Fe- and Ln-DOTAm-F12 Are Effective Paramagnetic Fluorine Contrast Agents for MRI in Water and Blood.

A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is LaIII, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, TmIII, YbIII, and FeII, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic 19F probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantial-up to 100-fold-decrease in the longitudinal relaxation time (T1) of the fluorine nuclei. The shorter T1 allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T2/T1 ratio. In water, the optimal metal complexes for imaging applications are those containing HoIII and FeII, and to a lesser extent TmIII and YbIII. Whereas T1 of the lanthanide complexes are little affected by blood, the T2 are notably shorter in blood than in water. The sensitivity of Ln-DOTAm-F12 complexes is lower in blood than in water, such that the most sensitive complex in water, HoIII-DOTAm-F12, could not be detected in blood. TmIII yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of FeII-DOTAm-F12 are similar in water and in blood. That complex has the highest T2/T1 ratio (0.57) and the lowest limit of detection (300 µM) in blood. The combination of high water solubility, single fluorine signal, and high T2/T1 of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.

Polyphosphoric acid capping radioactive/upconverting NaLuF4:Yb,Tm,153Sm nanoparticles for blood pool imaging in vivo.

Nanoparticles that circulate in the bloodstream for a prolonged period of time have important biomedicine applications. However, no example of lanthanide-based nanoparticles having a long-term circulation bloodstream has been reported to date. Herein, we report on difunctional radioactive and upconversion nanoparticles (UCNP) coated with polyphosphoric acid ligand, that is ethylenediamine tetramethylenephosphonic acid (EDTMP), for an application in single-photon emission computed tomography (SPECT) blood pool imaging. The structure, size and zeta-potential of the EDTMP-coated nanoparticles (EDTMP-UCNP) are verified using transmission electron microscopy and dynamic light scattering. Injection of radioisotope samarium-153-labeled EDTMP-UCNP (EDTMP-UCNP:(153)Sm) into mice reveal superior circulation time compared to control nanoparticles coated with citric acid (cit-UCNP:(153)Sm) and (153)Sm complex of EDTMP (EDTMP-(153)Sm). The mechanism for the extended circulation time may be attributed to the adhesion of EDTMP-UCNP on the membrane of red blood cells (RBCs). In vivo toxicity results show no toxicity of EDTMP-UCNP at the dose of 100 mg/kg, validating its safety as an agent for blood pool imaging. Our results provide a new strategy of nanoprobe for a long-term circulation bloodstream by introducing polyphosphoric acid as surface ligand.

ICP-MS analysis of lanthanide-doped nanoparticles as a non-radiative, multiplex approach to quantify biodistribution and blood clearance.

Recent advances in material science and chemistry have led to the development of nanoparticles with diverse physicochemical properties, e.g. size, charge, shape, and surface chemistry. Evaluating which physicochemical properties are best for imaging and therapeutic studies is challenging not only because of the multitude of samples to evaluate, but also because of the large experimental variability associated with in vivo studies (e.g. differences in tumor size, injected dose, subject weight, etc.). To address this issue, we have developed a lanthanide-doped nanoparticle system and analytical method that allows for the quantitative comparison of multiple nanoparticle compositions simultaneously. Specifically, superparamagnetic iron oxide (SPIO) with a range of different sizes and charges were synthesized, each with a unique lanthanide dopant. Following the simultaneous injection of the various SPIO compositions into tumor-bearing mice, inductively coupled plasma mass spectroscopy (ICP-MS) was used to quantitatively and orthogonally assess the concentration of each SPIO composition in serial blood samples and the resected tumor and organs. The method proved generalizable to other nanoparticle platforms, including dendrimers, liposomes, and polymersomes. This approach provides a simple, cost-effective, and non-radiative method to quantitatively compare tumor localization, biodistribution, and blood clearance of more than 10 nanoparticle compositions simultaneously, removing subject-to-subject variability.

A generic biokinetic model for predicting the behaviour of the lanthanide elements in the human body.

Information on the biokinetics of the 15 elements of the lanthanide series, 57La to 71Lu, is too sparse to permit individual development of meaningful biokinetic models to describe the behaviour of each of the elements in humans. The lanthanides show a regular gradation in chemical properties across the series, and animal studies indicate that this is reflected in regular differences in their deposition in tissues such as the liver and skeleton. These regular differences in chemical and biological behaviour have been utilised to construct a generic lanthanide biokinetic model and to define element-specific parameters for each element in the series. This report describes the use of the available biokinetic data for humans and animals to derive the parameters for each of the elements.