We report a simple, yet effective method to disperse NaYF4 nanocrystals (NCs) doped with luminescent Ln3+ ions in water and physiological buffers using an amphiphilic polymer poly(ethylene glycol) monooleate. These water-dispersible NCs were used for in vivo imaging by employing two-photon upconversion laser scanning microscopy (TPULSM) and two-photon upconversion wide field microscopy (TPUWFM) techniques. Using the 800 nm upconverted emission from Tm3+ ions, we show that (i) TPULSM imaging can be performed up to a depth of ∼600 μm inside an agar-milk gel tissue phantom and (ii) the edges of the object can still be identified. At depths beyond 600 μm, we observed a drastic decrease in the lateral resolution. Images of a mouse lung tissue obtained using this technique resulted in a lateral resolution with which we could observe the capillaries surrounding the alveoli air caps. The images lacked optical sectioning due to the high power density (∼2000 W/cm2) necessary to achieve an adequate signal-to-noise ratio. In addition, the time taken to obtain these images was prolonged because of the slow scanning speed necessitated by the long lifetimes and the poor quantum yield of the upconversion process. Conversely, in vivo TPUWFM imaging using the same 800 nm emission of brain blood vessels of a mouse after skull thinning gave excellent lateral resolution to differentiate blood vessels separated by a few micrometers. In addition to this, optical sectioning was observed over a depth of 100 μm, which is the first instance of optical sectioning shown in in vivo imaging employing Ln3+-doped NCs as imaging agents. Experiments with the aforementioned tissue phantom showed that imaging up to a depth of ∼400 μm could be obtained with the 800 nm emission from Tm3+/Yb3+ codoped NaYF4 NCs with a lateral resolution that allows us to distinguish micrometer-sized biological structures. In contrast, when employing the green upconverted emission from Er3+/Yb3+ codoped NaYF4 NCs, lateral resolution was completely lost at a depth of ∼300 μm.
Ligands on the nanoparticle surface provide steric stabilization, resulting in good dispersion stability. However, because of their highly dynamic nature, they can be replaced irreversibly in buffers and biological medium, leading to poor colloidal stability. To overcome this, we report a simple and effective cross-linking methodology to transfer oleate-stabilized upconverting NaYF(4) core/shell nanoparticles (UCNPs) from hydrophobic to aqueous phase, with long-term dispersion stability in buffers and biological medium. Amphiphilic poly(maleic anhydride-alt-1-octadecene) (PMAO) modified with and without poly(ethylene glycol) (PEG) was used to intercalate with the surface oleates, enabling the transfer of the UCNPs to water. The PMAO units on the phase transferred UCNPs were then successfully cross-linked using bis(hexamethylene)triamine (BHMT). The primary advantage of cross-linking of PMAO by BHMT is that it improves the stability of the UCNPs in water, physiological saline buffers, and biological growth media and in a wide range of pH values when compared to un-cross-linked PMAO. The cross-linked PMAO-BHMT coated UCNPs were found to be stable in water for more than 2 months and in physiological saline buffers for weeks, substantiating the effectiveness of cross-linking in providing high dispersion stability. The PMAO-BHMT cross-linked UCNPs were extensively characterized using various techniques providing supporting evidence for the cross-linking process. These UCNPs were found to be stable in serum supplemented growth medium (37 °C) for more than 2 days. Utilizing this, we demonstrate the uptake of cross-linked UCNPs by LNCaP cells (human prostate cancer cell line), showing their utility as biolabels.
