Publications by authors named "Magali Gary-Bobo"

78 Publications

A rational study of the influence of Mn-insertion in Prussian blue nanoparticles on their photothermal properties.

J Mater Chem B 2021 Nov 2. Epub 2021 Nov 2.

IBMM, Univ. Montpellier, CNRS, ENSCM, Montpellier, France.

We investigated a series of Mn-Prussian blue (PB) nanoparticles NaMnFe[Fe(CN)]·HO of similar size, surface state and cubic morphology with various amounts of Mn synthesized through a one step self-assembly reaction. We demonstrated by a combined experimental-theoretical approach that during the synthesis, Mn substituted Fe up to a Mn/Na-Mn-Fe ratio of 32 at% in the PB structure, while for higher amounts, the Mn[Fe(CN)] analogue is obtained. For comparison, the post-synthetic insertion of Mn2+ in PB nanoparticles was also investigated and completed with Monte-Carlo simulations to probe the plausible adsorption sites. The photothermal conversion efficiency () of selected samples was determined and showed a clear dependence on the Mnamount with a maximum efficiency for a Mn/Na-Mn-Fe ratio of 10 at% associated with a dependence on the nanoparticle concentration. Evaluation of the photothermal properties of these nanoparticles performed on triple negative human breast adenocarcinoma (MDA-MB-231) cells by using continuous and pulsed laser irradiation confirm their excellent PTT efficiency permitting low dose use.
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http://dx.doi.org/10.1039/d1tb00888aDOI Listing
November 2021

Modified Indulines: From Dyestuffs to Theranostic Agents.

ACS Appl Mater Interfaces 2021 Jul 23;13(26):30337-30349. Epub 2021 Jun 23.

Aix Marseille Université, CNRS, CINaM, UMR 7325, Campus de Luminy, 13288 Marseille Cedex 09, France.

The efficient, versatile, and straightforward synthesis of the first -alkyl analogues of induline 3B ( and ) is reported. Thanks to the introduction of lipophilic substituents and their attractive photophysical properties (far-red emission and production of singlet oxygen), phenazinium can be used as a theranostic agent and shows, at very low concentrations (100 nM), a remarkable ability to (i) image cells and zebrafish embryos with high quality under both mono- (514 nm) and biphotonic (790 and 810 nm) excitations, (ii) efficiently and quickly penetrate cancer cells rather than healthy fibroblasts, and (iii) induce a total or almost total cancer cell death and after illumination (λ = 540-560 nm). The molecular structure of is based on a triamino-phenazinium core only, with no need for additional components, highlighting the emergence of a minimalistic and versatile class of fluorescent probes for targeted photodynamic cancer therapy.
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http://dx.doi.org/10.1021/acsami.1c05933DOI Listing
July 2021

Pivotal Role for Cxcr2 in Regulating Tumor-Associated Neutrophil in Breast Cancer.

Cancers (Basel) 2021 May 25;13(11). Epub 2021 May 25.

CNRS, SYS2DIAG-ALCEDIAG, Cap Delta, 1682 rue de la Valsière, 34184 Montpellier, France.

Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis. The analysis of tumor content of PyMT-Cxcr2-/- animals highlighted an increased infiltration of tumor associated neutrophils (TANs), mirrored by a decreased recruitment of tumor associated macrophages (TAMs) compared to PyMT animals. Analysis of PyMT-Cxcr2-/- TANs revealed that they lost their killing ability compared to PyMT-Cxcr2+/+ TANs. The transcriptomic analysis of PyMT-Cxcr2-/- TANs showed that they had a more pronounced pro-tumor TAN2 profile compared to PyMT TANs. In particular, PyMT-Cxcr2-/- TANs displayed an up-regulation of the pathways involved in reactive oxygen species (ROS) production and angiogenesis and factors favoring metastasis, but reduced apoptosis. In summary, our data reveal that a lack of Cxcr2 provides TANs with pro-tumor effects.
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http://dx.doi.org/10.3390/cancers13112584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197482PMC
May 2021

Study of Cytotoxic and Photodynamic Activities of Dyads Composed of a Zinc Phthalocyanine Appended to an Organotin.

Pharmaceuticals (Basel) 2021 Apr 28;14(5). Epub 2021 Apr 28.

CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, CNRS, UMR CNRS 6230, Université de Nantes, 2, rue de la Houssinière-BP 92208, CEDEX 3, 44322 Nantes, France.

The combination of photodynamic therapy and chemotherapy is a promising strategy to enhance cancer therapeutic efficacy and reduce drug resistance. In this study two zinc(II) phthalocyanine-tin(IV) conjugates linked by a triethylene glycol chain were synthesized and characterized. In these complexes, the zinc(II) phthalocyanine was used as a potential photosensitizer for PDT and the tin complex was selected as cytostatic moiety. The two dyads composed of zinc(II) phthalocyanine and tin complexes exhibited high cytotoxicity, in absence of light stimulation, against MCF-7 human breast cancer cells with low LC values in the range of 0.016-0.453 µM. In addition, these complexes showed superior cytotoxicity than their mixture of equimolar component, accompanied with a higher activity towards cancer cells compared to human healthy fibroblasts. However, under irradiation of the zinc phthalocyanine unit (at 650 nm) no photodynamic activity could be detected, due to the most likely quenching of zinc(II) phthalocyanine singlet excited state by the nearby tin complex according to a photoinduced electron transfer process. This study demonstrates the potential of heterometallic anticancer chemotherapeutics composed of a zinc phthalocyanine and tin complex, and it highlights that the development of such conjugates requires that the sensitizer preserves its photophysical properties and in particular its singlet oxygen sensitization ability in the conjugate in order to combine the PDT activity with the cytotoxicity of the anticancer drug.
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http://dx.doi.org/10.3390/ph14050413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145453PMC
April 2021

Synergetic anticancer activity of gold porphyrin appended to phenyl tin malonate organometallic complexes.

