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Herein, we report the design, the synthesis, and the study of novel triphenyl phosphonium-based nucleoside conjugates. 2'-Deoxycytidine was chosen as nucleosidic cargo, as it allows the introduction of fluorescein on the exocyclic amine of the nucleobase and grafting of the vector was envisaged through the formation of a biolabile ester bond with the hydroxyl function at the 5'-position. Compound 3 was identified as a potential nucleoside prodrug, showing ability to be internalized efficiently into cells and to be co-localized with mitochondria.
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Phthalocyanines have been described as effective photosensitizers for photodynamic therapy and are therefore, being studied for their biomedical applications. The metalation of photosensitizers can improve their photodynamic therapy potential. Here, we focus on the biological properties of [1,4-Bis(3,6,9,12-Tetraoxatridec-1-yloxy)phthalocyaninato]zinc(II) (ZnPc(αEG4)2) and demonstrate its exceptional anticancer activity upon light stimulation to kill preferentially cancer cells with a start of efficiency at 10 pM. Indeed, in this work we highlighted the high selectivity of ZnPc(αEG4)2 for cancer cells compared with healthy ones and we establish its mechanism of action, enabling us to conclude that ZnPc(αEG4)2 could be a powerful tool for cancer therapy.
Assuntos
Indóis , Compostos Organometálicos , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Zinco , Compostos Organometálicos/farmacologia , Compostos de ZincoRESUMO
Herein, we report for the first time a biocompatible cross-linked trianglamine (Δ) network for the efficient iodine removal from the vapor phase, water, and seawater. In the vapor phase, the cross-linked network could capture 6 g g-1 of iodine, ranking among the most performant materials for iodine vapor capture. In the liquid phase, this cross-linked network is also capable of capturing iodine at high rates from aqueous media (water and seawater). This network displayed fast adsorption kinetics, and they are fully recyclable. This study reveals the high affinity of iodine for the intrinsic cavity of the trianglamine. The synthesized materials are extremely interesting since they are environmentally friendly and inexpensive and the synthesis could easily be scaled up to be used as the material of choice in response to accidents in the nuclear industry.
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Dendritic mesoporous organosilica nanoparticles (DMON) are a new class of biodegradable nanoparticles suitable for biomolecule delivery. We studied the photochemical internalization (PCI) and photodynamic therapy (PDT) of DMON to investigate new ways for DMON to escape from the endosomes-lysosomes and deliver biomolecules into the cytoplasm of cells. We added photosensitizers in the framework of DMON and found that DMON were loaded with siRNA or FVIII factor protein. We made four formulations with four different photosensitizers. The photosensitizers allowed us to perform imaging of DMON in cancer cells, but the presence of the tetrasulfide bond in the framework of DMON quenched the formation of singlet oxygen. Fortunately, one formulation allowed us to efficiently deliver proapoptotic siRNA in MCF-7 cancer cells leading to 31% of cancer cell death, without irradiation. As for FVIII protein, it was loaded in two formulations with drug-loading capacities (DLC) up to 25%. In conclusion, DMON are versatile nanoparticles capable of loading siRNA and delivering it into cancer cells, and also loading FVIII protein with good DLC. Due to the presence of tetrasulfide, it was not possible to perform PDT or PCI.
Assuntos
Nanopartículas , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/farmacologia , RNA Interferente Pequeno/metabolismo , Nanopartículas/química , Fotoquimioterapia/métodos , Células MCF-7 , Linhagem Celular TumoralRESUMO
The concept of using two-photon excitation in the NIR for the spatiotemporal control of biological processes holds great promise. However, its use for the delivery of nucleic acids has been very scarcely described and the reported procedures are not optimal as they often involve potentially toxic materials and irradiation conditions. This work prepares a simple system made of biocompatible porous silicon nanoparticles (pSiNP) for the safe siRNA photocontrolled delivery and gene silencing in cells upon two-photon excitation. PSiNP are linked to an azobenzene moiety, which possesses a lysine group (pSiNP@ICPES-azo@Lys) to efficiently complex siRNA. Non-linear excitation of the two-photon absorber system (pSiNP) followed by intermolecular energy transfer (FRET) to trans azobenzene moiety, result in the photoisomerization of the azobenzene from trans to cis and in the destabilization of the azobenzene-siRNA complex, thus inducing the delivery of the cargo siRNA to the cytoplasm of cells. Efficient silencing in MCF-7 expressing stable firefly luciferase with siRNAluc against luciferase is observed. Furthermore, siRNA against inhibitory apoptotic protein (IAP) leads to over 70% of MCF-7 cancer cell death. The developed technique using two-photon light allows a unique high spatiotemporally controlled and safe siRNA delivery in cells in few seconds of irradiation.
