Fluorescent and magnetic stellate mesoporous silica for bimodal imaging and magnetic hyperthermia

There is currently a crucial need of innovative multifunctional nanoparticles combining, in one formulation, imaging and therapy capacities allowing thus an accurate diagnosis and a therapy monitored by imaging. Multimodal imaging will ensure to speed up diagnosis, and to increase its sensitivity, reliability and specificity for a better management of the disease. Combined with a therapeutic action, it will also enable to treat the disease in a specific personalized manner in feedback mode. The mastered design of such bioprobes as well as the demonstration of their efficiency are still challenges to face in nanomedicine. In this work, novel fluorescent and magnetic core–shell nanocomposites have been designed to ensure, in one nanoformulation, bimodal fluorescence and MRI imaging coupled with therapy by magnetic hyperthermia. They consist in the coating of a magnetic iron oxide (IO) core (ca. 18 nm diameter to ensure magnetic hyperthermia) by an original large pore stellate mesoporous silica (STMS) shell to produce uniform and mono-core magnetic core–shell nanocomposites denoted IO@STMS NPs. To confer fluorescence properties, CdSe/ZnS quantum dots (QDs) NPs were grafted inside the large pores of the IO@STMS nanocomposites. To provide biocompatibility and opsonization-resistance, a tightly-bound human serum albumin (HSA) coating is added around the nanocomposite using an original IBAM-based strategy. Cellular toxicity and non-specific cell–nanomaterial interactions allowed to determine a concentration range for safe application of these NPs. Cellular endosomes containing spontaneously-uptaken NPs displayed strong and photostable QD fluorescence signals while magnetic relaxivity measurements confirm their suitability as contrast agent for MRI. HeLa cell-uptaken NPs exposed to a magnetic field of 100 kHz and 357 Gauss (or 28.5 kA m−1) display an outstanding 65% cell death at a very low iron concentration (1.25 μg Fe mL−1), challenging current magnetic hyperthermia nanosystems. Furthermore, at the particularly demanding conditions of clinical use with low frequency and amplitude field (100 kHz, 117 Gauss or 9.3 kA m−1), magnetic hyperthermia combined with the delivery of a chemotherapeutic drug, doxorubicin, allowed 46% cell death, which neither the drug nor the NPs alone yielded, evidencing thus the synergistic effect of this combined treatment.Facultad de Ciencias VeterinariasInstituto de Investigaciones Fisicoquímicas Teóricas y AplicadasInstituto de Física La Plat

High temperature flow synthesis of iron oxide nanoparticles : size tuning via reactor engineering

Batch thermal decomposition syntheses of iron oxide nanoparticles (IONPs) provide precise control of particle properties, but their scalability and reproducibility is challenging. This is addressed in this work via a versatile high temperature flow reactor with adjustable temperature profiles through three individual stages operated between 180 °C and 280 °C. The tuneable temperature profiles in combination with self-seeded growth methods made it possible to synthesise IONPs between 2 and 17 nm (a size increase that corresponds to a >600 fold particle volume increase) at production rates of several gIONP per day. The precursor solutions contained only iron(III) acetylacetonate in a polyol solvent and no nucleation or growth inhibitors, oxidation or reducing agents, ligands or any other additives . This broad size range covers most biomedical applications and is of special interest for T1 MRI contrast agents (2–5 nm), as well as for magnetic hyperthermia cancer therapy (>10 nm). The potential of the IONPs produced was demonstrated by their high longitudinal relaxivity >16 mM−1 s−1 at a transversal/longitudinal relaxivity ratio <2.5 (small IONPs) and specific absorption rates increasing with the IONP size up to180 W/gFe. In addition, the polyol method employed allowed for simple ligand exchange with biocompatible sodium tripolyphosphate to make the IONPs stable in water, thus rendering them suitable for biomedical applications. The continuous high temperature process presented shows how to control the particle size not via the chemistry (e.g., chemical additives affecting the particle size through the surface chemistry), but engineering parameters, i.e., reactor temperature profiles, reagent addition sequences and seeded growth strategies

Unveiling the role of surface, size, shape and defects of iron oxide nanoparticles for theranostic applications