Colloidal upconverter nanocrystals (UCNCs) that convert near-infrared photons to higher energies are promising for applications ranging from life sciences to solar energy harvesting. However, practical applications of UCNCs are hindered by their low upconversion quantum yield (UCQY) and the high irradiances necessary to produce relevant upconversion luminescence. Achieving high UCQY under practically relevant irradiance remains a major challenge. The UCQY is severely limited due to non-radiative surface quenching processes. We present a rate equation model for migration of the excitation energy to show that surface quenching does not only affect the lanthanide ions directly at the surface but also many other lanthanide ions quite far away from the surface. The average migration path length is on the order of several nanometers and depends on the doping as well as the irradiance of the excitation. Using Er3+-doped β-NaYF4 UCNCs, we show that very isotropic and thick (∼10 nm) β-NaLuF4 inert shells dramatically reduce the surface-related quenching processes, resulting in much brighter upconversion luminescence at simultaneously considerably lower irradiances. For these UCNCs embedded in poly(methyl methacrylate), we determined an internal UCQY of 2.0% ± 0.2% using an irradiance of only 0.43 ± 0.03 W/cm2 at 1523 nm. Normalized to the irradiance, this UCQY is 120× higher than the highest values of comparable nanomaterials in the literature. Our findings demonstrate the important role of isotropic and thick shells in achieving high UCQY at low irradiances from UCNCs. Additionally, we measured the additional short-circuit current due to upconversion in silicon solar cell devices as a proof of concept and to support our findings determined using optical measurements
In this feature article we will critically discuss the synthesis and characterisation aspects of Ln(3+)-doped nanoparticles (NPs) that show upconversion, upon 980 nm excitation. Upconversion is a non-linear process that converts two or more low-energy photons, often near-infrared photons, into one of higher energy, e.g. blue and 800 nm from Tm(3+) and green and red from Er(3+) or Ho(3+). Nearly all researchers use the absorption of 980 nm light by Yb(3+) as the sensitiser for the co-doped emissive Ln(3+) ions. The focus will be on LnF(3) and MLnF(4) (M = alkali metal) as the host matrix, because most progress has been made with these. In particular we will argue that a detailed understanding of how the dopant ions and the host Ln(3+) ions are distributed (in the core) and how (doped) shell growth occurs is not well understood. Moreover, their use as optical and magnetic resonance imaging contrast agents will be discussed. We will argue that deep-tissue imaging beyond 600 μm with retention of optical resolution, i.e. to see fine structure such as blood capillaries in brain tissues, has not yet been achieved. Three key parameters have been identified as impediments: (i) the low absorption efficiency of the Yb(3+) sensitiser, (ii) the low quantum yield of upconversion, and (iii) the long-lived excited states. On the other hand, there are very encouraging results that suggest that these nanoparticles could be developed into very potent magnetic resonance imaging (MRI) contrast agents.
Poly(acrylic acid) consisting of 25 monomer units (PAA 25 ) was used to stabilize nanoparticle aggregates (NPAs) consisting of either NaGdF 4 or 50/50 mixtures of GdF 3 and CeF 3 . The resulting polymer-stabilized nanoparticle aggregates (NPAs) were developed and tested for their application as contrast agents for magnetic resonance imaging (MRI) and computed tomography (CT). The PAA 25 -stabilized NPAs exhibit low polydispersity and are colloidally stable at concentrations of 40 mg/mL, while their sizes can be be controlled by choosing a specific ratio of Gd 3þ to Ce 3þ . Scanning transmission electron microscopy (STEM) reveals that NaGdF 4 NPAs possess an average diameter of 400 nm. High-resolution STEM and powder X-ray diffraction (XRD) both show that these NPAs consist of a stable aggregate of smaller NPs, whose diameters are 20-22 nm. PAA 25stabilized NPAs consisting of a 50/50 mixture of GdF 3 and CeF 3 possess an average diameter of 70 nm, while the fundamental unit size is estimated to be 10-12 nm in diameter. The PAA 25 -stabilized GdF 3 /CeF 3 NPAs possess mass relaxivities of 40 ( 2 and 30 ( 2 s -1 (mg/mL) -1 at 1.5 T and 3.0 T, respectively. Their effectiveness as contrast agents for CT X-ray imaging at various X-ray energies was also tested and compared to that of equivalent mass concentrations of Gd 3þ -diethylene triamine pentaacetic acid (Gd 3þ -DTPA) and iopromide. Gd-based NPAs exhibit superior CT contrast to equal-mass concentrations of either iopromide or Gd 3þ -DTPA below 30 keV and above 50 keV. Finally, PAA 25 was functionalized by folic acid to explore targeted imaging. Confocal microscopy revealed that, by functionalizing the PAA 25 -stabilized NaGdF 4 :Tb 3þ NPAs with ∼0.8 folates per polymer, binding and endocytosis occurred in SK-BR-3 human breast cancer cells. The utility of the PAA 25 -stabilized GdF 3 /CeF 3 NPAs for MRI is demonstrated in rat perfusion MRI experiments, where T 1 -weighted MRI images of equivalent concentrations of either Gd 3þ -DTPA or the above NPAs are directly compared. The high relaxivities provide an opportunity to conduct perfusion MRI experiments with significantly lower concentrations than those needed for current commercial agents.
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