Dalton Trans 2021 Apr 11;50(13):4583-4592. Epub 2021 Mar 11.

IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France.

The discovery of novel anticancer chemotherapeutics is fundamental to treat cancer more efficiently. Towards this goal, two dyads consisting of a gold porphyrin appended to organotin(iv) entities were synthesized and their physicochemical and biological properties were characterized. One dyad contains a gold porphyrin connected to a tin(iv) cation via a malonate and two phenyl ligands (AuP-SnPh), while the other contains two tin(iv) cations each chelated to one carboxylic acid group of the malonate and three phenyl ligands (AuP-SnPh). The mode of chelation of Sn(iv) to the malonate was elucidated by IR spectroscopy and Sn NMR. In the solid state, the complexes exist as coordination polymers in which the tin is penta-coordinated and bridged to two different malonate units. In solution the chemical shifts of Sn signals indicate that the tin complexes are in the form of monomeric species associated with a tetra-coordinated tin cation. The therapeutic potential of these new compounds was assessed by determining their cytotoxic activities on human breast cancer cells (MCF-7) and on healthy human fibroblasts (FS 20-68). The study reveals that the dyads are more potent anticancer drugs than the mixture of their individual components (gold porphyrin and reference tin complexes). Therefore, the covalent link of organotin complexes to a gold porphyrin induces a synergistic cytotoxic effect. The dyad AuP-SnPh shows high cytotoxicity (0.13 μM) against MCF-7 along with good selectivity for cancer cells versus healthy cells. Finally, it was also shown that the dyad AuP-SnPh exhibits a very high anticancer activity (LC = 0.024 μM), but the presence of two tin units induces strong cytotoxicity on healthy cells too (LC = 0.032 μM). This study underscores, thus, the potential of the association of gold porphyrin and organotin complexes to develop anticancer metallo-drugs.
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http://dx.doi.org/10.1039/d0dt03792cDOI Listing
April 2021

Mesoporous silica adsorbents modified with amino polycarboxylate ligands - functional characteristics, health and environmental effects.

J Hazard Mater 2021 03 2;406:124698. Epub 2020 Dec 2.

ICGM, Univ. Montpellier, CNRS, ENSCM, Case 1701, Place Eugène Bataillon, CEDEX 05, 34095 Montpellier, France. Electronic address:

A series of hybrid adsorbents were produced by surface modification with amino polycarboxylate ligands of industrially available microparticles (MP) of Kromasil® mesoporous nanostructured silica beads, bearing grafted amino propyl ligands. Produced materials, bearing covalently bonded functions as EDTA and TTHA, original Kromasil®, bearing amino propyl ligands, and bare particles, obtained by thermal treatment of Kromasil® in air, were characterized by SEM-EDS, AFM, FTIR, TGA and gas sorption techniques. Adsorption kinetics and capacity of surface-modified particles to adsorb Rare Earth Elements (REE), crucial for extraction in recycling processes, were evaluated under dynamic conditions, revealing specificity matching the ligand nature and the size of REE cations. A detailed comparison with earlier reported adsorbents for REE extraction was presented. The cytotoxicity was assessed using four different types of healthy cells, human skeletal muscles derived cells (SKMDC), fibroblast cells, macrophage cells (RAW264.7), and human umbilical vein endothelial cells (HUVECs), indicating lower toxicity of ligand-free MP than MP bearing amino poly-carboxylate functions. Internalization of the MP inside the cells and release of nitric oxide were observed. In addition, zebrafish embryos were exposed to high concentrations of MP and did not show any pronounced toxicity.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124698DOI Listing
March 2021

Cell-Selective siRNA Delivery Using Glycosylated Dynamic Covalent Polymers Self-Assembled In Situ by RNA Templating.

Angew Chem Int Ed Engl 2021 03 28;60(11):5783-5787. Epub 2021 Jan 28.

Institut des Biomolécules Max Mousseron (IBMM), CNRS, Université de Montpellier, ENSCM, Montpellier, France.

Dynamic covalent libraries enable exploring complex chemical systems from which bioactive assemblies can adaptively emerge through template effects. In this work, we studied dynamic covalent libraries made of complementary bifunctional cationic peptides, yielding a diversity of species from macrocycles to polymers. Although polymers are typically expressed only at high concentration, we found that siRNA acts as a template in the formation of dynamic covalent polymers at low concentration in a process guided by electrostatic binding. Using a glycosylated building block, we were able to show that this templated polymerization further translates into the multivalent presentation of carbohydrate ligands, which subsequently promotes cell uptake and even cell-selective siRNA delivery.
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http://dx.doi.org/10.1002/anie.202014066DOI Listing
March 2021

Two-Photon Absorbing AIEgens: Influence of Stereoconfiguration on Their Crystallinity and Spectroscopic Properties and Applications in Bioimaging.