Iron oxide nanoparticles (IONPs) are well-known contrast agents for MRI for a wide range of sizes and shapes. Their use as theranostic agents requires a better understanding of their magnetic hyperthermia properties and also the design of a biocompatible coating ensuring their stealth and a good biodistribution to allow targeting of specific diseases. Here, biocompatible IONPs of two different shapes (spherical and octopod) were designed and tested in vitro and in vivo to evaluate their abilities as high-end theranostic agents. IONPs featured a dendron coating that was shown to provide anti-fouling properties and a small hydrodynamic size favoring an in vivo circulation of the dendronized IONPs. While dendronized nanospheres of about 22 nm size revealed good combined theranostic properties (r2 = 303 mM s−1, SAR = 395 W gFe−1), octopods with a mean size of 18 nm displayed unprecedented characteristics to simultaneously act as MRI contrast agents and magnetic hyperthermia agents (r2 = 405 mM s−1, SAR = 950 W gFe−1). The extensive structural and magnetic characterization of the two dendronized IONPs reveals clear shape, surface and defect effects explaining their high performance. The octopods seem to induce unusual surface effects evidenced by different characterization techniques while the nanospheres show high internal defects favoring Néel relaxation for magnetic hyperthermia. The study of octopods with different sizes showed that Néel relaxation dominates at sizes below 20 nm while the Brownian one occurs at higher sizes. In vitro experiments demonstrated that the magnetic heating capability of octopods occurs especially at low frequencies. The coupling of a small amount of glucose on dendronized octopods succeeded in internalizing them and showing an effect of MH on tumor growth. All measurements evidenced a particular signature of octopods, which is attributed to higher anisotropy, surface effects and/or magnetic field inhomogeneity induced by tips. This approach aiming at an analysis of the structure–property relationships is important to design efficient theranostic nanoparticles.The Region Alsace, France, and the Labex Chimie des Systemes Complexes, University of Strasbourg, France are gratefully acknowledged for the doctoral fellowship to Geoffrey Cotin. This research project was also co-funded by Labex CSC, Alsace contre le cancer, INCA (project PRTK14, THERAMAG 2014-225) and the INTERREG project NANOTRANSMED. The “NANOTRANSMED” project is co-funded by the European Regional Development Fund (ERDF) and by the Swiss Confederation and the Swiss cantons of Aargau, Basel-Landschaft and Basel-Stadt, in the framework of the INTERREG V Upper Rhine program (“Transcending borders with every project”). The authors thank Morgane Rabineau for epifluorescence imaging and Nadia Messaddeq for TEM imaging of cells. The authors thank the Center for Microscopy and Molecular Imaging (CMMI, supported by the European Regional Development Fund and the Walloon Region). This work was supported by the Fond National de la Recherche Scientifique (FNRS), UIAP VII, ARC Programs of the French Community of Belgium and the Walloon region (Gadolymph and Holocancer programs). All the authors acknowledge the COST action TD1402 “RADIOMAG”. D. Ortega and F. J. Teran acknowledge support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, Grant SEV-2016-0686), the Spanish Ministry of Economy and Competitiveness for the NANOLICO project (MAT2017-85617-R), the Spanish Ministry of Science through the NaNoCAR grant PID2020-117544RB-I00, the Ramón y Cajal grant RYC2018-025253-I and Research Networks grant RED2018-102626-T, the HEATOOLS project (BIO2017-84246-C2-1-R), the Comunidad de Madrid for grant NANOMAGCOST (P2018/NMT-4321), DGA for public funding from Fondo Social (grupos DGA), and the European Commission for the funding received through the H2020 “NoCanTher” project (GA No. 685795).Peer reviewe

Films multicouches de polyélectrolytes répondant aux stimuli mécaniques : applications à la libération de molécules et à la biocatalyse contrôlées

