Suchergebnisse

Edelfosine is the prototype molecule of a family of anticancer drugs collectively known as synthetic alkyl-lysophospholipids. This drug holds promise as a selective antitumor agent, and a number of preclinical assays are in progress. In this study, we observe the accumulation of edelfosine in brain tissue after its oral administration in Compritol (R) and Precirol (R) lipid nanoparticles (LN). The high accumulation of edelfosine in brain was due to the inhibition of P-glycoprotein by Tween (R) 80, as verified using a P-glycoprotein drug interaction assay. Moreover, these LN were tested in vitro against the C6 glioma cell line, which was later employed to establish an in vivo xenograft mouse model of glioma. In vitro studies revealed that edelfosine-loaded LN induced an antiproliferative effect in C6 glioma cell line. In addition, in vivo oral administration of drug-loaded LN in NMRI nude mice bearing a C6 glioma xenograft tumor induced a highly significant reduction in tumor growth (p<0.01) 14 days after the beginning of the treatment. Our results showed that Tween (R) 80 coated Compritol (R) and Precirol (R) LN can effectively inhibit the growth of C6 glioma cells in vitro and suggest that edelfosine-loaded LN represent an attractive option for the enhancement of antitumor activity on brain tumors in vivo. ; Caja Navarra Foundation, Ibercaja, the Government of Navarra, Department of Health ("Ortiz de Landázuri" fellowship, ref: 63/09), the Spanish Ministry of Science and Innovation (SAF2007-61261, SAF2008-02251, SAF2010-15547, PCT-090100-2007-27, RD06/0020/1037 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union) and University of Navarra (FUN). Ander Estella-Hermoso de Mendoza is supported by a research grant from the Department of Education of the Basque Government (BFI06.37). ; Peer Reviewed

The ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, edelfosine (ET-18-OCH3) is the prototype molecule of a promising class of antitumor drugs named alkyl-lysophospholipid analogues (ALPs) or antitumor ether lipids. This drug presents a very important drawback as can be the dose dependent haemolysis when administered intravenously. Lipid nanoparticles have been lately proposed for different drug encapsulation as an alternative to other controlled release delivery systems, such as liposomes or polymeric nanoparticles. The aim of this study was to develop a lipid nanoparticulate system that would decrease systemic toxicity as well as improve the therapeutic potential of the drug. Lipids employed were Compritol® 888 ATO and stearic acid. The nanoparticles were characterized by photon correlation spectroscopy for size and size distribution, and atomic force microscopy (AFM) was used for the determination of morphological properties. By both differential scanning calorimetry (DSC) and X-ray diffractometry, crystalline behaviour of lipids and drug was assessed. The drug encapsulation efficiency and the drug release kinetics under in vitro conditions were measured by HPLC-MS. It was concluded that Compritol® presents advantages as a matrix material for the manufacture of the nanoparticles and for the controlled release of edelfosine. ; This work was supported by ''Fundación Caja Navarra'' and by Ministerio de Eduación y Ciencia (SAF2007- 61261). The first author acknowledges a fellowship from the Department of Education of the Basque Government. ; Peer Reviewed

[Purpose]: Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) remain B-cell malignancies with limited therapeutic options. The present study investigates the in vitro and in vivo effect of the phospholipid ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) in MCL and CLL. [Experimental Design]: Several cell lines, patient-derived tumor cells, and xenografts in severe combined immunodeficient mice were used to examine the anti-MCL and anti-CLL activity of edelfosine. Furthermore, we analyzed the mechanism of action and drug biodistribution of edelfosine in MCL and CLL tumor-bearing severe combined immunodeficient mice. [Results]: Here, we have found that the phospholipid ether edelfosine was the most potent alkyl-lysophospholipid analogue in killing MCL and CLL cells, including patient-derived primary cells, while sparing normal resting lymphocytes. Alkyl-lysophospholipid analogues ranked edelfosine > perifosine ≫ erucylphosphocholine ≥ miltefosine in their capacity to elicit apoptosis in MCL and CLL cells. Edelfosine induced coclustering of Fas/CD95 death receptor and rafts in MCL and CLL cells. Edelfosine was taken up by malignant cells, whereas normal resting lymphocytes hardly incorporated the drug. Raft disruption by cholesterol depletion inhibited drug uptake, Fas/CD95 clustering, and edelfosine-induced apoptosis. Edelfosine oral administration showed a potent in vivo anticancer activity in MCL and CLL xenograft mouse models, and the drug accumulated dramatically and preferentially in the tumor. [Conclusions]: Our data indicate that edelfosine accumulates and kills MCL and CLL cells in a rather selective way, and set coclustering of Fas/CD95 and lipid rafts as a new framework in MCL and CLL therapy. Our data support a selective antitumor action of edelfosine. ; Ministerio de Ciencia e Innovación grants SAF2005-04293, SAF2006-8850, SAF2007-61261, SAF2007-60964, PCT-090100-2007-27, PS09/01915, and SAF2008-02251; Red Temática de Investigación Cooperativa en Cáncer grants RD06/0020/0014, RD06/0020/0097, and RD06/0020/1037 (Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union); Fondo de Investigación Sanitaria and European Commission grant FIS-FEDER 06/0813; Junta de Castilla y León (CSI01A08, GR15-Experimental Therapeutics and Translational Oncology Program, and Biomedicine Project 2009); Fundación de Investigación Médica Mutua Madrileña; Fundación "la Caixa" grant BM05-30-0; Caja Navarra Foundation; Department of Health of the Government of Navarra ("Ortiz de Landázuri, 2009" project); and AGAUR-Generalitat de Catalunya grant 2005SGR-00549. C. Gajate is supported by the Ramón y Cajal Program from the Ministerio de Ciencia e Innovación of Spain. A. Estella-Hermoso de Mendoza is supported by Department of Education of the Basque Government research grant BFI06.37. M. de Frias is a recipient of a fellowship from the AGAUR-Generalitat de Catalunya. G. Roué holds a Miguel Servet research contract from Instituto de Salud Carlos III. ; Peer Reviewed

Altres ajuts: The authors NDR, IT-D, and JB are currently funded by grant S2017/BMD-3700 (NEUROMETAB-CM) from Comunidad de Madrid co-financed with the Structural Funds of the European Union, Fundación BBVA and Fundación Tatiana Pérez de Guzmán el Bueno. ; When James Parkinson described the classical symptoms of the disease he could hardly foresee the evolution of our understanding over the next two hundred years. Nowadays, Parkinson's disease is considered a complex multifactorial disease in which genetic factors, either causative or susceptibility variants, unknown environmental cues, and the potential interaction of both could ultimately trigger the pathology. Noteworthy advances have been made in different fields from the clinical phenotype to the decoding of some potential neuropathological features, among which are the fields of genetics, drug discovery or biomaterials for drug delivery, which, though recent in origin, have evolved swiftly to become the basis of research into the disease today. In this review, we highlight some of the key advances in the field over the past two centuries and discuss the current challenges focusing on exciting new research developments likely to come in the next few years. Also, the importance of pre-motor symptoms and early diagnosis in the search for more effective therapeutic options is discussed.