ACS Appl Mater Interfaces 2020 Dec 20;12(49):55157-55168. Epub 2020 Nov 20.

Univ. Lyon, ENS Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie, UMR 5182, 46 Allée d'Italie, 69364 Lyon, France.

This paper aims at designing chromophores with efficient aggregation-induced emission (AIE) properties for two-photon fluorescence microscopy (2PFM), which is one of the best-suited types of microscopy for the imaging of living organisms or thick biological tissues. Tetraphenylethylene (TPE) derivatives are common building blocks in the design of chromophores with efficient AIE properties. Therefore, in this study, extended TPE AIEgens specifically optimized for two-photon absorption (2PA) are synthesized and the resulting (/) isomers are separated using chromatography on chiral supports. Comparative characterization of the AIE properties is performed on the pure () and () isomers and the mixture, allowing us, in combination with powder X-ray diffraction and solid-state NMR, to document a profound impact of crystallinity on solid-state fluorescence properties. In particular, we show that stereopure AIEgens form aggregates of superior crystallinity, which in turn exhibit a higher fluorescence quantum yield compared to diastereoisomers mixtures. Preparation of stereopure organic nanoparticles affords very bright fluorescent contrast agents, which are then used for cellular and intravital two-photon microscopy on human breast cancer cells and on zebrafish embryos.
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http://dx.doi.org/10.1021/acsami.0c15810DOI Listing
December 2020

Biological Assessment of Laser-Synthesized Silicon Nanoparticles Effect in Two-Photon Photodynamic Therapy on Breast Cancer MCF-7 Cells.

Nanomaterials (Basel) 2020 Jul 26;10(8). Epub 2020 Jul 26.

IBMM, Univ Montpellier, CNRS, ENSCM, 34093 Montpellier, France.

Driven by their distinctive physiological activities, biological properties and unique theranostic modalities, silicon nanoparticles (SiNPs) are one of the promising materials for the development of novel multifunctional nanoplatforms for biomedical applications. In this work, we assessed the possibility to use laser-synthesized Si NPs as photosensitizers in two-photon excited photodynamic therapy (TPE-PDT) modality. Herein, we used an easy strategy to synthesize ultraclean and monodispersed SiNPs using laser ablation and fragmentation sequences of silicon wafer in aqueous solution, which prevent any specific purification step. Structural analysis revealed the spherical shape of the nanoparticles with a narrow size distribution centered at the mean size diameter of 62 nm ± 0.42 nm, while the negative surface charge of -40 ± 0.3 mV ensured a great stability without sedimentation over a long period of time. In vitro studies on human cancer cell lines (breast and liver) and healthy cells revealed their low cytotoxicity without any light stimulus and their therapeutic potential under TPE-PDT mode at 900 nm with a promising cell death of 45% in case of MCF-7 breast cancer cells, as a consequence of intracellular reactive oxygen species release. Their luminescence emission inside the cells was clearly observed at UV-Vis region. Compared to Si nanoparticles synthesized via chemical routes, which are often linked to additional modules with photochemical and photobiological properties to boost photodynamic effect, laser-synthesized SiNPs exhibit promising intrinsic therapeutic and imaging properties to develop advanced strategy in nanomedicine field.
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http://dx.doi.org/10.3390/nano10081462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466460PMC
July 2020

Porphyrin-based bridged silsesquioxane nanoparticles for targeted two-photon photodynamic therapy of zebrafish xenografted with human tumor.

Cancer Rep (Hoboken) 2019 10 30;2(5):e1186. Epub 2019 May 30.

CNRS, ENSCM, Institut de Biomolécules Max Mousseron, UMR 5247, Univ Montpellier, Montpellier, France.

Background: Bridged silsesquioxane nanoparticles (BSNs) recently described represent a new class of nanoparticles exhibiting versatile applications and particularly a strong potential for nanomedicine.

Aims: In this work, we describe the synthesis of BSNs from an octasilylated functional porphyrin precursor (PORBSNs) efficiently obtained through a click reaction. These innovative and very small-sized nanoparticles were functionalized with PEG and mannose (PORBSNs-mannose) in order to target breast tumors in vivo.

Methods And Results: The structure of these nanoparticles is constituted of porphyrins J aggregates that allow two-photon spatiotemporal excitation of the nanoparticles. The therapeutic potential of such photoactivable nanoparticles was first studied in vitro, in human breast cancer cells in culture and then in vivo on zebrafish embryos bearing human tumors. These animal models were intravenously injected with 5 nL of a solution containing PORBSNs-mannose. An hour and half after the injection of photoactivable and targeted nanoparticles, the tumor areas were excited for few seconds with a two-photon beam induced focused laser. We observed strong tumor size decrease, with the involvement of apoptosis pathway activation.

Conclusion: We demonstrated the high targeting, imaging, and therapeutic potential of PORBSNs-mannose injected in the blood stream of zebrafish xenografted with human tumors.
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http://dx.doi.org/10.1002/cnr2.1186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941560PMC
October 2019

Polythiophenes with Cationic Phosphonium Groups as Vectors for Imaging, siRNA Delivery, and Photodynamic Therapy.

