Ln3+-doped nanoparticles with enhanced NIR-II luminescence for lighting up blood vessels in mice.

Probes functioning in the second near-infrared window (1000-1700 nm, NIR-II) exhibit higher resolution and diminished auto-fluorescence compared to those in the traditional NIR region (700-950 nm). Here, we designed and synthesized rare earth ion doped probes with core/shell/shell structures and bright luminescence in the NIR-II region excited at 808 nm. With the doping of Ce3+ ions, the emission intensity of Er3+ at 1530 nm increased 10 times, while the upconversion luminescence decreased to less than 1%. After being modified with polyacrylic acid and polyethylene glycol, the as-obtained water-soluble probe exhibits continuous high-resolution for distinguishing 0.25 mm blood vessels even 10 h after injection. Noteworthily, the imaging of tumors was achieved by injecting the probe, indicating that the designed NIR-II probe has sufficient brightness and the ability to passively target tumor tissue.

Scandium, yttrium, and lanthanide contents in soil from Serbia and their accumulation in the mushroom Macrolepiota procera (Scop.) Singer.

The mobility (fractionation) of rare earth elements (REEs) and their possible impacts on ecosystems are still relatively unknown. Soil samples were collected from two sites in central Serbia, an unpolluted mountain region (site 1) and a forest near a city (site 2). In order to investigate REE fractions (acid-soluble/exchangeable, reducible, oxidizable, and residual) in soils, BCR sequential extraction was performed. Additionally, the content of REEs was also determined in stipes and caps of the mushroom Macrolepiota procera, growing in the observed sites. Sc, Y, and lanthanide contents were determined by inductively coupled plasma mass spectrometry (ICP-MS), and results were subjected to multivariate data analysis. Application of pattern recognition technique revealed the existence of two distinguished clusters belonging to different geographical sites and determined by greater levels of Sc, Y, and lanthanides in Goc soil compared to Trstenik soil. Additionally, PCA analysis showed that REEs in soil were concentrated in two groups: the first consisted of elements belonging to light REEs and the second contained heavy REEs. These results suggest that the distribution of REEs in soils could indicate the geographical origin and type of soil. The bioconcentration factors and translocation factors for each REE were also calculated. This study provides baseline data on the rare earth element levels in the wild edible mushroom M. procera, growing in Serbia. In terms of bioconcentration and bioexclusion concept, Sc, Y, and REEs were bioexcluded in M. procera for both studied sites.

Supramolecularly Engineered NIR-II and Upconversion Nanoparticles In Vivo Assembly and Disassembly to Improve Bioimaging.

Contrast agents for bioimaging suffer from low accumulation at lesion area and high uptake in the reticuloendothelial system (RES). Assembly of nanoparticles in vivo improves their enrichment at tumors and inflamed areas. However, uncontrollable assembly also occurs at the liver and spleen owing to the uptake of nanoparticles by the RES. This is known to probably cause a higher bioimaging background and more severe health hazards, which may hamper the clinical application. Herein, a new near-infrared (NIR)-controlled supramolecular engineering strategy is developed for in vivo assembly and disassembly between lanthanide upconversion nanoparticles and second near-infrared window (NIR-II, 1000-1700 nm) nanoprobes to realize precision bioimaging of tumors. A supramolecular structure is designed to realize assembly via host-guest interactions of azobenzene and ß-cyclodextrin to enhance the retention of NIR-II nanoprobes in the tumor area. Meanwhile NIR-laser-controllable nanoprobes disassembly brings about a reduction in the bioimaging background as well as acceleration of their RES clearance rate. This strategy may also be used in other nano-to-micro-scale contrast agents to improve bioimaging signal-to-noise ratio and reduce long-term cytotoxicity.

H4octox: Versatile Bimodal Octadentate Acyclic Chelating Ligand for Medicinal Inorganic Chemistry.

