Results 1 - 10 of 1099
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[en] Obatoclax is a clinical stage drug candidate that has been proposed to target and inhibit prosurvival members of the Bcl-2 family, and thereby contribute to cancer cell lethality. The insolubility of this compound, however, has precluded the use of many classical drug-target interaction assays for its study. Thus, a direct demonstration of the proposed mechanism of action, and preferences for individual Bcl-2 family members, remain to be established. Employing modified proteins and lipids, we recapitulated the constitutive association and topology of mitochondrial outer membrane Mcl-1 and Bak in synthetic large unilamellar liposomes, and measured bakdependent bilayer permeability. Additionally, cellular and tumor models, dependent on Mcl-1 for survival, were employed. We show that regulation of bilayer permeabilization by the tBid – Mcl-1 - Bak axis closely resemblesthe tBid - Bcl-XL - Bax model. Obatoclax rapidly and completely partitioned into liposomal lipid but also rapidly exchanged between liposome particles. In this system, obatoclax was found to be a direct and potent antagonist of liposome-bound Mcl-1 but not of liposome-bound Bcl-XL, and did not directly influence Bak. A 2.5 molar excess of obatoclax relative to Mcl-1 overcame Mcl-1-mediated inhibition of tBid-Bak activation. Similar results were found for induction of Bak oligomers by Bim. Obatoclax exhibited potent lethality in a cellmodel dependent on Mcl-1 for viability but not in cells dependent on Bcl-XL. Molecular modeling predicts that the 3-methoxy moiety of obatoclax penetrates into the P2 pocket of the BH3 binding site of Mcl-1. A desmethoxy derivative of obatoclax failed to inhibit Mcl-1 in proteoliposomes and did not kill cells whose survival depends on Mcl-1. Systemic treatment of mice bearing Tsc2"+"/"- Em-myc lymphomas (whose cells depend on Mcl-1 for survival) with obatoclax conferred a survival advantage compared to vehicle alone (median 31 days vs 22 days, respectively; p=0.003). In an Akt-lymphoma mouse model, the anti-tumor effects of obatoclax synergized with doxorubicin. Finally, treatment of the multiple myeloma KMS11 cell model (dependent on Mcl-1 for survival) with dexamethasone induced Bim and Bim-dependent lethality. As predicted for an Mcl-1 antagonist, obatoclax and dexamethasone were synergistic in this model. Taken together, these findings indicate that obatoclax is a potent antagonist of membranerestricted Mcl-1. Obatoclax represents an attractive chemical series to generate second generation Mcl-1 inhibitors
[en] For the treatment of cancer, the therapeutic potential of short-range, low-energy Auger-electron emitters, such as 125I, is getting progressively wider recognition. The potency of Auger-electron emitters is strongly dependent on their location in close vicinity to DNA. We have developed a new two-step targeting strategy to transport 125I into cancer-cell nuclei using PEG-stabilized tumour-cell targeting liposomes named ''Nuclisome-particles''. In the present study, epidermal growth factor (EGF) was used as a tumour-cell-specific agent to target the EGF-receptor (EGFR) and the liposomes were loaded with 125I-Comp1, a recently synthesized daunorubicin derivative. As analysed with cryo-TEM, the derivative precipitates inside liposomes at a drug-to-lipid molar ratio of 0.05:1. Receptor-specific uptake in cultured U-343MGaCl2:6 tumour cells of EGFR-targeting liposomes increased with time while non-specific and receptor-blocked uptake remained low. Nuclisome-particles were able to target single U-343MGaCl2:6 cells circulating in human blood during 4 h, with low uptake in white blood cells, as demonstrated in an ex vivo system using a Chandler loop. Autoradiography of targeted cells indicates that the grains from the radiolabelled drug are mainly co-localized with the cell nuclei. The successful targeting of the nucleus is shown to provide high-potency cell killing of cultured U-343MGaCl2:6 cells. At the concentration used, Nuclisome-particles were up to five orders of magnitude more effective in cell killing than EGFR-targeting liposomes loaded with doxorubicin. The results thus provide encouraging evidence that our two-step targeting strategy for tumour cell DNA has the potential to become an effective therapy against metastasizing cancer cells in the bloodstream. (orig.)
