Search

Vascular microcalcifications are associated with atherosclerosis plaque instability and, therefore, to increased mortality. Because of this key role, several imaging probes have been developed for their in vivo identification. Among them, [18F]FNa is the gold standard, showing a large uptake in the whole skeleton by positron emission tomography. Here, we push the field toward the combined anatomical and functional early characterization of atherosclerosis. For this, we have developed hydroxyapatite (HAP)-multitag, a bisphosphonate- functionalized 68Ga core-doped magnetic nanoparticle showing high affinity toward most common calcium salts present in microcalcifications, particularly HAP. We characterized this interaction in vitro and in vivo, showing a massive uptake in the atherosclerotic lesion identified by positron emission tomography (PET) and positive contrast magnetic resonance imaging (MRI). In addition, this accumulation was found to be dependent on the calcification progression, with a maximum uptake in the microcalcification stage. These results confirmed the ability of HAP-multitag to identify vascular calcifications by PET/(T1)MRI during the vulnerable stages of the plaque progression., This work was supported by the Spanish Ministry of Science (grant nos. SAF2016-79593-P, RED2018-102469-T, and PID2019-104059RB-I00) and from the Gobierno Vasco, Dpto. Industria, Innovación, Comercio y Turismo under the ELKARTEK Program (grant no. KK-2019/bmG19). JR-C received funding from the BBVA Foundation (Ayudas a Equipos de investigación científica Biomedicina 2018). The CNIC is supported by the MICINN and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MICINN award SEV-2015-0505). CIC biomaGUNE is supported by the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agencygrant no. MDM-2017-0720. L.G. acknowledges financial support from the Ramón y Cajal program (RYC-2014-15512 0)

Dedicated to Prof. Dr. Jan Balzarini (KU Leuven, Belgium), in recognition of his exem- plary life-long dedication to virology and con- stant encouragement, We have recently described a novel family of compounds of reduced size and dual anti-HIV and anti-EV71 ac- tivity that encompasses tripodal and tetrapodal derivatives. The tripodal prototype, AL-470, has a nitro group at the focal point of the central scaffold and three attached tryptophan residues, each of which bearing an iso- phthaloyl moiety at the C2 position of the indole ring. A nitro to amino substitution has allowed us now to introduce a chemically addressable functionality to perform further structural modifications consisting of both direct and linker-mediated attachment of several aromatic groups, including the fluorescent dye Alexa Fluor 647 and the antibody-recruiting 2,4-dinitrophenyl motif. Some of the derivatives turned out to be more potent and selective than AL-470 against HIV-1, HIV-2 and EV-A71. The fluorescent probe demonstrated a specific tropism for intestines and lungs, two important niches for the human microbiome in health and disease, This work was supported by the Spanish MICINN (Projects PID2019- 104070RB-C21 and PID2019-104070RB-C22), and by the Spanish “Agencia Estatal Consejo Superior de Investigaciones Científicas” (CSIC, Projects CSIC-PIE-201980E100 and CSIC-PIE-201980E028). “The Cen- ters of Excellence” of the KU Leuven (EF-05/15 and PF-10/18), EU FP7 (FP7/2007-2013) Project EUVIRNA (Grant 408 Agreement 264286), EU FP7 SILVER (Contract HEALTH-F3-2010-260644), a grant from the Belgian Interuniversity Attraction Poles (IAP) Phase VII–P7/45 (BEL- VIR) and the EU FP7 Industry-Academia Partnerships and Pathways Project AIROPICO. The Spanish MEC/MINECO is also acknowledged for grants to B.M-G and O.M-M. We thank Charlotte Vanderheydt, Sandra Claes, Caroline Collard, Daisy Ceusters and Kim Donckers, for helping with the evaluation and processing of the antiviral data. This work has been awarded with the Ramón Madroñero (XX call) prize within the “Prizes for Young Researchers of the Spanish Society of Medicinal Chemistry (SEQT).

