Engineering Iron Oxide Nanoparticles for Clinical Settings

Iron oxide nanoparticles (IONPs) occupy a privileged position among magnetic nanomaterials with potential applications in medicine and biology. They have been widely used in preclinical experiments for imaging contrast enhancement, magnetic resonance, immunoassays, cell tracking, tissue repair, magnetic hyperthermia and drug delivery. Despite these promising results, their successful translation into a clinical setting is strongly dependent upon their physicochemical properties, toxicity and functionalization possibilities. Currently, IONPs-based medical applications are limited to the use of non-functionalized IONPs smaller than 100 nm, with overall narrow particle size distribution, so that the particles have uniform physical and chemical properties. However, the main entry of IONPs into the scene of medical application will surely arise from their functionalization possibilities that will provide them with the capacity to target specific cells within the body, and hence to play a role in the development of specific therapies. In this review, we offer an overview of their basic physicochemical design parameters, giving an account of the progress made in their functionalization and current clinical applications. We place special emphasis on past and present clinical trials

Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia and anti-cancer drug delivery

Introduction: Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death. Methods: The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice. Results: All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H = 15.4 kA/m, f = 435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced. Conclusion: The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorallyThe described work was carried out within the project, Multifunctional Nanoparticles for the Selective Detection and Treatment of Cancer (Multifun), which is funded by the European Seventh Framework Program (FP7/2007-2013) under grant agreement number 262943. We thank Dr Vijay Patel and Liquids Research Ltd (Mentec, Deiniol Road, Bangor, Gwynedd, North Wales, UK,) for the supply of MF66 MNP. We gratefully acknowledge Julia Göring and Susann Burgold for technical assistance in carrying out in vivo experiments and Yvonne Ozegowski for animal handling. We thank Francisco J. Teran (Unidad Asociada de Nanobiotecnología CNB-CSIC & IMDEA Nanociencia, Madrid) for helpful discussions. AS and ALC acknowledge financial support from Ministerio de Economia y Competitividad (grants: SAF-15440 and BIO2012-34835) and IMDEA Nanociencia. This work was partially founded by the Comunidad de Madrid NANOFRONTMAG-CM project (S2013/MIT-2850) (IMDEA-Nanociencia)

Engineering conductive protein films through nanoscale self-assembly and gold nanoparticles doping

Protein-based materials are usually considered as insulators, although conductivity has been recently shown in proteins. This fact opens the door to develop new biocompatible conductive materials. While there are emerging efforts in this area, there is an open challenge related to the limited conductivity of protein-based systems. This work shows a novel approach to tune the charge transport properties of protein-based materials by using electron-dense AuNPs. Two strategies are combined in a unique way to generate the conductive solid films: (1) the controlled self-assembly of a protein building block; (2) the templating of AuNPs by the engineered building block. This bottom-up approach allows controlling the structure of the films and the distribution of the AuNPs within, leading to enhanced conductivity. This work illustrates a promising strategy for the development of effective hybrid protein-based bioelectrical materialsThis work was partially supported by the European Research Council ERC-CoG-648071-ProNANO, ERC-PoC-841063-NIMM, Agencia Estatal de Investigación, Spain (PID2019- 111649RB-I00; and MAT2017-88693-R), and the Basque Government (Elkartek KK-2017/00008), E.L-M thanks the Spanish Ministry of Science and Innovation for the FPI grant (BES-2017-079646). This work was performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency – Grant No. MDM-2017-0720 (CIC biomaGUNE) and SEV-2016-0686 (IMDEA Nanociencia

Peptide functionalization of multifunctional hybrid nanoparticles for photodynamic therapy targeting neuropilin-1

