Bd25 et Bd37.2 (deux nouvelles protéines parasitaires impliquées dans l'invasion des érythrocytes par Babesia divergens ?)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUP (751062107) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Substantial Cellular Penetration of Fluorescent Imidazoquinoxalines.

International audienceFluorescent tools have revolutionized our capability to visualize, probe, study, and understand the biological cellular properties, processes and dynamics, enabling researchers to improve their knowledge for example in cancer field. In this paper, we use the peculiar properties of our Imiqualines derivatives to study their cellular penetration and distribution in a human melanoma cell line A375 using confocal microscopy. Preliminary results on colocalization with the potent protein target c-Kit of our lead are also described

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

International audienceThe 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-SnPh2), while the other contains two tin(iv) cations each chelated to one carboxylic acid group of the malonate and three phenyl ligands (AuP-Sn2Ph6). The mode of chelation of Sn(iv) to the malonate was elucidated by IR spectroscopy and 119Sn 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 119Sn 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-SnPh2 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-Sn2Ph6 exhibits a very high anticancer activity (LC50 = 0.024 μM), but the presence of two tin units induces strong cytotoxicity on healthy cells too (LC50 = 0.032 μM). This study underscores, thus, the potential of the association of gold porphyrin and organotin complexes to develop anticancer metallo-drug

Lysosomes and unfolded protein response, determinants of differential resistance of melanoma cells to vinca alkaloids

International audienceOn account of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma (MM) remains a therapeutic challenge. This study focuses on acquired resistance to vinca alkaloids (VAs) using VA-resistant MM cell lines (CAL1R-VCR, CAL1R-VDS, and CAL1R-VRB), established by long-term continuous exposure of parental CAL1-wt cells to vincristine (VCR), vindesine (VDS), or vinorelbine (VRB), respectively. Transcriptomic profiling using rma and rdam methods led to distinguish two cell groups: CAL1R-VCR and CAL1R-VDS, CAL1R-VRB, and CAL1-wt. mgsa of the specifically altered genes in the first group evidenced the GO terms 'lysosomal lumen' and 'vacuolar lumen' linked to underexpressed genes, and 'endoplasmic reticulum (ER) stress response' associated with overexpressed genes. A specific reduction of lysosomal enzymes, independent of acidic vacuole organelle (AVO) turnover, was observed (LTG probe) in CAL1R-VCR and CAL1R-VDS cells. It was associated with the specific lowering of cathepsin B and L, known to be involved in the lysosomal pathway of apoptosis. Confirming gene profiling, the same groups (CAL1R-VCR and CAL1R-VDS, CAL1-wt and CAL1R-VRB) could be distinguished regarding the VA-mediated changes on mean size areas and on acidic compartment volumes. These two parameters were reduced in CAL1R-VCR and CAL1R-VDS cells, suggesting a smaller AVO accumulation and thus a reduced sensitivity to lysosomal membrane permeabilization-mediated apoptosis. In addition, 'ER stress response' inhibition by tauroursodeoxycholic acid induced a higher VA sensitization of the first cell group. In conclusion, lysosomes and unfolded protein response could be key determinants of the differential resistance of MM to VAs

Synthèse des composés de type imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline et pyrazolo [1,5-a] quinoxaline comme inhibiteurs d'IKK1 et IKK2

International audienceThe transcription nuclear factor NF-κB plays a pivotal role in chronic and acute inflammatory diseases. Among the several and diverse strategies for inhibiting NF-κB, one of the most effective approach considered by the pharmaceutical industry seems to be offered by the development of IKK inhibitors. In a former study, two potential IKK2 inhibitors have been highlighted among a series of imidazo[1,2-a]quinoxaline derivatives. In order to enhance this activity, we present herein the synthesis of twenty-one new compounds based on the imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline or pyrazolo[1,5-a]quinoxaline structures. Their potential to inhibit IKK1 and IKK2 activities is also tested.Le facteur de transcription nucléaire NF-κB joue un rôle important dans les maladies inflammatoires chroniques et aiguës. Parmi les nombreuses stratégies d'inhibition de NF-KB, l'une des approches les plus efficaces envisagées par l'industrie pharmaceutique est le développement d'inhibiteurs d'IKK. Dans une étude antérieure, deux inhibiteurs potentiels de l'IKK2 ont été mis en évidence parmi une série de composés de type imidazo[1,2-a]quinoxaline. Afin d’améliorer cette activité, nous présentons ici la synthèse de 21 nouveaux composés de type imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline et pyrazolo[1,5-a]quinoxaline. Leurs activités biologiques en tant qu’inhibiteurs potentiels de I'KK1 et I'KK2 sont également décrites

Photosensitivity of Different Nanodiamond–PMO Nanoparticles in Two-Photon-Excited Photodynamic Therapy

Background: In addition to their great optical properties, nanodiamonds (NDs) have recently proved useful for two-photon-excited photodynamic therapy (TPE-PDT) applications. Indeed, they are able to produce reactive oxygen species (ROS) directly upon two-photon excitation but not with one-photon excitation; Methods: Fluorescent NDs (FNDs) with a 100 nm diameter and detonation NDs (DNDs) of 30 nm were compared. In order to use the gems for cancer-cell theranostics, they were encapsulated in a bis(triethoxysilyl)ethylene-based (ENE) periodic mesoporous organosilica (PMO) shell, and the surface of the formed nanoparticles (NPs) was modified by the direct grafting of polyethylene glycol (PEG) and amino groups using PEG-hexyltriethoxysilane and aminoundecyltriethoxysilane during the sol–gel process. The NPs’ phototoxicity and interaction with MDA-MB-231 breast cancer cells were evaluated afterwards; Results: Transmission electronic microscopy images showed the formation of core–shell NPs. Infrared spectra and zeta-potential measurements confirmed the grafting of PEG and NH2 groups. The encapsulation of the NDs allowed for the imaging of cancer cells with NDs and for the performance of TPE-PDT of MDA-MB-231 cancer cells with significant mortality. Conclusions: Multifunctional ND@PMO core–shell nanosystems were successfully prepared. The NPs demonstrated high biocompatibility and TPE-PDT efficiency in vitro in the cancer cell model. Such systems hold good potential for two-photon-excited PDT applications

