Frank C. J. M. van Veggel

Magnetic resonance imaging (MRI) is widely used as a medical imaging technique due to its non-invasive nature, high spatial contrast, and virtually unlimited depth of penetration. Different modalities can be used for contrast in MRI, including T₁ (spin–lattice) and T₂ or T₂ * (spin–spin) proton relaxation times, and specific contrast agents (CAs) have been developed that locally enhance the contrasts in MRI images. We present a method combining T₁- and T₂-specific CAs in a single imaging technique, referred to as correlation MRI. This technique allows different CAs to be used simultaneously to visualize contrast between multiple types of tissue in the same image when applied as targeted CAs. An obstacle for the quantitative use of correlation MRI is that T₁ and T₂ relaxivity changes generated by CAs are not independent of each other. Here, we measured relaxivities in mixtures with various concentrations of Cas, including Magnevist (Gd³⁺-based, primarily a T₁ CA) and Feridex (Fe²⁺- and Fe³⁺-based, primarily a T₂ CA), and compared them to theoretically predicted values. It was found that, at clinically relevant concentrations, relaxivities of the mixtures deviate from linearly added values. We finally propose a three-dimensional calibration curve to quantitatively determine the concentration in mixtures of CAs, based on the measured relaxivities.

Temperature changes in plasmonic traps can affect biomolecules and quantum emitters; therefore, several works have sought out the capability of measuring the local temperature. Those works used ionic nanopore currents, fluorescence emission variations, and fluorescence-based diffusion tracking to measure the temperature dependence of shaped nanoapertures in metal films. Here, we make use of a stable erbium-containing NaYF₄ nanocrystal that gives local temperature dependence while trapped in the nanoaperture hot spot. Ratiometric analysis of the emission at different wavelengths gives local temperature variation. Since the gold film dominates the thermal characteristic, we find that films of thickness 70, 100, and 130 nm give 0.64, 0.37, and 0.25 K/mW temperature change with laser power. Therefore, using thicker films can be effective in reducing the heating when it is not desired.

Ionizing radiation has become widely used in medicine, with application in diagnostic techniques, such as computed tomography (CT) and radiation therapy (RT), where X-rays are used to diagnose and treat tumors. The X-rays used in CT and, in particular, in RT can have harmful side effects; hence, an accurate determination of the delivered radiation dose is of utmost importance to minimize any damage to healthy tissues. For this, medical specialists mostly rely on theoretical predictions of the delivered dose or external measurements of the dose. To extend the practical use of ionizing radiation-based medical techniques, such as magnetic resonance imaging (MRI)-guided RT, a more precise measurement of the internal radiation dose internally is required. In this work, a novel approach is presented to measure dose in liquids for potential future in vivo applications. The strategy relies on MRI contrast agents (CAs) that provide a dose-sensitive signal. The demonstrated materials are (citrate-capped) CaF₂ nanoparticles (NPs) doped with Eu³⁺ or Fe²⁺/Fe³⁺ ions. Free electrons generated by ionizing radiation allow the reduction of Eu³⁺, which produces a very small contrast in MRI, to Eu²⁺, which induces a strong contrast. Oxidative species generated by high-energy X-rays can be measured indirectly using Fe²⁺ because it oxidizes to Fe³⁺, increasing the contrast in MRI. Notably, in the results, a strong increase in the proton relaxation rates is observed for the Eu³⁺-doped NPs at 40 kV. At 6 MV, a significant increase in proton relaxation rates is observed using CaF₂ NPs doped with Fe²⁺/Fe³⁺ after irradiation. The presented concept shows great promise for use in the clinic to measure in vivo local ionizing radiation dose, as these CAs can be intravenously injected in a saline solution.

Temperature measurement in plasmonic traps is important because biological molecules and quantum emitters are sensitive to temperature. While other works have used ion pore currents, fluorescence emission variation, and fluorescent diffusion tracking to measure the temperature dependence of shaped nanoapertures in metal films, here we make use of a stable erbium (Er) containing NaYF₄ nanocrystals that gives local temperature dependence. The local temperature variation is determined by a ratiometric analysis of the emission at different wavelengths.

Gd- and Fe-based contrast agents reduce T₁ and T₂ relaxation times, respectively, are frequently used in MRI, providing improved cancer detection. Recently, contrast agents changing both T₁/T₂ times, based on core/shell nanoparticles, have been introduced. Although advantages of the T₁/T₂ agents were shown, MR image contrast of cancerous versus normal adjacent tissue induced by these agents has not yet been analyzed in detail as authors considered changes in cancer MR signal or signal-to-noise ratio after contrast injection rather than changes in signal differences between cancer and normal adjacent tissue. Furthermore, the potential advantages of T₁/T₂ contrast agents using image manipulation such as subtraction or addition have not been yet discussed in detail. Therefore, we performed theoretical calculations of MR signal in a tumor model using T₁-weighted, T₂-weighted, and combined images for T₁-, T₂-, and T₁/T₂-targeted contrast agents. The results from the tumor model are followed by in vivo experiments using core/shell NaDyF₄/NaGdF₄ nanoparticles as T₁/T₂ non-targeted contrast agent in the animal model of triple negative breast cancer. The results show that subtraction of T₂-weighted from T₁-weighted MR images provides additional increase in the tumor contrast: over two-fold in the tumor model and 12% in the in vivo experiment.

Single-photon sources are required for quantum technologies and can be created from individual atoms and atom-like defects. Erbium ions produce single photons at low-loss fiber optic wavelengths, but they have low emission rates, making them challenging to isolate reliably. Here, we tune the size of gold double nanoholes (DNHs) to enhance the emission of single erbium emitters, achieving 50× enhancement over rectangular apertures previously demonstrated. This produces enough enhancement to show emission from single nanocrystals at wavelengths not seen in our previous work, i.e., 400 and 1550 nm. We observe discrete levels of emission for nanocrystals with low numbers of emitters and demonstrate isolating single emitters. We describe how the trapping time is proportional to the enhancement factor for a given DNH structure, giving us an independent way to measure the enhancement. This shows a promising path to achieving single emitter sources at 1550 nm.