H4octox, a versatile new octadentate acyclic chelating ligand, has been investigated as an alternative to the acyclic DTPA and the macrocyclic DOTA for trivalent metal ions useful in diagnostic medical imaging or therapeutic applications (Y3+, In3+, La3+, Gd3+, Lu3+). The synthesis of H4octox is straightforward in less steps and thus more economical than those of most previously reported chelators. Complex formation equilibria in the presence of Y3+, In3+, La3+, Gd3+, and Lu3+ revealed fast chelation and high metal-sequestering capacity. Quantitative labeling with 111In3+ was achieved within 15 min at room temperature at ligand concentrations as low as 10-7 M, exactly the properties required for the development of kit-based radiopharmaceuticals. In vitro serum stability studies and in vivo SPECT imaging confirmed excellent complex stability of [111In(octox)]-. Moreover, it is more lipophilic than most of the multidentate carboxylate- or picolinate-based chelators; it therefore shows more liver clearance and provides a complementary choice in the design of metal-based pharmaceuticals and in the tuning of their pharmacokinetic properties. Finally, H4octox showed a large fluorescence enhancement upon complexation with different metals, in particular, with Y3+ and Lu3+, which could be useful for non-radioactive fluorescent stability and cell studies as well as bimodal imaging. Excellent in vitro stability of [Y(octox)]- against transferrin and Fe3+ was confirmed employing this fluorescence.

Kinetics-mediate fabrication of multi-model bioimaging lanthanide nanoplates with controllable surface roughness for blood brain barrier transportation.

Effective delivery of imaging agents or therapeutics to the brain has remained elusive due to the poor blood-brain barrier (BBB) permeability, resulting in the apparent risks of inefficient diagnosis and therapeutic agents for brain disease. Herein, we report on the surface roughness mediated BBB transportation for the first time. The lanthanide-based core/shell/shell structured NaYF4:Yb,Er@NaGdF4:Yb@NaNdF4:Yb nanoplates with controllable surface roughness and multi-model bioimaging features were synthesized and used to evaluate the surface roughness dependent BBB permeability without any surface bio-functionalization. By controlling the kinetics of the shell coating process, the hexagon-disc, multi-petals and six-petals nanoplates with different surface roughness can be obtained. Comparing with the NPs with less Ra and receptor-conjugated NPs, the obtained six-petals nanoplates with highest roughness exhibit excellent performance in BBB transportation and tumor targeting, which lay solid foundation for the diagnosis and the therapy of brain tumor.

Efficient Tailoring of Upconversion Selectivity by Engineering Local Structure of Lanthanides in Na(x)REF(3+x) Nanocrystals.

Efficient tailoring of upconversion emissions in lanthanide-doped nanocrystals is of great significance for extended optical applications. Here, we present a facile and highly effective method to tailor the upconversion selectivity by engineering the local structure of lanthanides in Na(x)REF(3+x) nanocrystals. The local structure engineering was achieved through precisely tuning the composition of nanocrystals, with different [Na]/[RE] ([F]/[RE]) ratio. It was found that the lattice parameter as well as the coordination number and local symmetry of lanthanides changed with the composition. A significant difference in the red to green emission ratio, which varied from 1.9 to 71 and 1.6 to 116, was observed for Na(x)YF(3+x):Yb,Er and Na(x)GdF(3+x):Yb,Er nanocrystals, respectively. Moreover, the local structure-dependent upconversion selectivity has been verified for Na(x)YF(3+x):Yb,Tm nanocrystals. In addition, the local structure induced upconversion emission from Er(3+) enhanced 9 times, and the CaF2 shell grown epitaxially over the nanocrystals further promoted the red emission by 450 times, which makes it superior as biomarkers for in vivo bioimaging. These exciting findings in the local structure-dependent upconversion selectivity not only offer a general approach to tailoring lanthanide related upconversion emissions but also benefit multicolor displays and imaging.

Environmental fate and ecotoxicity of lanthanides: are they a uniform group beyond chemistry?