Nanomaterials (Basel) 2020 Jul 22;10(8). Epub 2020 Jul 22.

ICGM, University of Montpellier, CNRS, ENSCM, CC1701, Place Eugène Bataillon, 34095 Montpellier, France.

In this work, we exploit the versatile function of cationic phosphonium-conjugated polythiophenes to develop multifunctional platforms for imaging and combined therapy (siRNA delivery and photodynamic therapy). The photophysical properties (absorption, emission and light-induced generation of singlet oxygen) of these cationic polythiophenes were found to be sensitive to molecular weight. Upon light irradiation, low molecular weight cationic polythiophenes were able to light-sensitize surrounding oxygen into reactive oxygen species (ROS) while the highest were not due to its aggregation in aqueous media. These polymers are also fluorescent, allowing one to visualize their intracellular location through confocal microscopy. The most promising polymers were then used as vectors for siRNA delivery. Due to their cationic and amphipathic features, these polymers were found to effectively self-assemble with siRNA targeting the luciferase gene and deliver it in cancer cells expressing luciferase, leading to 30-50% of the gene-silencing effect. In parallel, the photodynamic therapy (PDT) activity of these cationic polymers was restored after siRNA delivery, demonstrating their potential for combined PDT and gene therapy.
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http://dx.doi.org/10.3390/nano10081432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466636PMC
July 2020

The mannose 6-phosphate receptor targeted with porphyrin-based periodic mesoporous organosilica nanoparticles for rhabdomyosarcoma theranostics.

Biomater Sci 2020 Jul 29;8(13):3678-3684. Epub 2020 May 29.

NanoMedSyn Avenue Charles Flahault, 34093, Montpellier Cedex 05, France.

Porphyrin-based periodic mesoporous organosilica nanoparticles (PMO) synthesized from a large functional octatriethoxysilylated porphyrin precursor and allowing two-photon excitation photodynamic therapy (TPE-PDT) and NIR imaging were synthesized. These PMO were grafted with polyethylene glycol (PEG) moieties and an analogue of mannose 6-phosphate functionalized at the anomeric position (AMFA). AMFAs are known to efficiently target mannose 6-phosphate receptors (M6PRs) which are over-expressed in various cancers. Here, we demonstrated for the first time that M6PRs were over-expressed in rhabdomyosarcoma (RMS) cells and could be efficiently targeted with PMO-AMFA allowing TPE imaging and TPE-PDT of RMS cells. The comparison with healthy myoblasts demonstrated an absence of biological effects, suggesting a cancer cell specificity in the biomedical action observed.
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http://dx.doi.org/10.1039/d0bm00586jDOI Listing
July 2020

Pyclen-Based Ln(III) Complexes as Highly Luminescent Bioprobes for and One- and Two-Photon Bioimaging Applications.

J Am Chem Soc 2020 06 21;142(22):10184-10197. Epub 2020 May 21.

Univ Brest, UMR CNRS 6521 CEMCA, 6 Avenue Victor le Gorgeu, 29200 Brest, France.

In addition to the already described ligand , two pyclen-based lanthanide chelators, and , bearing two specific picolinate two-photon antennas (tailor-made for each targeted metal) and one acetate arm arranged in a dissymmetrical manner, have been synthesized, to form a complete family of lanthanide luminescent bioprobes: [Eu], [Sm], [Yb], [Tb], and [Dy]. Additionally, the symmetrically arranged regioisomer was also synthesized as well as its [Eu] complex to highlight the astonishing positive impact of the dissymmetrical -distribution of the functional chelating arms. The investigation clearly shows the high performance of each bioprobe, which, depending on the complexed lanthanide, could be used in various applications. Each presents high brightness, quantum yields, and lifetimes. Staining of the complexes into living human breast cancer cells was observed. In addition, two-photon microscopy was performed for the first time on a living zebrafish model with [Eu]. No apparent toxicity was detected on the growth of the zebrafish, and images of high quality were obtained.
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http://dx.doi.org/10.1021/jacs.0c03496DOI Listing
June 2020

Fashioning Prussian Blue Nanoparticles by Adsorption of Luminophores: Synthesis, Properties, and Imaging.

Inorg Chem 2020 Apr 9;59(7):4567-4575. Epub 2020 Mar 9.

UMR 5253, Equipe Ingénierie Moléculaire et Nano-Objets, Université de Montpellier, ENSCM, CNRS, Institut Charles Gerhardt, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.

We report the postsynthetic functionalization of Prussian blue (PB) nanoparticles by two different luminophores (2-aminoanthracene and rhodamine B). We show that the photoluminescence properties of the fluorophores are modified by a confinement effect upon adsorption and demonstrate that such multifunctional nanosized systems could be used for in vitro imaging.
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http://dx.doi.org/10.1021/acs.inorgchem.9b03699DOI Listing
April 2020

Sequential delivery of synergistic drugs by silica nanocarriers for enhanced tumour treatment.

J Mater Chem B 2020 02;8(7):1472-1480

ICGM, Univ. Montpellier, CNRS, ENSCM, Montpellier, France.