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Nanopartículas , Neoplasias , Humanos , RNA Interferente Pequeno/genética , Silício , Porosidade , Transfecção , Linhagem Celular TumoralRESUMO
The efficient, versatile, and straightforward synthesis of the first N-alkyl analogues of induline 3B (8a and 8b) is reported. Thanks to the introduction of lipophilic substituents and their attractive photophysical properties (far-red emission and production of singlet oxygen), phenazinium 8b 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 in vitro and in vivo after illumination (λexc = 540-560 nm). The molecular structure of 8b 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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Antineoplásicos/uso terapêutico , Corantes Fluorescentes/uso terapêutico , Fenazinas/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Fibroblastos/metabolismo , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/efeitos da radiação , Humanos , Luz , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fenazinas/síntese química , Fenazinas/metabolismo , Fenazinas/efeitos da radiação , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/efeitos da radiação , Medicina de Precisão/métodos , Oxigênio Singlete/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
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 MDA-MB-231 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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A series of 19 novel pyrido-imidazodiazepinones, with modulations of positions 2, 3 and 4 of the diazepine ring were synthesised and screened for their in vitro cytotoxic activities against two melanoma cell lines (A375 and MDA-MB-435) and for their potential toxicity against NIH-3T3 non-cancerous cells. Selected compounds were also evaluated on the NCI-60 cell line panel. The SAR study revealed that the molecular volume and the cLogP of compounds modified at position 2 were significantly correlated with the activity of these compounds on melanoma cell lines. Moreover, introduction of a heterocyclic group at position 2 or an azido-alkyl chain at position 4 led to compounds displaying a significantly different activity profile on the NCI-60 cell line panel, compared to phenyl-substituted compounds at position 2 of the diazepinone. This study provides us crucial information for the development of new derivatives active against melanoma.
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Antineoplásicos/farmacologia , Azepinas/farmacologia , Imidazóis/farmacologia , Melanoma/tratamento farmacológico , Piridinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Azepinas/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/química , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Estrutura Molecular , Células NIH 3T3 , Piridinas/química , Relação Estrutura-AtividadeRESUMO
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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Antibióticos Antineoplásicos/farmacologia , Dextranos/química , Doxorrubicina/farmacologia , Nanopartículas/química , Poliésteres/química , Antibióticos Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Micelas , Estrutura Molecular , Tamanho da Partícula , Relação Estrutura-Atividade , Propriedades de SuperfícieRESUMO
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 (H2PG) 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 H2PG was shown by incubating human breast cancer cells (MDA-MB-231) with H2PG followed by light-irradiation at 405â¯nm. On the other hand, while siRNA do not enter cells alone, we showed, by fluorescence confocal microscopy and flow cytometry, that H2PG 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 H2PG is capable of acting both as a photosensitizer and supramolecular siRNA vector.