Lanthanides are a chemically uniform group of metals (La-Lu) that, together with yttrium (Y) and scandium (Sc), form the group of rare earth elements (REEs). Because of their many applications (e.g., agriculture, medicine, motor industry), their global production has increased exponentially in the last decades and their biogeochemical cycles are being disrupted by human uses (e.g., gadolinium anomalies in freshwater and tap water, REEs enrichment of soils as a consequence of agricultural practices). However, ecotoxicological effects and mechanism of action of these elements are still poorly understood. In particular, there is no consensus as to lanthanides showing a coherent and predictable pattern of (eco)toxicity in the same way as their atomic properties. For aquatic organisms, contradictory conclusions on this issue can be found in the bibliography. This review shows that the variable composition of culture media used in ecotoxicology, and the associated differences in lanthanide's speciation, are the most likely cause for such discrepancies. In particular, the formation of insoluble species in some highly complexing media likely leads to changes in the soluble concentration of lanthanide during some tests; with the potential for a generalized underestimation of their toxicity at the present state of knowledge. For terrestrial organisms, suitable studies to establish trends in lanthanides' toxicity are practically nonexistent; with most research focusing on the effects of REE mixtures. Molecular level studies to elucidate the mechanisms of action of lanthanides are essentially limited to La, pointing to the need for further research to identify common mechanisms of action or modes of action across lanthanides. Overall, agreement on the correct procedures to follow to obtain reliable and comparable data for individual lanthanide is the first action to take in order to arrive at a reliable risk assessment for this group of elements in both aquatic and terrestrial systems.

Lanthanide-based nanocrystals as dual-modal probes for SPECT and X-ray CT imaging.

Applications of lanthanide-based nanoparticles for bioimaging have attracted increasing attention. Herein, small size PEG-EuOF:(153)Sm nanocrystals (∼5 nm) (PEG = poly(ethylene glycol)bis(carboxymethyl)ether) combined with the radioactive and X-ray absorption properties were synthesized. The distribution of the PEG-EuOF nanocrystals in living animals was studied by ex vivo radioassay, inductively coupled plasma-atomic emission spectrum (ICP-AES) analysis and in vivo SPECT imaging, which indicated that the small size PEG-EuOF:(153)Sm had long blood retention time (blood half-life (t1/2) reach to 4.65 h) and were eliminated significantly through biliary/gastrointestinal pathway in vivo. Meanwhile, benefiting from the high attenuation ability of Eu, the small size PEG-EuOF was successfully applied for lymph node CT imaging, extending the bio-applications of these small nanocrystals. The results of cytotoxicity and in vivo toxicity also showed that the PEG-EuOF nanocrystals have relatively low toxicity, which suggest their safety for in vivo imaging. The studies provide preliminary validation for the use of PEG-EuOF nanocrystals for in vivo bioimaging applications.

Biokinetic data and models for occupational intake of lanthanoids.

PURPOSE: This paper reviews data related to the behavior of the lanthanoid elements (lanthanum through lutetium, atomic numbers 57-71) in the human body and proposes biokinetic models for internally deposited radio-lanthanoids in workers. MATERIALS AND METHODS: Published data on the following topics are reviewed and analyzed: Physico-chemical properties of the lanthanoids as indicators of the potential behavior of these elements in body fluids; the concentrations of the stable lanthanoids in the environment and human body; and results of biokinetic studies of radio-lanthanoids in human subjects and laboratory animals. Respiratory and systemic biokinetic models and gastrointestinal absorption fractions are developed or selected in an effort to represent the typical behavior of lanthanoids in adult humans. RESULTS AND CONCLUSIONS: Generic (element-independent) absorption rates from the respiratory and alimentary tracts to blood and systemic biokinetic models are proposed. The systemic models are largely generic but include some element-specific parameter values to reflect regular changes with ionic radius in certain aspects of the behavior of the lanthanoids, particularly fractional deposition in liver and bone and early removal in urine.

In vivo imaging of paraCEST agents using frequency labeled exchange transfer MRI.