Herein hybrid silica nanoparticles have been engineered to direct the sequential delivery of multiple chemotherapeutic drugs in response to external stimuli such as variations in pH. The nanocarriers consist of conventional MCM-41-type nanoparticles, which have been functionalised with an organic ligand (or stalk) grafted onto the external surface. The stalk is designed to "recognise" a complementary molecule, which serves as a "cap" to block the pores of the nanoparticles. First, camptothecin is introduced into the pores by diffusion prior to capping the pore apertures via molecular recognition. The cap, which is a derivative of 5-fluorouracil, serves as a second cytotoxic drug for synergistic chemotherapy. In vitro tests revealed that negligible release of the drugs occurred at pH 7.4, thus avoiding toxic side effects in the blood stream. In contrast, the stalk/cap complex is destabilised within the endolysosomal compartment (pH 5.5) of cancer cells, where release of the drugs was demonstrated. Furthermore, this environmentally responsive system exhibited a synergistic effect of the two drugs, where the pH-triggered release of the cytotoxic cap followed by diffusion-controlled release of the drug cargo within the pores led to essentially complete elimination of breast cancer cells.
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http://dx.doi.org/10.1039/c9tb02225bDOI Listing
February 2020

Reverse poly(ε-caprolactone)-g-dextran graft copolymers. Nano-carriers for intracellular uptake of anticancer drugs.

Carbohydr Polym 2020 Mar 24;232:115764. Epub 2019 Dec 24.

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université Montpellier, ENSCM, Faculté de Pharmacie, Bâtiment I, 15 Avenue Charles Flahault, BP14491, 34093, Montpellier Cedex 5, France. Electronic address:

A new fully biodegradable "reverse" oligosaccharide-based amphiphilic graft copolymer structure with a hydrophobic backbone and hydrophilic side chains, poly(ε-caprolactone)-g-dextran (PCL-g-Dex) was synthetized. For this purpose, "clickable" propargylated PCL (PCL-yne) and azido-dextran (Dex-N3) were prepared to further synthesize PCL-g-Dex copolymer by a Huisgen's cycloaddition. This "reverse" copolymer architecture self-assembled in biodegradable nano-carriers, in the shape of dynamic polymeric micelles, and were loaded with doxorubicin (Dox) anti-cancer drug. Dox-loaded micelles showed different drug releases depending on the pH. Cytotoxicity tests showed that Dox-loaded micelles can selectively kill colon cancer cells (HCT-116) while they have no cytotoxic effect towards healthy cells (CCD-45SK). Fluorescent micelles based on FITC-labelled PCL-g-Dex copolymer were used for fluorescence imaging and flow cytometry assays. These experiments proved the effective and specific internalization of micelles by cancer cells, whereas healthy cells showed a very poor uptake. These results show that PCL-g-Dex micelles may be a promising Dox nano-carrier in cancer chemotherapy.
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http://dx.doi.org/10.1016/j.carbpol.2019.115764DOI Listing
March 2020

Encapsulation of Upconversion Nanoparticles in Periodic Mesoporous Organosilicas.

Molecules 2019 Nov 9;24(22). Epub 2019 Nov 9.

Institut Charles Gerhardt Montpellier, case 1701, UMR5253, CNRS-UM-ENSCM, Place Eugène Bataillon, 34095 Montpellier, CEDEX 05, France.

(1) Background: Nanomedicine has recently emerged as a promising field, particularly for cancer theranostics. In this context, nanoparticles designed for imaging and therapeutic applications are of interest. We, therefore, studied the encapsulation of upconverting nanoparticles in mesoporous organosilica nanoparticles. Indeed, mesoporous organosilica nanoparticles have been shown to be very efficient for drug delivery, and upconverting nanoparticles are interesting for near-infrared and X-ray computed tomography imaging, depending on the matrix used. (2) Methods: Two different upconverting-based nanoparticles were synthesized with Yb-Er as the upconverting system and NaYF or BaLuF as the matrix. The encapsulation of these nanoparticles was studied through the sol-gel procedure with bis(triethoxysilyl)ethylene and bis(triethoxysilyl)ethane in the presence of CTAB. (3) Results: with bis(triethoxysilyl)ethylene, BaLuF: Yb-Er, nanoparticles were not encapsulated, but anchored on the surface of the obtained mesoporous nanorods BaLuF: [email protected] With bis(triethoxysilyl)ethane, BaLuF: Yb-Er and NaYF: Yb-Ernanoparticles were encapsulated in the mesoporous cubic structure leading to BaLuF: [email protected] and NaYF: [email protected], respectively. (4) Conclusions: upconversion nanoparticles were located on the surface of mesoporous nanorods obtained by hydrolysis polycondensation of bis(triethoxysilyl)ethylene, whereas encapsulation occurred with bis(triethoxysilyl)ethane. The later nanoparticles NaYF: [email protected] or BaLuF: [email protected] were promising for applications with cancer cell imaging or X-ray-computed tomography respectively.
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http://dx.doi.org/10.3390/molecules24224054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891486PMC
November 2019

Biocompatible conjugated fluorenylporphyrins for two-photon photodynamic therapy and fluorescence imaging.

Chem Commun (Camb) 2019 Oct;55(81):12231-12234

Univ Rennes, INSA Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) - UMR 6226, F-35000 Rennes, France.