Radioisotope-labelled nanoparticles permit novel applications in molecular imaging, while recent developments in imaging have enabled direct visualization of biological processes. While this holds true for pathological processes that are stable in time, such as cancer, imaging approaches are limited for phenomena that take place in the range of minutes, such as thrombotic events. Here, we take advantage of bioorthogonal chemistry to demonstrate the concept of nanoparticle-based fast pre-targeted imaging. Using a newly designed nanoparticle that targets platelets we show the applicability of this approach developing thrombo-tag, an in vivo produced nanoparticle that labels thrombi. We show that thrombo-tag allows specific labelling of platelets that accumulate in the injured pulmonary vasculature, or that aggregate in brains of mice suffering thrombotic processes. The fast kinetics and high specificity features of thrombo-tag may critically expand the application of molecular imaging to the most prevalent and debilitating diseases in the clinics., This work was supported by the Spanish Ministry of Science, grants number (SAF2016-79593-P, SAF2017-84494-C2-R and RED2018-102469-T), and from the Gobierno Vasco, Dpto. Industria, Innovación, Comercio y Turismo under the ELKARTEK Program (Grant No. KK-2019/bmG19). JR-C received funding from the BBVA Foundation (Ayudas a Equipos de investigación científica Biomedicina 2018). The study was also supported by Intramural grants from the Severo Ochoa program (IGP-SO), a grant from Fundació La Marató de TV3 (120/C/2015-20153032), grant SAF2015-65607-Rfrom Ministerio de Ciencia e Innovacion (MICINN) withcofunding from Fondo Europeo de Desarrollo Regional, grantRTI2018-095497-B-I00 from MICINN, and HR17_00527 from Fundación La Caixa (to A. H.), and fellowship BES-2013-065550from MICINN (to J. M. A.). The CNIC is supported by theMICINN and the Pro-CNIC Foundation, and is a Severo OchoaCenter of Excellence (MICINN award SEV-2015-0505). CICbiomaGUNE is supported by the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency–Grant No. MDM-2017-0720.The authors wish to thank the staffat the Advance ImagingUnit in the Spanish Cardiovascular Research Centre for theirhelp in the imaging studies. We acknowledge support of thepublication fee by the CSIC Open Access Publication SupportInitiative through its Unit of Information Resources forResearch (URICI). We thank Dr. M. Eugenio Vázquez for coverdesign.

Synthesizing iron oxide nanoparticles for positive contrast in magnetic resonance imaging is the most promising approach to bring this nanomaterial back to the clinical field. The success of this approach depends on several aspects: the longitudinal relaxivity values, the complexity of the synthetic protocol, and the reproducibility of the synthesis. Here, we show our latest results on this goal. We have studied the effect of Cu doping on the physicochemical, magnetic, and relaxometric properties of iron oxide nanoparticles designed to provide positive contrast in magnetic resonance imaging. We have used a one-step, 10 min synthesis to produce nanoparticles with excellent colloidal stability. We have synthesized three different Cu-doped iron oxide nanoparticles showing modest to very large longitudinal relaxivity values. Finally, we have demonstrated the in vivo use of these kinds of nanoparticles both in angiography and targeted molecular imaging. ©, This study was supported by grants from the Spanish Ministry for Economy and Competitiveness (MEyC) (SAF2016-79593-P, MAT2017-88148-R, and SAF2017-84494-C2-R), Comunidad de Madrid (S2017/BMD-3875), and Instituto de Salud Carlos III (DTS16/00059). L.G. received financial support from the Ramońy Cajal subprogram (RYC-2014-15512). J.R.-C. acknowledges funding from the Programa Red Guipuzcoana de Ciencia, Tecnología e Información (2018-CIEN-000058-01). I.F.-B. thanks Comunidad de Madrid (B2017/BMD-3875). This work was performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (Grant No. MDM-2017-0720)