PURPOSE: A main obstacle to in vivo applications of paramagnetic chemical exchange saturation transfer (paraCEST) is interference from endogenous tissue magnetization transfer contrast (MTC). The suitability of excitation-based frequency labeled exchange transfer (FLEX) to separate out such MTC effects in vivo was tested. METHODS: The FLEX sequence measures modulation of the water signal based on the chemical shift evolution of solute proton magnetization as a function of evolution time. Time-domain analysis of this water signal allows identification of different solute components and provides a mechanism to separate out the rapidly decaying MTC components with short effective transverse relaxation time ( T2*) values. RESULTS: FLEX imaging of paraCEST agents was possible in vitro in phantoms and in vivo in mouse kidneys and bladder. The results demonstrated that FLEX is capable of separating out the MTC signal from tissues in vivo while providing a quantitative exchange rate for the rapidly exchanging paraCEST water protons by fitting the FLEX time-domain signal to FLEX theory. CONCLUSIONS: The first in vivo FLEX images of a paraCEST agent were acquired, which allowed separation of the tissue MTC components. These results show that FLEX imaging has potential for imaging the distribution of functional paraCEST agents in biological tissues.

Lanthanide near infrared imaging in living cells with Yb3+ nano metal organic frameworks.

We have created unique near-infrared (NIR)-emitting nanoscale metal-organic frameworks (nano-MOFs) incorporating a high density of Yb(3+) lanthanide cations and sensitizers derived from phenylene. We establish here that these nano-MOFs can be incorporated into living cells for NIR imaging. Specifically, we introduce bulk and nano-Yb-phenylenevinylenedicarboxylate-3 (nano-Yb-PVDC-3), a unique MOF based on a PVDC sensitizer-ligand and Yb(3+) NIR-emitting lanthanide cations. This material has been structurally characterized, its stability in various media has been assessed, and its luminescent properties have been studied. We demonstrate that it is stable in certain specific biological media, does not photobleach, and has an IC50 of 100 µg/mL, which is sufficient to allow live cell imaging. Confocal microscopy and inductively coupled plasma measurements reveal that nano-Yb-PVDC-3 can be internalized by cells with a cytoplasmic localization. Despite its relatively low quantum yield, nano-Yb-PVDC-3 emits a sufficient number of photons per unit volume to serve as a NIR-emitting reporter for imaging living HeLa and NIH 3T3 cells. NIR microscopy allows for highly efficient discrimination between the nano-MOF emission signal and the cellular autofluorescence arising from biological material. This work represents a demonstration of the possibility of using NIR lanthanide emission for biological imaging applications in living cells with single-photon excitation.

Biodistribution of sub-10 nm PEG-modified radioactive/upconversion nanoparticles.

The biodistribution of lanthanide-based upconversion nanophosphors (UCNPs) has attracted increasing attention, and all of the reported UCNPs display metabolism in the liver and spleen mainly. Herein, ∼8 nm poly(ethylene glycol) (PEG)-coated NaYF4 nanoparticles codoped with Yb(3+), Er(3+), and (or) radioactive (153)Sm(3+) ions were synthesized, through a hydrothermal synthetic system assisted by binary cooperative ligands with oleic acid and PEG dicarboxylic acids. The as-prepared PEG-coating NaYF4:Yb,Er and NaYF4:Yb,Er,(153)Sm are denoted as PEG-UCNPs and PEG-UCNPs((153)Sm), respectively. PEG-UCNPs were characterized by transmission electron microscope (TEM), X-ray diffraction (XRD) analysis, and Fourier-transform infrared (FTIR) spectroscopy. The PEG-UCNPs showed excellent water solubility with a hydrodynamic diameter of ∼10 nm and displayed upconversion luminescence (UCL) under continuous-wave excitation at 980 nm. At the same time, the (153)Sm-doped nanoparticles PEG-UCNPs((153)Sm) displayed radioactivity, and time-dependent biodistribution of PEG-UCNPs((153)Sm) was investigated, through single-photon emission computed tomography (SPECT) imaging and γ-counter analysis. Interestingly, PEG-UCNPs((153)Sm) had a long blood retention time and were partly eliminated through urinary pathways in vivo. Therefore, the concept of fabricating PEG-coated, small nanosize (sub-10 nm) nanoparticles with radioactive property is a useful strategy for providing a potential method to monitor lanthanide nanoparticles renal clearable.

Synthesis and cell localization of self-assembled dinuclear lanthanide bioprobes.