The photophysical properties of a new series of fluorenyl porphyrins bearing water-solubilising oligoethyleneglycol chains are described. These biocompatible compounds present very good two-photon absorption and singlet oxygen generation properties, while retaining some fluorescence in water. After testing in vitro on breast cancer cells, some of them were shown to be efficient non-toxic two-photon photosensitisers allowing for fluorescence imaging, thus demonstrating their theranostic potential.
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http://dx.doi.org/10.1039/c9cc05657bDOI Listing
October 2019

Topological Requirements for CI-M6PR-Mediated Cell Uptake.

Bioconjug Chem 2019 10 26;30(10):2533-2538. Epub 2019 Sep 26.

Institut des Biomolécules Max Mousseron , UMR CNRS-UM-ENSCM 5247, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault , 34093 Montpellier Cedex 5, France.

The 300 kDa cation-independent M6P receptor (CI-MPR) mediates ligand internalization and trafficking to the endolysosomal compartments. Because of its endocytotic nature, it has been recognized as a promising class of receptors for target component delivery. Its cellular uptake involves the simultaneous binding of two protein units resulting in the formation of receptor dimers. While many multivalent glycoconjugates have been reported to date, little is known about the topological requests to induce an effective recruitment of CI-MPRs. We herein describe the synthesis and cell uptake ability of a set of highly organized glycoclusters bearing one to three saccharide units. The spatial arrangement of carbohydrate ligands is ensured by a heterocyclic γ-peptide central core.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00590DOI Listing
October 2019

Synthesis and Anticancer Activity of Gold Porphyrin Linked to Malonate Diamine Platinum Complexes.

Inorg Chem 2019 Sep 5;58(18):12395-12406. Epub 2019 Sep 5.

CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, CNRS, UMR CNRS 6230 , Université LUNAM, Université de Nantes, UFR des Sciences et des Techniques , 2, rue de la Houssinière , BP 92208, 44322 Nantes Cedex 3, France.

Recently, gold(III) porphyrins have gained great interest as anticancer drugs not only for the stability of gold(III) but also for the functionalization of the porphyrin to allow bridging with another metal such as platinum(II). We report here, for the first time, the synthesis of three new bimetal compounds containing a gold(III) porphyrin conjugated to a platinum diamine moiety through malonate bridging to obtain enhanced cytotoxicity from both metals combined with the phototoxicity of the porphyrin. The three complexes differ in the type of diamine ligand around platinum(II): ammonia (NH), cyclohexanediamine (CyDA), and pyridylmethylamine (Py). The synthesis was carried out using the complexation of activated malonic acid derivatives with aquadiaminoplatinum(II) complexes, and the products were characterized by IR, NMR, mass spectra, and elementary analysis. The cytotoxic activity of the conjugates was screened in both healthy cell lines and cancer cell lines, human fibroblast cells (FS-68) and human breast cancer cells (MCF-7), and was compared to that of the corresponding platinum(II) complexes. The cyclohexyldiamine (CyDA) derivative exhibited the greatest cytotoxic effect among the series. The results showed that Au(III)/Pt(II) conjugates are more potent by 2-5.6-fold than the corresponding platinum complexes. Moreover, the dyad AuP-PtCyDA is 18% more potent and also more selective toward cancer cells than the parent gold porphyrin substituted with malonic acid. On the other hand, the IC of the dyad AuP-PtCyDA is 43% lower than that of AuTPP but is more selective toward healthy cells. Singlet oxygen measurements indicated that gold(III) porphyrin derivatives are poor oxygen sensitizers and cell death occurred potentially due to generation of other reactive oxygen species (ROS) upon reductive quenching of the gold porphyrin excited state. In addition, the increase in cancer cell death obtained after light irradiation is totally absent in healthy cells, demonstrating the specificity of this PDT treatment on cancer cells. Our findings imply that the incorporation of two different cytotoxic metals in the same molecule represents a remarkable cytotoxic effect in comparison to traditional homometallic Pt(II) drugs.
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http://dx.doi.org/10.1021/acs.inorgchem.9b01981DOI Listing
September 2019

Phthalocyanine-based mesoporous organosilica nanoparticles: NIR photodynamic efficiency and siRNA photochemical internalization.

Chem Commun (Camb) 2019 Sep;55(77):11619-11622

Gebze Technical University, Department of Chemistry, Gebze, 41400 Kocaeli, Turkey.

Mesoporous organosilica nanoparticles (PHT-PMO) have been prepared from an octa-triethoxysilylated Zn phthalocyanine precursor. These PHT-PMO nanoparticles had no dark toxicity but high phototoxicity when irradiated at 650 nm, and remarkable near-infrared phototoxicity when excited at 760 and 810 nm. The PHT-PMO were then aminated to promote electrostatic complexation with siRNA. Transfection experiments were performed upon NIR irradiation and photochemical internalization was very efficient, leading to 65% luciferase extinction in MCF-7 cancer cells expressing stable luciferase.
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http://dx.doi.org/10.1039/c9cc05703jDOI Listing
September 2019

Combination of photodynamic therapy and gene silencing achieved through the hierarchical self-assembly of porphyrin-siRNA complexes.

Int J Pharm 2019 Oct 31;569:118585. Epub 2019 Jul 31.