Radioisotope-labelled nanoparticles permit novel applications in molecular imaging, while recent developments in imaging have enabled direct visualization of biological processes. While this holds true for pathological processes that are stable in time, such as cancer, imaging approaches are limited for phenomena that take place in the range of minutes, such as thrombotic events. Here, we take advantage of bioorthogonal chemistry to demonstrate the concept of nanoparticle-based fast pre-targeted imaging. Using a newly designed nanoparticle that targets platelets we show the applicability of this approach developing thrombo-tag, an in vivo produced nanoparticle that labels thrombi. We show that thrombo-tag allows specific labelling of platelets that accumulate in the injured pulmonary vasculature, or that aggregate in brains of mice suffering thrombotic processes. The fast kinetics and high specificity features of thrombo-tag may critically expand the application of molecular imaging to the most prevalent and debilitating diseases in the clinics.

© 2020 by the authors., Iron oxide nanoparticles have been extensively utilised as negative (T2) contrast agents in magnetic resonance imaging. In the past few years, researchers have also exploited their application as positive (T1) contrast agents to overcome the limitation of traditional Gd3+ contrast agents. To provide T1 contrast, these particles must present certain physicochemical properties with control over the size, morphology and surface of the particles. In this review, we summarise the reported T1 iron oxide nanoparticles and critically revise their properties, synthetic protocols and application, not only in MRI but also in multimodal imaging. In addition, we briefly summarise the most important nanoparticulate Gd and Mn agents to evaluate whether T1 iron oxide nanoparticles can reach Gd/Mn contrast capabilities, F.H. was funded through the Spanish Ministry for Economy and Competitiveness (MEyC), grant number [SAF2016-79593-P] and the Ministry of Science, grant number [RED2018-102469-T]. J.R-C. was funded through the Spanish Ministry for Economy and Competitiveness (MEyC), grant number [SAF2017-84494-C2-R], and the Gobierno Vasco, Dpto. Industria, Innovación, Comercio y Turismo under the ELKARTEK Program (Grant No. KK-2019/bmG19). CIC biomaGUNE is supported by the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency—Grant No. MDM-2017-0720.

Advanced uses of smartphones are changing lifestyles, and may have a great impact in materials science in the near future. In this work, the use of these devices to develop fast, simple, and cheap methods to characterize magnetic nanoparticle suspensions is tested. A series of dilutions of a wide library of magnetic nanoparticles, composed of iron oxide materials in the range between 3 and 43 nm, with two different shapes and four different coatings is prepared. The colloid color is analyzed using the RGB (red, green, blue) color model. Ratios of these parameters are correlated with the suspension iron concentration and with the nanoparticles average size. A linear relationship between the color (in particular the G/R ratio) and both the colloid iron content and the particles size is found. The link between these parameters allows the development of two new methods to determine either the concentration or the particle size of magnetic nanoparticle suspensions just by acquiring images from suspensions of iron oxide magnetic nanoparticles with a smartphone., This work was funded by European Commission (project NoCanTher, H2020, GA 685795), Spanish MINECO (SAF2016‐79593‐P to F.H., MAT2017‐88148R (AEI/FEDER, UE) to M.P.M., MAT2015‐71806‐R to G.S. and PGC2018‐096016‐B‐I00 to L.G.), and Fondo Social de la DGA (grupos DGA). Support from the Nanocare Network (RED2018‐102469‐T financed by the Spanish MCIU) is also acknowledged. Y.F‐A. thanks Santander‐Universidad Zaragoza Fellowship program for her Ph.D. position. L.G. acknowledges financial support from the Ramón y Cajal program (RYC‐2014‐15512).

Iron oxide nanomaterial is a typical example of a magnetic resonance imaging probe for negative contrast. It has also been shown how this nanomaterial can be synthesized for positive contrast by modification of the composition and size of the core. However, the role of the organic coating in the relaxometric properties is largely unexplored. Here, maghemite nanoparticles with either excellent positive or very good negative contrast performance are obtained by modifying coating thickness while the core is kept unchanged. Different nanoparticles with tailored features as contrast agent according to the coating layer thickness have been obtained in a single-step microwave-driven synthesis by heating at different temperatures. A comprehensive analysis is conducted of how the composition and structure of the coating affects the final magnetic, relaxometric, and imaging performance. These results show how the organic coating plays a fundamental role in the intrinsic relaxometric parameters of iron oxide-based contrast media., This study was supported by a grant from the Spanish Ministry for Economy and Competitiveness (MEyC) (grant nos. MAT2013-47303-P, MAT2014-52069-R, SAF2016-79593-P). L.G. received financial support from the Ramón y Cajal subprogram (RYC-2014-15512). The CNIC is supported by the MEyC and the Pro-CNIC Foundation and is a SO-Center of Excellence (SEV-2015-0505).