Controlled Assembly of AIE Active Bolaamphiphilic Macromolecules into Luminescent Organic Nanoparticles Optimized for Two-Photon Microscopy in vivo

The (Z) and (E) isomers of an extended tetraphenylethylene-based chromophore with optimized two-photon induced luminescence properties are separated and functionalized with water-solubilizing pendant polymer groups, promoting their self-assembly in physiological media in the form of small, colloidal stable organic nanoparticles. The two resulting fluorescent suspensions are then evaluated as potential two-photon luminescent contrast agents for intravital epifluorescence and two-photon fluorescence microscopy. Comparisons with previously reported works involving similar fluorophores devoid of polymer side chains illustrate the benefits of the later functionalization regarding the control of the self-assembly of the nano-objects, and ultimately their biocompatibility towards the imaged organism

Design of Polyazamacrocyclic Gd 3+ Theranostic Agent Combining MRI and Two-Photon PDT

New “all-in-one” theranostic systems, combining a magnetic resonance imaging (MRI) contrast agent with a biphotonic photodynamic therapy (2P-PDT) photosensitiser generating cytotoxic singlet oxygen, were envisaged and synthesised. They are based on azamacrocycles, regiospecifically functionalised by two-photon PDT π-conjugated dibromobenzene-picolinate photosensitisers and acetate, able to complex gadolinium(III) and allow an MRI signal. Our approach was to use two different macrocyclic platforms, tacn and pyclen, for modulating simultaneously the structures, properties and solubility of the complexes. Photophysical properties of the ligands and their gadolinium(III) complexes were fully investigated. The Gd3+-pyclen derivative showed the best water solubility and the greatest value of singlet oxygen generation of the series with φΔ = 0.53 enabling in vitro studies. The biological PDT activity under mono and biphotonic excitation was evaluated in human breast cancer cells (MCF-7). While a very low dark toxicity was observed, an almost total cell death was induced after only 3 successive irradiations of 1.57 sec. Finally, its relaxivity was measured in a DMSO/H2O solvents mixture with r1p = 11.21 and r2p = 24.60 mM-1s -1 at 3.0 T and T1- and T2-weighted phantom MR images were obtained highlighting a first generation of “all-in-one” PDT/MRI theranostic agents

Design of polyazamacrocyclic Gd3+ theranostic agents combining magnetic resonance imaging and two-photon photodynamic therapy

International audienceNew “all-in-one” theranostic systems, combining a magnetic resonance imaging (MRI) contrast agent with a biphotonic photodynamic therapy (2P-PDT) photosensitiser generating cytotoxic singlet oxygen, were envisaged and synthesised. They are based on azamacrocycles, regiospecifically functionalised by two-photon PDT π-conjugated dibromobenzene–picolinate photosensitisers and acetate, able to complex gadolinium(III) and allow an MRI signal. Our approach was to use two different macrocyclic platforms, tacn and pyclen, for modulating simultaneously the structures, properties and solubility of the complexes. Photophysical properties of the ligands and their gadolinium(III) complexes were fully investigated. The Gd3+–pyclen derivative showed the best water solubility and the greatest value of singlet oxygen generation of the series with ΦΔ = 0.53 enabling in vitro studies. The biological PDT activity under mono and biphotonic excitation was evaluated in human breast cancer cells (MCF-7). While a very low dark toxicity was observed, an almost total cell death was induced after only 3 successive irradiations of 1.57 s. Finally, its relaxivity was measured in a DMSO/H2O solvent mixture with r1p = 11.21 and r2p = 24.60 mM−1 s−1 at 3.0 T and T1- and T2-weighted phantom MR images were obtained highlighting a first generation of “all-in-one” PDT/MRI theranostic agents

Design of Polyazamacrocyclic Gd3+ Theranostic Agent Combining MRI and Two-Photon PDT

New “all-in-one” theranostic systems, combining a magnetic resonance imaging (MRI) contrast agent with a biphotonic photodynamic therapy (2P-PDT) photosensitiser generating cytotoxic singlet oxygen, were envisaged and synthesised. They are based on azamacrocycles, regiospecifically functionalised by two-photon PDT π-conjugated dibromobenzene-picolinate photosensitisers and acetate, able to complex gadolinium(III) and allow an MRI signal. Our approach was to use two different macrocyclic platforms, tacn and pyclen, for modulating simultaneously the structures, properties and solubility of the complexes. Photophysical properties of the ligands and their gadolinium(III) complexes were fully investigated. The Gd3+-pyclen derivative showed the best water solubility and the greatest value of singlet oxygen generation of the series with φΔ = 0.53 enabling in vitro studies. The biological PDT activity under mono and biphotonic excitation was evaluated in human breast cancer cells (MCF-7). While a very low dark toxicity was observed, an almost total cell death was induced after only 3 successive irradiations of 1.57 sec. Finally, its relaxivity was measured in a DMSO/H2O solvents mixture with r1p = 11.21 and r2p = 24.60 mM-1s -1 at 3.0 T and T1- and T2-weighted phantom MR images were obtained highlighting a first generation of “all-in-one” PDT/MRI theranostic agents