IBMM, Université de Montpellier, CNRS, ENSCM, Montpellier, France. Electronic address:

In this work, we implemented a supramolecular approach in order to combine photodynamic therapy (PDT) with gene therapy. We made use of a simple cationic guanidylated porphyrin (H‑PG) with the hypothesis that porphyrin aggregates should be capable of complexing siRNA through multivalent interactions and thus contribute to its intracellular delivery, while remaining active photosensitizers for PDT. The PDT effect of H‑PG was shown by incubating human breast cancer cells (MDA-MB-231) with H‑PG followed by light-irradiation at 405 nm. On the other hand, while siRNA do not enter cells alone, we showed, by fluorescence confocal microscopy and flow cytometry, that H‑PG promotes the internalization of Atto-488 siRNA. Finally, studying the combined PDT and delivery of siRNA directed against inhibitory apoptotic protein (IAP) family, we found an additive effect of the two therapies, thereby demonstrating that H‑PG is capable of acting both as a photosensitizer and supramolecular siRNA vector.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118585DOI Listing
October 2019

Mannose 6-phosphonate labelling: A key for processing the therapeutic enzyme in Pompe disease.

J Cell Mol Med 2019 09 10;23(9):6499-6503. Epub 2019 Jul 10.

NanoMedSyn, Montpellier, France.

In the search of a better enzyme therapy in Pompe disease, the conjugation of mannose 6-phosphonates to the recombinant enzyme appeared as an enhancer of its efficacy. Here, we demonstrated that the increased efficacy of the conjugated enzyme is partly due to a higher intracellular maturation because of its insensitiveness to acid phosphatases during the routing to lysosomes.
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http://dx.doi.org/10.1111/jcmm.14516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714136PMC
September 2019

Efficient Photodynamic Therapy of Prostate Cancer Cells through an Improved Targeting of the Cation-Independent Mannose 6-Phosphate Receptor.

Int J Mol Sci 2019 Jun 8;20(11). Epub 2019 Jun 8.

IBMM, Univ Montpellier, CNRS, ENSCM, 34093 Montpellier, France.

The aim of the present work is the development of highly efficient targeting molecules to specifically address mesoporous silica nanoparticles (MSNs) designed for the photodynamic therapy (PDT) of prostate cancer. We chose the strategy to develop a novel compound that allows the improvement of the targeting of the cation-independent mannose 6-phosphate receptor, which is overexpressed in prostate cancer. This original sugar, a dimannoside-carboxylate (M6C-Man) grafted on the surface of MSN for PDT applications, leads to a higher endocytosis and thus increases the efficacy of MSNs.
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http://dx.doi.org/10.3390/ijms20112809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600508PMC
June 2019

Biosafety of Mesoporous Silica Nanoparticles.

Biomimetics (Basel) 2018 Aug 15;3(3). Epub 2018 Aug 15.

Institute Charles Gerhardt of Montpellier (ICGM), Place E. Bataillon, 34095 Montpellier, France.

Careful analysis of any new nanomedicine device or disposal should be undertaken to comprehensively characterize the new product before application, so that any unintended side effect is minimized. Because of the increasing number of nanotechnology-based drugs, we can anticipate that regulatory authorities might adapt the approval process for nanomedicine products due to safety concerns, e.g., request a more rigorous testing of the potential toxicity of nanoparticles (NPs). Currently, the use of mesoporous silica nanoparticles (MSN) as drug delivery systems is challenged by a lack of data on the toxicological profile of coated or non-coated MSN. In this context, we have carried out an extensive study documenting the influence of different functionalized MSN on the cellular internalization and in vivo behaviour. In this article, a synthesis of these works is reviewed and the perspectives are drawn. The use of magnetic MSN ([email protected]) allows an efficient separation of coated NPs from cell cultures with a simple magnet, leading to results regarding corona formation without experimental bias. Our interest is focused on the mechanism of interaction with model membranes, the adsorption of proteins in biological fluids, the quantification of uptake, and the effect of such NPs on the transcriptomic profile of hepatic cells that are known to be readily concerned by NPs' uptake in vivo, especially in the case of an intravenous injection.
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http://dx.doi.org/10.3390/biomimetics3030022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352691PMC
August 2018

A "Multi-Heavy-Atom" Approach toward Biphotonic Photosensitizers with Improved Singlet-Oxygen Generation Properties.

Chemistry 2019 Jul 30;25(38):9026-9034. Epub 2019 May 30.

Laboratoire de Chimie de l'ENS de Lyon, Univ Lyon, ENS de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, 69342, Lyon, France.

Two trispicolinate 1,4,7-triazacyclonane (TACN)-based ligands bearing three picolinate biphotonic antennae were synthetized and their Yb and Gd complexes isolated. One series differs from the other by the absence (L )/presence (L ) of bromine atoms on the antenna backbone, offering respectively improved optical and singlet-oxygen generation properties. Photophysical properties of the ligands, complexes and micellar Pluronic suspensions were investigated. Complexes exhibit high two-photon absorption cross-section combined either with NIR emission (Yb) or excellent O generation (Gd). The very large intersystem crossing efficiency induced by the combination of bromine atom and heavy rare-earth element was corroborated with theoretical calculations. The O generation properties of L Gd micellar suspension under two-photon activation leads to tumour cell death, suggesting the potential of such structures for theranostic applications.
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http://dx.doi.org/10.1002/chem.201901047DOI Listing
July 2019

Large Pore Mesoporous Silica and Organosilica Nanoparticles for Pepstatin A Delivery in Breast Cancer Cells.