Le développement de la thérapie photodynamique s’oriente vers la conception de photosensibilisateurs de 3ème génération, assemblages moléculaires adressés vers une cible biologique spécifique. Les nanoparticules développées dans un cadre de cette thèse sont constituées d’un cœur d’oxyde de gadolinium recouvert d’une couche de polysiloxane. Une chlorine est couplée de façon covalente dans cette couche de polysiloxane. Un surfactant hydrophile recouvre la surface des nanoparticules afin de les rendre biocompatibles. Enfin, les nanoparticules sont fonctionnalisées par le peptide ATWLPPR ciblant le récepteur d’intérêt neuropiline-1, surexprimé par les cellules endothéliales activées lors de l’angiogenèse tumorale. La stratégie est double : d'une part, il s'agit de traiter les lésions cancéreuses par thérapie photodynamique, d’autre part d'asphyxier le tissu tumoral en s'attaquant au réseau vasculaire qui l'alimente en nutriments et en oxygène. L'optimisation de la nanoplate-forme a porté sur la taille du cœur d’oxyde de gadolinium pour une intensité du signal IRM rehaussée, l’épaisseur de la coquille pour permettre la diffusion de l’oxygène indispensable à la réaction photodynamique donc à l’efficacité thérapeutique, le choix et la quantité d’unités peptidique couplées pour une sélectivité maximale pour les tissus tumoraux par rapport aux tissus sainsThe development of photodynamic therapy (PDT) is focused on the conception of 3rd generation of photosensitizers which are molecular constructs targeted to specific biological receptors. The nanoparticles we have developed in this thesis are made of a gadolinium oxide core, a polysiloxane shell in which are covalently entrapped chlorins. Hydrophilic surfactants are grafted on the nanoparticles in order to make it biocompatible. Finally, the nanoparticles are functionalized by ATWLPPR peptide to target neuropilin-1 which is over-expressed on endothelial cells during tumoral angiogenesis. The aim of this strategy is both to treat cancer lesion by photodynamic therapy and to asphyxiate the tumoral tissue by destroying the vasculature that brings nutrients and oxygen to the tumor. The optimization of the nanoplate-form has been done by modifying the size of the gadolinium core for the best MRI signal, the size of the polysiloxane shell in order to let the oxygen diffuse in and out of the nanoparticle, the type and the amount of peptides coupled to the surfactant for the best selectivity for tumoral tissue compared to normal tissu

Fonctionnalisation par des peptides de nanoparticules hybrides multifonctionnelles pour de la thérapie photodynamique ciblant neuropiline-1

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Microwave-assisted expeditious O-alkylation of meso-hydroxyphenylporphyrins

International audienceA mild method for O-alkylation of meso-hydroxyphenylporphyrin has been developed using microwave irradiation. This method is clean and efficient for many substrates and results in significant improvement in reaction yield and in a dramatic decrease in reaction time in comparison to thermal heatin

La septoriose du blé en France en 2004. Les strobilurines en péril ?

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Triazinyl porphyrin-based photoactive cotton fabrics: preparation, characterization, and antibacterial activity.

International audienceIn the present work, we report on the synthesis of cellulose cotton fibers bearing different types of photosensitizers with the aim to prepare new efficient polymeric materials for antimicrobial applications. Anionic, neutral, and cationic amino porphyrins have been covalently grafted on cotton fabric, without previous chemical modification of the cellulosic support, using a 1,3,5-triazine derivative as the linker. The obtained porphyrin-grafted cotton fabrics were characterized by infrared (ATR-FTIR), diffuse reflectance UV-vis (DRUV) spectroscopies, and thermogravimetric analysis (TGA) to confirm the triazine linkage. Antimicrobial activity of porphyrin-cellulose materials was tested under visible light irradiation against Staphylococcus aureus and Escherichia coli . The results showed excellent activity on the Gram-positive bacterium, showing structure-activity relationship, although no photodamage of the Gram-negative microorganism was recorded. A mechanism of bacterial inactivation by photosensitive surfaces is proposed

Carbohydrate-Porphyrin Conjugates with Two-Photon Absorption Properties as Potential Photosensitizing Agents for Photodynamic Therapy

International audienceWe report the synthesis of a series of conjugated zinc porphyrin oligomers designed as photodynamic therapy agents. These compounds exhibit exceptionally high two-photon absorption cross-sections, redshifted linear absorption spectra, and high singlet oxygen quantum yields, making them ideal for one-photon- and two-photon-excited photodynamic therapy. These products are substituted by three α-mannose units on each chromophore with the aim to target tumor cells with over-expressing lectin-type membrane receptors

Silica-based nanoparticles for photodynamic therapy applications

International audienceSilica-based nanoparticles for applications in photodynamic therapy (PDT) have emerged as a promising field for the treatment of cancer. In this review, based on the pathway the photosensitizer is entrapped inside the silica matrix, the different methods for the synthesis of silica-based nanoparticles are described from the pioneering works to the latest achievements which concern multifunctional nanoplatforms, up-converting nanoparticles, two-photon PDT, vectorization and in vivo applications