Ce travail de thèse a consisté à étudier le comportement de films multicouches de polyélectrolytes soumis à des stimuli mécaniques. L’objectif principal a été le développement d’assemblages polymériques à réponse biologique ou chimique sous l’action de forces mécaniques. 1) D’abord, nous nous sommes intéressés à ouvrir la barrière de films à multi-compartiments (systèmes composés de strates alternées réservoir/barrière), par application de contraintes d’étirement. Nous avons montré que des barrières pouvaient agir comme des nanovalves à commande mécanique, permettant ainsi la libération contrôlée de molécules. 2) Ensuite, nous avons élaboré des assemblages constitués de multicouches de polyélectrolytes et d’une enzyme, la phosphatase alcaline. L’application de forces mécaniques d'étirement sur ces systèmes a permis de déclencher la réaction enzymatique et également de moduler de façon réversible la biocatalyse entre un état activé et un état désactivé.In this thesis, the behavior of functional polyelectrolyte multilayer (PEM) films was investigated under mechanical stimuli. The aim was to design chemically or biologically active films responding to mechanical forces. The study was divided in two parts: i) First, we studied the barrier opening of multi-compartment films (systems composed of reservoir/barrier strata made of PEM) induced by mechanical stretching. We demonstrated that multilayer barriers could act as nanovalves reversibly controlled by stretching, allowing thus the controlled release of molecules. ii) In a second step, we designed reservoir/barrier systems containing an enzyme, alkaline phosphatase, in order to develop surfaces with biocatalytic activities tuned by mechanical forces. Finally, by applying a mechanical stretching on these systems, the biocatalysis could be triggered and even controlled in a reversible manner

Films multicouches de polyélectrolytes répondant aux stimuli mécaniques : applications à la libération de molécules et à la biocatalyse contrôlées

Ce travail de thèse a consisté à étudier le comportement de films multicouches de polyélectrolytes soumis à des stimuli mécaniques. L'objectif principal a été le développement d'assemblages polymériques à réponse biologique ou chimique sous l'action de forces mécaniques. 1) D abord, nous nous sommes intéressés à ouvrir la barrière de films à multi-compartiments (systèmes composés de strates alternées réservoir/barrière), par application de contraintes d'étirement. Nous avons montré que des barrières pouvaient agir comme des nanovalves à commande mécanique, permettant ainsi la libération contrôlée de molécules. 2) Ensuite, nous avons élaboré des assemblages constitués de multicouches de polyélectrolytes et d'une enzyme, la phosphatase alcaline. L'application de forces mécaniques d'étirement sur ces systèmes a permis de déclencher la réaction enzymatique et également de moduler de façon réversible la biocatalyse entre un état activé et un état désactivé.In this thesis, the behavior of functional polyelectrolyte multilayer (PEM) films was investigated under mechanical stimuli. The aim was to design chemically or biologically active films responding to mechanical forces. The study was divided in two parts: i) First, we studied the barrier opening of multi-compartment films (systems composed of reservoir/barrier strata made of PEM) induced by mechanical stretching. We demonstrated that multilayer barriers could act as nanovalves reversibly controlled by stretching, allowing thus the controlled release of molecules. ii) In a second step, we designed reservoir/barrier systems containing an enzyme, alkaline phosphatase, in order to develop surfaces with biocatalytic activities tuned by mechanical forces. Finally, by applying a mechanical stretching on these systems, the biocatalysis could be triggered and even controlled in a reversible manner

Iron Oxide@Mesoporous Silica Core-Shell Nanoparticles as Multimodal Platforms for Magnetic Resonance Imaging, Magnetic Hyperthermia, Near-Infrared Light Photothermia, and Drug Delivery

The design of core-shell nanocomposites composed of an iron oxide core and a silica shell offers promising applications in the nanomedicine field, especially for developing efficient theranostic systems which may be useful for cancer treatments. This review article addresses the different ways to build iron oxide@silica core-shell nanoparticles and it reviews their properties and developments for hyperthermia therapies (magnetically or light-induced), combined with drug delivery and MRI imaging. It also highlights the various challenges encountered, such as the issues associated with in vivo injection in terms of NP–cell interactions or the control of the heat dissipation from the core of the NP to the external environment at the macro or nanoscale

Drug releasing nanoplatforms activated by alternating magnetic fields

The use of an alternating magnetic field (AMF) to generate non-invasively and spatially a localized heating from a magnetic nano-mediator has become very popular these last years to develop magnetic hyperthermia (MH) as a promising therapeutic modality already used in the clinics. AMF has become highly attractive this last decade over others radiations, as AMF allows a deeper penetration in the body and a less harmful ionizing effect. In addition to pure MH which induces tumor cell death through local T elevation, this AMF-generated magneto-thermal effect can also be exploited as a relevant external stimulus to trigger a drug release from drug-loaded magnetic nanocarriers, temporally and spatially. This review article is focused especially on this concept of AMF induced drug release, possibly combined with MH. The design of such magnetically responsive drug delivery nanoplatforms requires two key and complementary components: a magnetic mediator which collects and turns the magnetic energy into local heat, and a thermoresponsive carrier ensuring thermo-induced drug release, as a consequence of magnetic stimulus. A wide panel of magnetic nanomaterials/chemistries and processes are currently developed to achieve such nanoplatforms. This review article presents a broad overview about the fundamental concepts of drug releasing nanoplatforms activated by AMF, their formulations, and their efficiency in vitro and in vivo.This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials".Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader.Magnéto-Chimiothérapie : Modélisation de la Délivrance Induite par Champ Magnétique Radiofréquence d'Anticancéreux par des Nano-Vésicules Polymères et Suivi par IRM d'un Modèle de Glioblastom