The importance of atherosclerosis is driving research to create improved diagnostic tools based on molecular imaging. Pretargeted imaging is the use of bioorthogonal probes that selectively accumulate upon reaction with a pre-modified biomolecule in vivo. To date, this very promising approach has not been applied to atherosclerosis. Neither has been the use of a single nano-radiomaterial for PET / T-MR imaging of atherosclerosis. Here, we synthesized bioorthogonal nano-radiomaterials for in vivo pretargeted molecular imaging in a mouse model of atherosclerosis. Based on tetrazine-ligation, these functionalized Ga iron oxide nano-radiomaterials provide simultaneous PET and T-MRI signals and selectively accumulate in atherosclerotic plaques in mice sequentially injected with trans-cyclooctene-modified antibodies against oxidized LDL followed by the hybrid nano-radiomaterial. Our results demonstrate the ability of this approach to unambiguously detect atherosclerosis. Furthermore, we show the first example of how hybrid imaging can be used for pretargeted bioorthogonal molecular imaging with nanomaterials., This work was funded by the Spanish Ministry for Economy and Competitiveness (MEyC) (grant number: SAF2016-79593-P and SAF2017-84494-C2-R) and Carlos III Health Institute (grant number: DTS16/00059). L.G. was funded by Ramon y Cajal grant (RYC-2014-15512).

Here, we describe a microwave synthesis to obtain iron oxide nanoparticles core-doped with

Here, we describe a microwave synthesis to obtain iron oxide nanoparticles core-doped with 68Ga. Microwave technology enables fast and reproducible synthetic procedures. In this case, starting from FeCl3 and citrate trisodium salt, iron oxide nanoparticles coated with citric acid are obtained in 10 min in the microwave. These nanoparticles present a small core size of 4.2 ± 1.1 nm and a hydrodynamic size of 7.5 ± 2.1 nm. Moreover, they have a high longitudinal relaxivity (r1) value of 11.9 mM-1·s-1 and a modest transversal relaxivity value (r2) of 22.9 mM-1·s-1, which results in a low r2/r1 ratio of 1.9. These values enable positive contrast generation in magnetic resonance imaging (MRI) instead of negative contrast, commonly used with iron oxide nanoparticles. In addition, if a 68GaCl3 elution from a 68Ge/68Ga generator is added to the starting materials, a nano-radiotracer doped with 68Ga is obtained. The product is obtained with a high radiolabeling yield (> 90%), regardless of the initial activity used. Furthermore, a single purification step renders the nano-radiomaterial ready to be used in vivo.

The combination of radioisotopes and nanomaterials is creating a new library of tracers for molecular imaging, exploiting the sensitivity of nuclear imaging techniques and the size-dependent properties of nanomaterials. This new approach is expanding the range of applications, including the possibility of theranostics. Among the many different combinations, the use of Ga-68 as the radioisotope in the radio-nanomaterial is particularly convenient. The physicochemical properties of this isotope allow incorporating it into many materials with great chemical flexibility. Furthermore, its production from a benchtop generator eases the preparation of the tracer. Here, we review main results from the last years in which a nanomaterial has been radiolabeled with Ga-68. In thus process, we pay attention to the use of nanomaterials for biomedical imaging in general and main properties of this radioisotope. We study the main methods to carry out such radiolabeling and the most important applications for molecular imaging. We thank Ministerio de Economia, Industria y Competitividad (MEIC) for financial support (SAF2016-79593-P) and Instituto de Salud Carlos III (DTS16/00059). Sí

