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1.
Nanoscale Res Lett ; 13(1): 17, 2018 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-29327307

RESUMO

Although the application of sorafenib, a small inhibitor of tyrosine protein kinases, to cancer treatments remains a worldwide option in chemotherapy, novel strategies are needed to address the low water solubility (< 5 µM), toxicity, and side effects issues of this drug. In this context, the use of nanocarriers is currently investigated in order to overcome these drawbacks. In this contribution, we report a new type of sorafenib-based nanoparticles stabilized by hybrid nucleoside-lipids. The solid lipid nanoparticles (SLNs) showed negative or positive zeta potential values depending on the nucleoside-lipid charge. Transmission electron microscopy of sorafenib-loaded SLNs revealed parallelepiped nanoparticles of about 200 nm. Biological studies achieved on four different cell lines, including liver and breast cancers, revealed enhanced anticancer activities of Sorafenib-based SLNs compared to the free drug. Importantly, contrast phase microscopy images recorded after incubation of cancer cells in the presence of SLNs at high concentration in sorafenib (> 80 µM) revealed a total cancer cell death in all cases. These results highlight the potential of nucleoside-lipid-based SLNs as drug delivery systems.

2.
Cell Chem Biol ; 23(9): 1147-1156, 2016 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-27662254

RESUMO

Complex antigens require processing within antigen-presenting cells (APCs) to form T cell stimulatory complexes with CD1 antigen-presenting molecules. It remains unknown whether lipids with multi-acylated moieties also necessitate digestion by lipases to become capable of binding CD1 molecules and stimulate T cells. Here, we show that the mycobacterial tetra-acylated glycolipid antigens phosphatidyl-myo-inositol mannosides (PIM) are digested to di-acylated forms by pancreatic lipase-related protein 2 (PLRP2) and lysosomal phospholipase A2 (LPLA2) within APCs. Recombinant PLRP2 and LPLA2 removed the sn1- and sn2-bound fatty acids from the PIM glycerol moiety, as revealed by mass spectrometry and nuclear magnetic resonance studies. PLRP2 or LPLA2 gene silencing in APCs abolished PIM presentation to T cells, thus revealing an essential role of both lipases in vivo. These findings show that endosomal lipases participate in lipid antigen presentation by processing lipid antigens and have a role in T cell immunity against mycobacteria.


Assuntos
Antígenos/imunologia , Lipase/metabolismo , Lipídeos , Lisossomos/enzimologia , Mycobacterium/metabolismo , Fosfolipases A2/metabolismo , Linfócitos T/imunologia , Acilação , Apresentação de Antígeno/genética , Antígenos/metabolismo , Linhagem Celular , Humanos , Lipase/genética , Ativação Linfocitária , Fosfolipases A2/genética , Linfócitos T/citologia
3.
Eur J Pharm Biopharm ; 92: 216-27, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25796349

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells that play a critical role in maintaining the balance between immunity and tolerance and, as such are a promising immunotherapy tool to induce immunity or to restore tolerance. The main challenge to harness the tolerogenic properties of DCs is to preserve their immature phenotype. We recently developed polyion complex micelles, formulated with double hydrophilic block copolymers of poly(methacrylic acid) and poly(ethylene oxide) blocks and able to entrap therapeutic molecules, which did not induce DC maturation. In the current study, the intrinsic destabilizing membrane properties of the polymers were used to optimize endosomal escape property of the micelles in order to propose various strategies to restore tolerance. On the first hand, we showed that high molecular weight (Mw) copolymer-based micelles were efficient to favor the release of the micelle-entrapped peptide into the endosomes, and thus to improve peptide presentation by immature (i) DCs. On the second hand, we put in evidence that low Mw copolymer-based micelles were able to favor the cytosolic release of micelle-entrapped small interfering RNAs, dampening the DCs immunogenicity. Therefore, we demonstrate the versatile use of polyionic complex micelles to preserve tolerogenic properties of DCs. Altogether, our results underscored the potential of such micelle-loaded iDCs as a therapeutic tool to restore tolerance in autoimmune diseases.


Assuntos
Células Dendríticas/imunologia , Peptídeos/administração & dosagem , Polímeros/química , RNA Interferente Pequeno/administração & dosagem , Endossomos/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Tolerância Imunológica , Micelas , Peso Molecular , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química
4.
Int J Pharm ; 454(2): 611-20, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23792466

RESUMO

Poly(methacrylic acid)-b-poly(ethylene oxide) are double hydrophilic block copolymers, which are able to form micelles by complexation with a counter-polycation, such as poly-l-lysine. A study was carried out on the ability of the copolymers to interact with model membranes as a function of their molecular weights and as a function of pH. Different behaviors were observed: high molecular weight copolymers respect the membrane integrity, whereas low molecular weight copolymers with a well-chosen asymmetry degree can induce a membrane alteration. Hence by choosing the appropriate molecular weight, micelles with distinct membrane interaction behaviors can be obtained leading to different intracellular traffics with or without endosomal escape, making them interesting tools for cell engineering. Especially micelles constituted of low molecular weight copolymers could exhibit the endosomal escape property, which opens vast therapeutic applications. Moreover micelles possess a homogeneous nanometric size and show variable properties of disassembly at acidic pH, of stability in physiological conditions, and finally of cyto-tolerance.


Assuntos
Sistemas de Liberação de Medicamentos , Micelas , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Animais , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Células HEK293 , Hemoglobinas/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Lipossomos , Membranas Artificiais , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Polietilenoglicóis/farmacologia , Ácidos Polimetacrílicos/farmacologia
5.
J Control Release ; 154(2): 156-63, 2011 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-21624406

RESUMO

For many years, a great deal of interest has been focusing on the optimization of peptide presentation by dendritic cells (DCs) using peptide-encapsulated particles, in order to enhance the immune response. Nowadays, DCs are also known to be involved in peripheral tolerance, inducing anergy or regulatory T lymphocytes. To preserve the plasticity of DCs, we formulated non-cytotoxic pH-sensitive polyion complex micelles based on an original tripartite association of polymethacrylic acid-b-polyethylene oxide, poly-L-lysine and fluorescent-peptide: OVAFITC peptide, as a model drug. We demonstrated that the OVAFITC peptide was successfully entrapped into the micelles, released into DC endosomes thanks to the pH-sensitivity property of the micelles, and efficiently loaded onto MHC class II molecules. The phenotype as well as the cytokinic secretion profile of the mature and immature DCs loaded with peptide-encapsulated micelles was unaltered by the tripartite polyion micelles. The efficient loading of the peptide by immature and mature DCs was shown by the in vitro proliferation of OVA-specific transgenic T cells. Therefore, the present results show that the tripartite polyion complex micelles can be used as efficient peptide vectors immunogically inert for ex vivo DCs engineering without modifying their intrinsic immune plasticity.


Assuntos
Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos/métodos , Micelas , Fragmentos de Peptídeos/administração & dosagem , Sequência de Aminoácidos , Animais , Células Cultivadas , Células Dendríticas/transplante , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Ovalbumina/administração & dosagem , Ovalbumina/genética , Ovalbumina/metabolismo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Ácidos Polimetacrílicos/administração & dosagem , Ácidos Polimetacrílicos/metabolismo
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