department of Molecular Sciences and Nanosystems. Her research interests focus on materials characterisation by means of electron microscopy and quantum dots materials.
Marta Quintanilla received her PhD in Physics at the Universidad Autonoma de Madrid, Madrid, Spain. She has a post-doc position CIC biomaGUNE, Donostia/San Sebastián, Gipuzkoa. Spain. Currently, her research interests focus on Plasmonic Heaters Linked to Lanthanide-Based Nanothermometers for Photodynamic Therapy in the Near-Infrared.
Fiorenzo Vetrone is an Associate Professor at the Centre Énergie Matériaux Télécommunications, Institut National de la Recherche Scientifique, Université du Québec, Canada. His research interests focus on the development of multifunctional nanoplatforms excited by near-infrared light for applications in biology and nanomedicine.
Adolfo Speghini is an Associate Professor of Inorganic Chemistry at the University of Verona, Italy, Department of Biotechnology. His research interests focus on the chemistry of luminescent nanomaterials and development of organic-inorganic nanostructures for biotechnology and medicine.