In vivo detection and quantification of inflammation is a major goal in molecular imaging. Furthermore, cell-specific detection of inflammation would be a tremendous advantage in the characterization of many diseases. Here, we show how this goal can be achieved through the synergistic combination of nanotechnology and nuclear imaging. One of the most remarkable features of this hybrid approach is the possibility to tailor the pharmacokinetics of the nanomaterial-incorporated biomolecule and radionuclide. A good example of this approach is the covalent binding of a large amount of a neutrophil-specific, hydrophobic peptide on the surface of 68Ga core-doped nanoparticles. This new nano-radiotracer has been used for non-invasive in vivo detection of acute inflammation with very high in vivo labelling efficiency, i.e. a large percentage of labelled neutrophils. Furthermore, we demonstrate that the tracer is neutrophil-specific and yields images of neutrophil recruitment of unprecedented quality. Finally, the nano-radiotracer was successfully detected in chronic inflammation in atherosclerosis-prone ApoE-/- mice after several weeks on a high-fat diet. This study was supported by a grant from the Spanish Ministry for Economy and Competitiveness (MEyC) (grant number: SAF2016-79593-P) and from Carlos III Health Research Institute (grant number: DTS16/00059). We thank Simon Bartlett for editorial assistance and manuscript preparation. The CNIC is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro CNIC Foundation, and is a Severo Ochoa Centre of Excellence (MEIC award SEV-2015-0505). Sí

In vivo detection and quantification of inflammation is a major goal in molecular imaging. Furthermore, cell-specific detection of inflammation would be a tremendous advantage in the characterization of many diseases. Here, we show how this goal can be achieved through the synergistic combination of nanotechnology and nuclear imaging. One of the most remarkable features of this hybrid approach is the possibility to tailor the pharmacokinetics of the nanomaterial-incorporated biomolecule and radionuclide. A good example of this approach is the covalent binding of a large amount of a neutrophil-specific, hydrophobic peptide on the surface of 68Ga core-doped nanoparticles. This new nano-radiotracer has been used for non-invasive in vivo detection of acute inflammation with very high in vivo labelling efficiency, i.e. a large percentage of labelled neutrophils. Furthermore, we demonstrate that the tracer is neutrophil-specific and yields images of neutrophil recruitment of unprecedented quality. Finally, the nano-radiotracer was successfully detected in chronic inflammation in atherosclerosis-prone ApoE−/− mice after several weeks on a high-fat diet.

Nowadays,thanks to the successful discoveries in the biomedical field achieved in the last two decades,a deeper understanding about the complexity of mechanistic aspects of different pathological processes has been obtained. As a consequence,even the standard therapeutic protocols have undergone a vast redesign. In fact,the awareness about the necessity to progress towards a combined multitherapy in order to potentially increase the final healing chances has become a reality. One of the crucial elements of this novel approach is that large amounts of detailed information are highly needed and in vivo imaging techniques represent one of the most powerful tools to visualize and monitor the pathological state of the patient. To this scope,due to their unique features,nanostructured materials have emerged as attractive elements for the development of multifunctional tools for diagnosis and therapy. Hence,in this review,the most recent and relevant advances achieved by applying multifunctional nanostructures in multimodal theranosis of different diseaseswill be discussed. Inmore detail,the preparation and application of single multifunctional nano-radiotracers based on iron oxides and enabling PET/MRI dual imaging will be firstly detailed. After that,especially considering their highly promising clinical potential,the preparation and application of multifunctional liposomes useful for multimodal imaging and therapy will be reviewed. In both cases,a special focus will be set on the application of such a multifunctional nanocarriers in cancer as well as cardiovascular diseases., The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro CNIC Foundation and by Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). We also thank MINECO for grant MAT2013-47303-P, SAF2016-79593-P and for the research grant no. SAF2014-59118-JIN (‘Proyectos de IþDþi para jóvenes investigadores’, 2014) also co-funded by Fondo Europeo de Desarrollo Regional (FEDER).