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Inativação Gênica , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Linhagem Celular Tumoral , Terapia Genética , Humanos , Proteínas Inibidoras de Apoptose/genética , Fármacos Fotossensibilizantes/química , Porfirinas/química , RNA Interferente Pequeno/químicaRESUMO
(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 solâ»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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Neoplasias da Mama/metabolismo , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Pepstatinas/administração & dosagem , Dióxido de Silício/química , Linhagem Celular Tumoral , Feminino , Humanos , Nanopartículas/ultraestrutura , Pepstatinas/química , PorosidadeRESUMO
A challenge regarding the design of nanocarriers for drug delivery is to prevent their recognition by the immune system. To improve the blood residence time and prevent their capture by organs, nanoparticles can be designed with stealth properties using polymeric coating. In this study, we focused on the influence of surface modification with polyethylene glycol and/or mannose on the stealth behavior of porous silicon nanoparticles (pSiNP, ~200 nm). In vivo biodistribution of pSiNPs formulations were evaluated in mice 5 h after intravenous injection. Results indicated that the distribution in the organs was surface functionalization-dependent. Pristine pSiNPs and PEGylated pSiNPs were distributed mainly in the liver and spleen, while mannose-functionalized pSiNPs escaped capture by the spleen, and had higher blood retention. The most efficient stealth behavior was observed with PEGylated pSiNPs anchored with mannose that were the most excreted in urine at 5 h. The biodegradation kinetics evaluated in vitro were in agreement with these in vivo observations. The biocompatibility of the pristine and functionalized pSiNPs was confirmed in vitro on human cell lines and in vivo by cytotoxic and systemic inflammation investigations, respectively. With their biocompatibility, biodegradability, and stealth properties, the pSiNPs functionalized with mannose and PEG show promising potential for biomedical applications.
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We recently described a pyrido-imidazodiazepinone derivative which could be a promising hit compound for the development of new drugs acting against melanoma cells. In this study, a series of 28 novel pyrido-imidazodiazepinones were synthesized and screened for their in vitro cytotoxic activities against the melanoma MDA-MB-435 cell line. Among the derivatives, seven of them showed 50% growth inhibitory activity at 1 µM concentration, and high selectivity against the melanoma cell line MDA-MB-435.
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Antineoplásicos/química , Azepinas/química , Proliferação de Células/efeitos dos fármacos , Melanoma/tratamento farmacológico , Piridinas/química , Antineoplásicos/farmacologia , Azepinas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melanoma/metabolismo , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Bis(clickable) mesoporous silica nanospheres (ca. 100â nm) were obtained by the co-condensation of TEOS with variable amounts (2-5 % each) of two clickable organosilanes in the presence of CTAB. Such nanoparticles could be easily functionalized with two independent functions using the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction to transform them into nanomachines bearing cancer cell targeting ligands with the ability to deliver drugs on-demand. The active targeting was made possible after anchoring folic acid by CuAAC click reaction, whereas the controlled delivery was performed by clicked azobenzene fragments. Indeed, the azobenzene groups are able to obstruct the pores of the nanoparticles in the dark whereas upon irradiation in the UV or in the blue range, their trans-to-cis photoisomerization provokes disorder in the pores, enabling the delivery of the cargo molecules. The on-command delivery was proven in solution by dye release experiments, and in vitro by doxorubicin delivery. The added value of the folic acid ligand was clearly evidenced by the difference of cell killing induced by doxorubicin-loaded nanoparticles under blue irradiation, depending on whether the particles featured the clicked folic acid ligand or not.
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Alcinos/química , Azidas/química , Compostos Azo/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Nanosferas/química , Dióxido de Silício/química , Química Click , Reação de Cicloadição , Doxorrubicina/química , Humanos , Ligantes , PorosidadeRESUMO
The synthesis of mesoporous silica nanoparticles bearing organic functionalities is strained by the careful adjustment of the reaction parameters, as the incorporation of functional and/or voluminous organosilanes during the sol-gel synthesis strongly affects the final structure of the nanoparticles. In this paper we describe the design of new clickable mesoporous silica nanoparticles as spheres or rods, synthesized by the co-condensation of TEOS with two clickable organosilanes (bearing alkyne and azide groups) and readily multi-functionalizable by CuAAC click chemistry. We show that controlled loadings of clickable functions can be homogeneously distributed within the MSN, allowing us to efficiently click-graft various pairs of functionalities while preserving the texture and morphology of the particles. The homogeneous distribution of the grafted functionalities was probed by FRET experiments between two anchored fluorophores. Moreover, a communication by proton transfer between two functions was demonstrated by constructing a light-actuated nanomachine that works through a proton transfer between a photoacid generator and a pH-sensitive supramolecular nanogate. The activation of the nanomachine enabled the successful release of rhodamine B in buffered solutions and the delivery of doxorubicin in breast cancer cells (MCF-7) upon blue irradiation.