Films multicouches de polyélectrolytes répondant aux stimuli mécaniques (Applications à la libération de molécules et à la biocatalyse contrôlées)

Ce travail de thèse a consisté à étudier le comportement de films multicouches de polyélectrolytes soumis à des stimuli mécaniques. L objectif principal a été le développement d assemblages polymériques à réponse biologique ou chimique sous l action de forces mécaniques. 1) D abord, nous nous sommes intéressés à ouvrir la barrière de films à multi-compartiments (systèmes composés de strates alternées réservoir/barrière), par application de contraintes d étirement. Nous avons montré que des barrières pouvaient agir comme des nanovalves à commande mécanique, permettant ainsi la libération contrôlée de molécules. 2) Ensuite, nous avons élaboré des assemblages constitués de multicouches de polyélectrolytes et d une enzyme, la phosphatase alcaline. L application de forces mécaniques d'étirement sur ces systèmes a permis de déclencher la réaction enzymatique et également de moduler de façon réversible la biocatalyse entre un état activé et un état désactivé.In this thesis, the behavior of functional polyelectrolyte multilayer (PEM) films was investigated under mechanical stimuli. The aim was to design chemically or biologically active films responding to mechanical forces. The study was divided in two parts: i) First, we studied the barrier opening of multi-compartment films (systems composed of reservoir/barrier strata made of PEM) induced by mechanical stretching. We demonstrated that multilayer barriers could act as nanovalves reversibly controlled by stretching, allowing thus the controlled release of molecules. ii) In a second step, we designed reservoir/barrier systems containing an enzyme, alkaline phosphatase, in order to develop surfaces with biocatalytic activities tuned by mechanical forces. Finally, by applying a mechanical stretching on these systems, the biocatalysis could be triggered and even controlled in a reversible manner.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Serum Albumin Antifouling Effects of Hydroxypropylcellulose and Pluronic F127 Adsorbed on Isobutyramidegrafted Stellate Silica Nanoparticles

International audienceLimiting the serum protein fouling is a major challenge in the design of nanoparticles (NPs) for nanomedicine applications. Suitable chemical surface modification strategies allow to limit the interactions with adsorbing proteins. In this communication, we address the potential of isobutyramide (IBAM) groups grafted on stellate silica nanoparticles (STMS) for the immobilization of two biocompatible polymers renown for biomedical and low fouling applications: Hydroxypropylcellulose (HPC) and Pluronic F127 (PF127). We report that both polymers can be loaded on STMS@IBAM NPs surface with a maximum loading content close to 10 wt %. Regarding their antifouling properties, we report that the coatings of such HPC or PF127 polymers allow to reduce significantly the human serum albumin (HSA) adsorption in average by 70 % as compared to the surface of the free polymer STMS@IBAM. These results highlight the antifouling potential of these polymer pretreatments on IBAM-modified STMS NPs surface

A Low-Cost Motion Capture Corpus in French Sign Language for Interpreting Iconicity and Spatial Referencing Mechanisms

The automatic translation of sign language videos into transcribed texts is rarely approached in its whole, as it implies to finely model the grammatical mechanisms that govern these languages. The presented work is a first step towards the interpretation of French sign language (LSF) by specifically targeting iconicity and spatial referencing. This paper describes the LSF-SHELVES corpus as well as the original technology that was designed and implemented to collect it. Our final goal is to use deep learning methods to circumvent the use of models in spatial referencing recognition. In order to obtain training material with sufficient variability, we designed a lightweight (and low-cost) capture protocol that enabled us to collect data from a large panel of LSF signers. This protocol involves the use of a portable device providing a 3D skeleton, and of a software developed specifically for this application to facilitate the post-processing of handshapes. The LSF-SHELVES includes simple and compound iconic and spatial dynamics, organized in 6 complexity levels, representing a total of 60 sequences signed by 15 LSF signers