Lanthanide bioprobes and bioconjugates are ideal luminescent stains in view of their low propensity to photobleaching, sharp emission lines and long excited state lifetimes permitting time-resolved detection for enhanced sensitivity. In this paper, we expand our previous work which demonstrated that self-assembled dinuclear triple-stranded helicates [Ln2(L(C2X))3] behave as excellent cell and tissue labels in immunocytochemical and immunohistochemical assays. The synthetic strategy of the hexadentate ditopic ligands incorporating dipicolinic acid, benzimidazole units and polyoxyethylene pendants is revisited in order to provide a more straightforward route and to give access to further functionalization of the polyoxyethylene arms by incorporating a terminal function X. Formation of the helicates [Ln2(L(C2X))3] (X=COOH, CH2OH, COEt, NH2, phthalimide) is ascertained by several experimental techniques and their stability tested against diethylenetriaminepentaacetate. Their photophysical properties (quantum yield, lifetime, radiative lifetime and sensitization efficiency) are presented and compared with those of the parent helicates [Ln2(L(C2))3]. Finally, the cellular uptake of five Eu(III) helicates is monitored by time-resolved luminescence microscopy and their localization in HeLa cells established by co-staining experiments.

Bone as target organ for metals: the case of f-elements.

The skeleton is a target organ for most metals. This leads to their bioaccumulation, either as storage of useful oligoelements or as a protection against damage by toxic elements. The different events leading to their accumulation in this organ, under constant remodeling, are not fully understood, nor the full subsequent impact on bone metabolism. This lack of knowledge is particularly true for lanthanides and actinides, whose use has been increasing over recent decades. These metals, known as f-elements, present chemical similarities and differences. After a comparison of the biologically relevant physicochemical properties of lanthanides and actinides, and a brief reminder of the main events of bone metabolism, this review considers the results published over the past decade regarding the interaction between bones and f-elements. Emphasis will be given to the molecular events, which constitute the basis of the most recent toxicological studies in this domain but still need further investigation. Ionic exchanges with the inorganic matrix, interactions with bone proteins, and cellular mechanism disturbances are mainly considered in this review.

Nanoparticle augmented radiation treatment decreases cancer cell proliferation.

We report significant and controlled cell death using novel x-ray-activatable titania nanoparticles (NPs) doped with lanthanides. Preferential incorporation of such materials into tumor tissue can enhance the effect of radiation therapy. Herein, the incorporation of gadolinium into the NPs is designed to optimize localized energy absorption from a conventional medical x-ray. This result is further optimized by the addition of other rare earth elements. Upon irradiation, energy is transferred to the titania crystal structure, resulting in the generation of reactive oxygen species (ROS). FROM THE CLINICAL EDITOR: The authors report significant and controlled cell death using x-ray-activated titania nanoparticles doped with lanthanides as enhancers. Upon irradiation X-ray energy is transferred to the titania crystal structure, resulting in the generation of reactive oxygen species.

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.

In vitro and in vivo evaluation of melanin-binding decapeptide 4B4 radiolabeled with 177Lu, 166Ho, and 153Sm radiolanthanides for the purpose of targeted radionuclide therapy of melanoma.

Melanoma is a malignancy with increasing incidence. Although primary tumors that are localized to the skin can be successfully treated by surgical removal, there is no satisfactory treatment for metastatic melanoma, a condition that has currently an estimated 5-year survival of just 6%. During the last decade, ß- or α-emitter-radiolabeled peptides that bind to different receptors on a variety of tumors have been investigated as potential therapeutic agents in both the preclinical and clinical settings with encouraging results. A recent study demonstrated that 188-Rhenium ((188)Re)-labeled, via HYNIC ligand, fungal melanin-binding decapeptide 4B4 was effective against experimental MNT1 human melanoma and was safe to normal melanized tissues. The availability of radiolanthanides with diverse nuclear emission schemes and half-lives provides an opportunity to expand the repertoire of peptides for radionuclide therapy of melanoma. The melanin-binding decapeptide 4B4 was radiolabeled with (177)Lu, (166)Ho, and (153)Sm via a DO3A chelate. The stability studies of Ln*-DO3A-4B4 in phosphate-buffered saline, serum, and a hydroxyapatite assay demonstrated that (177)Lu-labeled peptide was more stable than (166)Ho- and (153)Sm-labeled peptides, most likely because of the smallest ionic radius of the former allowing for better complexation with DO3A. Binding of Ln*-DO3A-4B4 to the lysed highly melanized MNT1 melanoma cells demonstrated the specificity of peptides binding to melanin. In vivo biodistribution data for (177)Lu-DO3A-4B4 given by intraperitoneal administration to lightly pigmented human metastatic A2058 melanoma-bearing mice demonstrated very high uptake in the kidneys and low tumor uptake. Intravenous administration did not improve the tumor uptake. The plausible explanation of low tumor uptake of (177)Lu-DO3A-4B4 could be its decreased ability to bind to melanin during in vitro binding studies in comparison with (188)Re-HYNIC-4B4, exacerbated by the very fast clearance from the blood and the kidneys "sink" effect.

