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1.
Int J Nanomedicine ; 7: 1275-86, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22419874

RESUMO

Nanoparticles (NPs) are in clinical use or under development for therapeutic imaging and drug delivery. However, relatively little information exists concerning the uptake and transport of NPs across human colon cell layers, or their potential to invade three-dimensional models of human colon cells that better mimic the tissue structures of normal and tumoral colon. In order to gain such information, the interactions of biocompatible ultrasmall superparamagnetic iron oxide nanoparticles (USPIO NPs) (iron oxide core 9-10 nm) coated with either cationic polyvinylamine (aminoPVA) or anionic oleic acid with human HT-29 and Caco-2 colon cells was determined. The uptake of the cationic USPIO NPs was much higher than the uptake of the anionic USPIO NPs. The intracellular localization of aminoPVA USPIO NPs was confirmed in HT-29 cells by transmission electron microscopy that detected the iron oxide core. AminoPVA USPIO NPs invaded three-dimensional spheroids of both HT-29 and Caco-2 cells, whereas oleic acid-coated USPIO NPs could only invade Caco-2 spheroids. Neither cationic aminoPVA USPIO NPs nor anionic oleic acid-coated USPIO NPs were transported at detectable levels across the tight CacoReady™ intestinal barrier model or the more permeable mucus-secreting CacoGoblet™ model.


Assuntos
Colo/metabolismo , Nanopartículas de Magnetita/química , Ânions/química , Ânions/farmacocinética , Células CACO-2 , Cátions/química , Cátions/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Colo/citologia , Células HT29 , Histocitoquímica , Humanos , Espaço Intracelular , Ácido Oleico/química , Ácido Oleico/farmacocinética , Tamanho da Partícula , Polivinil/química , Esferoides Celulares/metabolismo
2.
Nanomedicine (Lond) ; 5(7): 1075-87, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20874022

RESUMO

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) are currently under development for the intracellular delivery of therapeutics. However, the mechanisms of cellular uptake and the cellular reaction to this uptake, independent of therapeutics, are not well defined. The interactions of biocompatible cationic aminoUSPIONs with human cells was studied in 2D and 3D cultures using biochemical and electron microscopy techniques. AminoUSPIONs were internalized by human melanoma cells in 2D and 3D cultures. Uptake was clathrin mediated and the particles localized in lysosomes, inducing activation of the lysosomal cathepsin D and decreasing the expression of the transferrin receptor in human melanoma cells and/or skin fibroblasts. AminoUSPIONs deeply invaded 3D spheroids of human melanoma cells. Thus, aminoUSPIONs can invade tumors and their uptake by human cells induces cell reaction.


Assuntos
Compostos Férricos/metabolismo , Melanoma/patologia , Nanopartículas Metálicas , Sequência de Bases , Cátions , Linhagem Celular Tumoral , Primers do DNA , Humanos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
ChemMedChem ; 4(6): 988-97, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19347834

RESUMO

Drug-nanoparticle conjugates: The anticancer drug camptothecin (CPT) was covalently linked at the surface of ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) via a linker, allowing drug release by cellular esterases. Nanoparticles were hierarchically built to achieve magnetically-enhanced drug delivery to human cancer cells and antiproliferative activity.The linking of therapeutic drugs to ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) allowing intracellular release of the active drug via cell-specific mechanisms would achieve tumor-selective magnetically-enhanced drug delivery. To validate this concept, we covalently attached the anticancer drug camptothecin (CPT) to biocompatible USPIOs (iron oxide core, 9-10 nm; hydrodynamic diameter, 52 nm) coated with polyvinylalcohol/polyvinylamine (PVA/aminoPVA). A bifunctional, end-differentiated dicarboxylic acid linker allowed the attachment of CPT to the aminoPVA as a biologically labile ester substrate for cellular esterases at one end, and as an amide at the other end. These CPT-USPIO conjugates exhibited antiproliferative activity in vitro against human melanoma cells. The intracellular localization of CPT-USPIOs was confirmed by transmission electron microscopy (iron oxide core), suggesting localization in lipid vesicles, and by fluorescence microscopy (CPT). An external static magnetic field applied during exposure increased melanoma cell uptake of the CPT-USPIOs.


