Mannose-modified hyaluronic acid nanocapsules for the targeting of tumor-associated macrophages

Tumor-associated macrophages (TAMs), a class of immune cells that play a key role in tumor immunosuppression, are recognized as important targets to improve cancer prognosis and treatment. Consequently, the engineering of drug delivery nanocarriers that can reach TAMs has acquired special relevance. This work describes the development and biological evaluation of a panel of hyaluronic acid (HA) nanocapsules (NCs), with different compositions and prepared by different techniques, designed to target macrophages. The results showed that plain HA NCs did not significantly influence the polarization of M0 and M2-like macrophages towards an M1-like pro-inflammatory phenotype; however, the chemical functionalization of HA with mannose (HA-Man) led to a significant increase of NCs uptake by M2 macrophages in vitro and to an improved biodistribution in a MN/MNCA1 fibrosarcoma mouse model with high infiltration of TAMs. These functionalized HA-Man NCs showed a higher accumulation in the tumor compared to non-modified HA NCs. Finally, the pre-administration of the liposomal liver occupying agent Nanoprimer™ further increased the accumulation of the HA-Man NCs in the tumor. This work highlights the promise shown by the HA-Man NCs to target TAMs and thus provides new options for the development of nanomedicine and immunotherapy-based cancer treatmentsOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by the 2^2-INTRATARGET project (A20/00028) funded by the ISCIII under the umbrella of the ERA NET EuroNanoMed GA N 723770 of the EU Horizon 2020 Research and Innovation Programme. This work was also supported by the Xunta de Galicia (ED431C 2018/30, and “Centro singular de investigación de Galicia” accreditation 2019 − 2022, ED431G2019/03), and the European Union (European Regional Development Fund-ERDF)S

Développement de nanoparticules magnétiques et fluorescentes pour le ciblage de béta-amyloide dans le diagnostic des maladies neurodégénératives

Alzheimer's disease is the most common neurodegenerative disorder, affecting around 35 million people worldwide. One of the characteristic pathological hallmarks of AD is amyloid plaques; consist of beta-amyloid peptide aggregates. Today’s diagnosis depends essentially on neuropsychological tests and in highlighting change in brain structure such as cortical atrophy. A major issue is that symptoms appear only at a developed stage of the disease. Then in vivo detection of beta-amyloid deposits at an early stage could lead to earlier and more conclusive diagnosis of AD and help monitoring the effect of therapeutic interventions. In this work, we develop an innovative and early diagnosis method, able to target and detect beta-amyloid deposits aggregates both by magnetic resonance and fluorescence imaging. Thus we develop a new kind of smart contrast agent for multimodal imaging, based on magnetic nanoparticles on which are grafted luminescent conjugated polythiophenes (LCPs). LCPs on the surface of the magnetic nanoparticles bound to beta-amyloid aggregates selectively and specifically. Upon biding to beta-amyloid aggregates the conformational freedom of the backbone is restricted, leading to specific conformation-dependent emission spectra from the LCPs, opening the way for magnetic resonance and fluorescence imaging of the beta-amyloid plaquesAvec 35 millions de personnes atteintes dans le monde, la maladie d'Alzheimer (MA) est la maladie neurodégénérative la plus répandue. L'une des caractéristiques pathologiques de cette maladie est l'apparition de plaques amyloïdes, composées d'agrégats de peptide beta-amyloïde. Aujourd'hui, le diagnostic repose essentiellement sur des tests neuropsychologiques et sur la mise en évidence de changements dans la structure du cerveau tels que l'atrophie corticale (diminution du volume du cerveau). Cependant les symptômes de cette maladie n'apparaissent qu'à un stade très développé. Ainsi la détection in vivo des dépôts de peptide beta-amyloïde avant le développement de la maladie pourrait conduire à un diagnostic plus précoce et plus probant. Elle pourrait également faciliter le suivi et l'évaluation des effets des interventions thérapeutiques au cours du traitement. Dans ce travail, nous avons développé une méthode de diagnostic précoce innovante, capable de cibler et de détecter les plaques Abeta à la fois par l'imagerie par résonance magnétique et par l'imagerie de fluorescence. Nous avons développé un nouveau type d'agents de contraste intelligents pour l'imagerie multimodale, basé sur des nanoparticules magnétiques sur lesquelles sont greffés les polythiophènes luminescents (LCPs). Les LCPs à la surface des nanoparticules magnétiques se lient aux plaques Abeta de manière sélective et spécifique. Lors de cette liaison, la liberté conformationnelle des polythiophènes se trouve limitée, ce qui conduit à des spectres d'émission spécifiques dépendant de la conformation, et rend pertinent l'usage de l'imagerie par résonance magnétique et de fluorescence des plaques Abet

Rare Earth Fluoride Nanoparticles Obtained Using Charge Transfer Complexes: A Versatile and Efficient Route toward Colloidal Suspensions and Monolithic Transparent Xerogels

International audienceCrystalline rare earth fluoride nanoparticles were synthesized by reacting rare earth ions with charge-transfer complexes, in solution, under mild conditions. An infrared study showed that these intermediate complexes are made up of solvent molecules (amide: N,N-dimethylformamide, 1-methyl-2-pyrrolidinone, etc.) and fluoride ions coming from hydrofluoric acid. The size and shape of the particles can be controlled through the process parameters. The complete study of the particles obtained through this process is carried out in this document, especially for the YbF3 system. However, the process can easily be extended to the whole series of rare earth elements. We also show the ability of these objects to be transferred from an aqueous medium to an organic phase thanks to their surface modification. Finally, transparent monolithic xerogels of rare earth fluoride have been developed starting from the prepared colloidal solutions

Two-Photon Fluorescence and Magnetic Resonance Specific Imaging of Aβ Amyloid Using Hybrid Nano-GdF 3 Contrast Media

International audienceReal time in vivo detection of Amyloid β (Aβ) deposits at an early stage may lead to faster and more conclusive diagnosis of Alzheimer’s disease (AD) and can facilitate the follow up of the effect of therapeutic interventions. In this work, the capability of new hybrid nanomaterials to target and detect Aβ aggregates using magnetic resonance (MRI) and fluorescence imaging is demonstrated. These smart contrast agents contain paramagnetic nanoparticles surrounded by luminescent conjugated oligothiophenes (LCOs) known to selectively bind to Aβ aggregates, with emission spectra strongly dependent on their conformations, opening the possibilities for several fluorescence imaging modes for AD diagnostics. Relaxivity is evaluated in vitro and ex vivo. The capability of these contrast media to link to Aβ fibrils in stained sections is revealed using transmission electron microscopy and fluorescence microscopy. Preliminary in vivo experiments show the ability of the contrast agent to diffuse through the blood–brain barrier of model animals and specifically stain amyloid deposits

In vivo targeting and multimodal imaging of cerebral amyloid-β aggregates using hybrid GdF 3 nanoparticles

International audienceAim: To propose a new multimodal imaging agent targeting amyloid-β (Aβ) plaques in Alzheimer’s disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimer’s disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood–brain barrier status. Nevertheless, multimodal imaging showed successful Aβ targeting in both transgenic mice and Aβ fibril-injected rats