The mechanism of cell uptake for luminescent lanthanide optical probes: the role of macropinocytosis and the effect of enhanced membrane permeability on compartmentalisation.

Inhibition studies and co-localisation experiments with several emissive lanthanide complexes reveal cell uptake by macropinocytosis.

Paramagnetic liposomes as innovative contrast agents for magnetic resonance (MR) molecular imaging applications.

This article illustrates some innovative applications of liposomes loaded with paramagnetic lanthanide-based complexes in MR molecular imaging field. When a relatively high amount of a Gd(III) chelate is encapsulated in the vesicle, the nanosystem can simultaneously affect both the longitudinal (R(1)) and the transverse (R(2)) relaxation rate of the bulk H2O H-atoms, and this finding can be exploited to design improved thermosensitive liposomes whose MRI response is not longer dependent on the concentration of the probe. The observation that the liposome compartmentalization of a paramagnetic Ln(III) complex induce a significant R(2) enhancement, primarily caused by magnetic susceptibility effects, prompted us to test the potential of such agents in cell-targeting MR experiments. The results obtained indicated that these nanoprobes may have a great potential for the MR visualization of cellular targets (like the glutamine membrane transporters) overexpressing in tumor cells. Liposomes loaded with paramagnetic complexes acting as NMR shift reagents have been recently proposed as highly sensitive CEST MRI agents. The main peculiarity of CEST probes is to allow the MR visualization of different agents present in the same region of interest, and this article provides an illustrative example of the in vivo potential of liposome-based CEST agents.

Radiolanthanide complexes with tetraazamacrocycles bearing methylphosphonate pendant arms as bone seeking agents.

AIM: Radiolanthanide complexes with ligands bearing phosphonate groups have demonstrated their usefulness as bone seeking agents. Herein, we report on the synthesis of 153Sm and 166Ho complexes with 12- to 14-membered macrocycles containing different number of methylphosphonate pendant arms and their in vitro and in vivo evaluation in order to assess the effect of the cavity size and type of appended arms on their biological behavior. METHODS: Radioactive macrocycle complexes were prepared by reaction of (153)Sm/(166)Ho nitrates with four different tetraazamacrocycles bearing methylphosphonate groups. Radiochemical behavior, in vitro stability and charge of complexes were studied by chromatography and electrophoresis. The lipophilicity, plasmatic protein binding and adsorption onto hydroxyapatite (HA) were evaluated by in vitro assays. Biodistribution was assessed in CD-1 mice. Radiolabeling efficiency depends both on radionuclide and ligand structure. All the complexes are hydrophilic with an overall negative charge and relatively low protein binding. High in vitro stability in human serum and adsorption onto HA was found for all the complexes. RESULTS: Biodistribution and in vivo stability studies have demonstrated promising biological profile for targeted radiotherapy, namely a rapid tissue clearance from most organs and rapid total excretion. Additionally, 166Ho-tritp has a high bone uptake, which led to high bone/ blood and bone/muscle ratios. CONCLUSIONS: Our results clearly demonstrate that 12- and 13-membered macrocyclic ligands led to stable complexes with biological profile adequate to radionuclide therapy. The favorable in vivo behavior highlights the interest to further investigate these or closely related complexes to be used as bone seeking agents.