Molecules 2019 Jan 17;24(2). Epub 2019 Jan 17.

Institut Charles Gerhardt Montpellier, UMR-5253 Univ Montpellier, CNRS, ENSCM, cc 1701, Place Eugène Bataillon, CEDEX 5, 34095 Montpellier, France.

(1) Background: Nanomedicine has recently emerged as a new area of research, particularly to fight cancer. In this field, we were interested in the vectorization of pepstatin A, a peptide which does not cross cell membranes, but which is a potent inhibitor of cathepsin D, an aspartic protease particularly overexpressed in breast cancer. (2) Methods: We studied two kinds of nanoparticles. For pepstatin A delivery, mesoporous silica nanoparticles with large pores (LPMSNs) and hollow organosilica nanoparticles (HOSNPs) obtained through the sol⁻gel procedure were used. The nanoparticles were loaded with pepstatin A, and then the nanoparticles were incubated with cancer cells. (3) Results: LPMSNs were monodisperse with 100 nm diameter. HOSNPs were more polydisperse with diameters below 100 nm. Good loading capacities were obtained for both types of nanoparticles. The nanoparticles were endocytosed in cancer cells, and HOSNPs led to the best results for cancer cell killing. (4) Conclusions: Mesoporous silica-based nanoparticles with large pores or cavities are promising for nanomedicine applications with peptides.
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http://dx.doi.org/10.3390/molecules24020332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359328PMC
January 2019

Dendrimeric Nanoparticles for Two-Photon Photodynamic Therapy and Imaging: Synthesis, Photophysical Properties, Innocuousness in Daylight and Cytotoxicity under Two-Photon Irradiation in the NIR.

Chemistry 2019 Mar 7;25(14):3637-3649. Epub 2019 Feb 7.

Univ. Bordeaux, ISM (CNRS-UMR 5255), 33405, Talence, France.

The synthesis and the photophysical properties of a new class of fully organic monodisperse nanoparticles for combined two-photon imaging and photodynamic therapy are described. The design of such nanoparticles is based on the covalent immobilization of a dedicated quadrupolar dye that combines excellent two-photon absorbing (2PA) properties, fluorescence and singlet oxygen generation ability, in a phosphorous-based dendrimeric architecture. First, a bifunctional quadrupolar dye bearing two different grafting moieties, a phenol function and an aldehyde function, was synthesized. It was then covalently grafted through its phenol function to a phosphorus-based dendrimer scaffold of generation 1. The remaining aldehyde functions were then used to continue the dendrimer synthesis up to generation 2, introducing finally 24 water-solubilizing triethyleneglycol chains at its periphery. A dendrimer confining 12 photoactive quadrupolar units in its inner scaffold and showing water solubility was thus obtained. Interestingly, the G1 and G2 dendrimers retain some fluorescence as well as significant singlet oxygen production efficiencies while they were found to show very high 2PA cross-sections in a broad range of the NIR biological spectral window. Hydrophilic dendrimer G2 was tested in vitro on breast cancer cells, first in one- and two-photon microscopy, which allowed for visualization of their cell internalization, then in two-photon photodynamic therapy. While being nontoxic in the dark and, more importantly, under exposure to daylight, dendrimer G2 proved to be a very efficient cell-death inducer only under two-photon irradiation in the NIR.
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http://dx.doi.org/10.1002/chem.201805617DOI Listing
March 2019

Biomolecular dynamic covalent polymers for DNA complexation and siRNA delivery.

J Mater Chem B 2018 Nov 26;6(44):7239-7246. Epub 2018 Jul 26.

IBMM, Université de Montpellier, CNRS, ENSCM, UM, Montpellier, France.

Synthetic delivery systems that are described as smart are considered essential for the successful development of gene therapies. Dynamic covalent polymers (DCP) are dynamic and adaptive species that can expand and shorten their main chain in a reversible fashion. In particular, polyacylhydrazone DCPs are pH-sensitive and undergo hydrolytic dissociation at acidic pH, which is an interesting feature for gene delivery. Building upon our previous finding that cationic DCPs can complex DNA through multivalent interactions, we report here on a new generation of DCPs that incorporate modified amino acids. The covalent self-assembly through polycondensation was extended towards multifunctional DCPs combining different building blocks and different molecular dynamics. These biomolecular DCPs were found able to complex both long DNA and siRNA, and biological studies demonstrate that they are able to deliver functional siRNA in living cells. This straightforward and modular approach to the self-production of multifunctional and biomolecular DCPs as siRNA vectors can therefore constitute a stepping stone in smart gene delivery using dynamic and adaptive biodynamers.
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http://dx.doi.org/10.1039/c8tb01278dDOI Listing
November 2018

Diazachlorin and diazabacteriochlorin for one- and two-photon photodynamic therapy.

Chem Commun (Camb) 2018 Dec;54(98):13829-13832

Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8603, Japan.

Diazachlorin and diazabacteriochlorin have been prepared through reduction of diazaporphyrin and their in vitro and in vivo activity in photodynamic therapy has been investigated.
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http://dx.doi.org/10.1039/c8cc07489eDOI Listing
December 2018
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