Assuntos
Antineoplásicos/administração & dosagem , Camptotecina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Magnetismo , Nanopartículas Metálicas/ultraestrutura , Antineoplásicos/química , Antineoplásicos/farmacologia , Camptotecina/química , Camptotecina/farmacologia , Linhagem Celular Tumoral , Esterases/metabolismo , Compostos Férricos/química , Humanos , Nanopartículas Metálicas/química , Microscopia Eletrônica de Transmissão , Polivinil/química , Propriedades de Superfície , Fatores de Tempo
4.
Bioorg Med Chem ; 16(6): 2921-31, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18226908

RESUMO

Superparamagnetic iron oxide nanoparticles (SPIONs) are in clinical use for disease detection by MRI. A major advancement would be to link therapeutic drugs to SPIONs in order to achieve targeted drug delivery combined with detection. In the present work, we studied the possibility of developing a versatile synthesis protocol to hierarchically construct drug-functionalized-SPIONs as potential anti-cancer agents. Our model biocompatible SPIONs consisted of an iron oxide core (9-10 nm diameter) coated with polyvinylalcohols (PVA/aminoPVA), which can be internalized by cancer cells, depending on the positive charges at their surface. To develop drug-functionalized-aminoPVA-SPIONs as vectors for drug delivery, we first designed and synthesized bifunctional linkers of varied length and chemical composition to which the anti-cancer drugs 5-fluorouridine or doxorubicin were attached as biologically labile esters or peptides, respectively. These functionalized linkers were in turn coupled to aminoPVA by amide linkages before preparing the drug-functionalized-SPIONs that were characterized and evaluated as anti-cancer agents using human melanoma cells in culture. The 5-fluorouridine-SPIONs with an optimized ester linker were taken up by cells and proved to be efficient anti-tumor agents. While the doxorubicin-SPIONs linked with a Gly-Phe-Leu-Gly tetrapeptide were cleaved by lysosomal enzymes, they exhibited poor uptake by human melanoma cells in culture.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/síntese química , Óxido Ferroso-Férrico , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/farmacologia , Doxorrubicina/administração & dosagem , Portadores de Fármacos/farmacocinética , Humanos , Melanoma/tratamento farmacológico , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Uridina/administração & dosagem , Uridina/análogos & derivados
5.
J Pharmacol Exp Ther ; 318(1): 108-16, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16608917

RESUMO

Super Paramagnetic Iron Oxide Nanoparticles (SPIONs) combined with magnetic resonance imaging (MRI) are under clinical evaluation to enhance detection of neurodegenerative diseases. A major improvement would be to link therapeutic drugs to the SPIONs to achieve targeted drug delivery, either at the cell surface or intracellularly, together with active disease detection, without inducing cell reaction. Our objectives were to define the characteristics of SPIONS able to achieve cell-specific interaction with brain-derived structures. Our system consisted in an iron oxide core (9-10 nm diameter) coated either with dextran (Sinerem and Endorem) or various functionalized polyvinyl alcohols (PVAs) (PVA-SPIONs). We investigated the cellular uptake, cytotoxicity, and interaction of these various nanoparticles with brain-derived endothelial cells, microglial cells, and differentiating three-dimensional aggregates. None of the nanoparticles coated with dextran or the various PVAs was cytotoxic or induced the production of the inflammatory mediator NO used as a reporter for cell activation. AminoPVA-SPIONs were taken up by isolated brain-derived endothelial and microglial cells at a much higher level than the other SPIONs, and no inflammatory activation of these cells was observed. AminoPVA-SPIONs did not invade brain cells aggregates lower than the first cell layer and did not induce inflammatory reaction in the aggregates. Fluorescent aminoPVA-SPIONs derivatized with a fluorescent reporter molecule and confocal microscopy demonstrated intracellular uptake by microglial cells. Fluorescent aminoPVA-SPIONs were well tolerated by mice. Therefore, functionalized aminoPVA-SPIONs represent biocompatible potential vector systems for drug delivery to the brain that may be combined with MRI detection of active lesions in neurodegenerative diseases.


Assuntos
Encéfalo/metabolismo , Compostos Férricos/metabolismo , Imageamento por Ressonância Magnética/métodos , Nanoestruturas , Animais , Células Cultivadas , Compostos Férricos/química , Camundongos , Camundongos Endogâmicos C57BL , Nanoestruturas/química , Ratos
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