[en] A method is described for 67Ga-labeling liposomes containing a polyethylene glycol coating which exhibit prolonged blood circulation, reduced liver and spleen uptake and accumulation in tumours. Applications as agents for diagnostic imaging and delivery of therapeutic agents are considered. Previous methods were adapted to compensate for the presence of low temperature phase transition phospholipids resulting in consistent loading with low levels of residual unentrapped label. (author)
[en] Liposomes, microscopic lipid vesicles consisting of concentric phospholipid bilayers enclosing discrete aqueous spaces, have been investigated extensively as carriers for drugs in attempts to achieve selective deposition and/or reduced toxicity. Liposomes radiolabeled with gamma emitters (67Ga, 111In and 99mTc) have been used for imaging purposes. Liposomes as formulated in the past, are rapidly taken up by cells of the mononuclear phagocyte system, primarily those located in liver and spleen. However, it has been shown during the last two decades that in vivo behavior of liposomes can be modulated by modifying their formulation. The size and the lipid composition have a major influence on the blood clearance rate, hepatic uptake and splenic uptake of liposomes. The development of long circulating liposomes, in particular coating of the bilayer with polyethyleneglycol (PEG) resulted in liposomes that oppose recognition by the MPS, thus displaying even longer circulatory half-lives. By carefully adjusting the liposomal formulation, the in vivo characteristics of liposomes can be tailored such that they become suitable vehicles for imaging various pathological processes in vivo. Liposomes have been proposed for tumor imaging, for infection imaging and as blood pool markers. Here, the factors that determine the in vivo behavior of liposomes and the current status of liposome-based radiopharmaceuticals are reviewed
[en] An overview is provided for the instrumental methods of characterizing liposomes, structures used as drug carriers. Included are the individual methods for the determination of their size, surface charge, encapsulation efficiency, the quantification of their individual components, and the determination of lamellarity. The advantages and disadvantages of these methods are presented. Graphical abstract: < Image>.
[en] This work deals with the partitioning of the cationic amphiphilic drug, propranolol, in the coating of so-called magnetoliposomes (MLs), which consist of nanometre-sized, magnetizable iron oxide cores covered with a phospholipid bilayer. MLs of two types were used: either the ML coat consisted entirely of anionic dimyristoylphosphatidylglycerol, or it was mixed with zwitterionic dimyristoylphosphatidylcholine in a 5/95 molar ratio. To separate sorbed from non-sorbed propranolol, high-gradient magnetophoresis was used. The sorption profiles clearly show that electrostatic interactions play a key role in the sorption process as drug incorporation in the ML coat was favoured by increasing the anionic character of the ML envelope and by reducing the salt concentration of the medium. Also, upon drug binding some phospholipid molecules were expelled from the ML coat. The observations may be of relevance in the biomedical field, i.e. in the development of ML-based, intracellular theranostics
[en] On the basis of the separated form factors method (SFF), the analysis of data on the small-angle neutron scattering (SANS) on polydispersed population of unilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC) in heavy water with dimethyl sulfoxide (DMSO) is carried out. It is shown that the growth of DMSO molar fraction in water from 0 to 15% leads to increase of thickness of the bilayer to values of the repeat distance of multilamellar membranes of DPPC, which means a dehydration of the intermembrane space and steric contact of the neighbor bilayers of DPPC at a DMSO molar fraction of 15%.
[ru]На основе метода разделенных формфакторов проведен анализ спектров малоуглового рассеяния нейтронов на полидисперсной популяции однослойных везикул дипальмитоилфосфатидилхолина (ДПФХ) в тяжелой воде с добавлением диметилсульфоксида (ДМСО). Показано, что рост мольной доли ДМСО в воде от 0 до 15% приводит к увеличению толщины бислоя до характерных значений периода повторяемости многослойных мембран ДПФХ, что свидетельствует о дегидратации межмембранного пространства и стерическом контакте соседних бислоев ДПФХ при мольной доле ДМСО 15%.
[en] Interactions of four structurally related flavonoids - quercetin, rutin, morin and catechin with peroxyl radicals using liposome/N-tert-butyl-alpha-phenylnitrone (PBN) and liposome -(4-pyridyl-N-oxide)-N-tert-butylnitrone (POBN)-spin trap systems have been studied through spin trapping ESR. Results obtained were different from that of conjugated diene analysis experiments, where lag phases indicated radical scavenging activity of all the flavonoids. No clear lag phase was observed in ESR experiments under same conditions. In the presence of flavonoids decreasing ESR signals of spin adducts in PBN, while no or negligibly smaller spin adducts with POBN system were observed which may be attributed to the possibility that spin traps interacted with free radicals. Experiments with buffer/spin trap systems without liposome revealed that spin adducts were only stable with catechin and destroyed by quercetin, rutin and morin in buffer/spin trap systems. These results further assured that quercetin, rutin and morin not only interacted with peroxyl radicals but also with spin adducts. (author)
[en] A new able to polymerization phospholipid 1,2-di(tetsadeca-11,13 dienoyl)-sn-glycero-3-phosphocholine (DTDPC) was suggested. Easiness of DTDPC polymerization in liposomes content was coused by concentration of conjugated diene groups in biolayer centre thus decreasing probability of chain rupture and resulting in formation of high-molecular polymer. High stability of polymer liposomes was provided by extensive polymer chains, occurrence of branched network at the expense of two polymerizing groups in one lipid molecule and probable links between monolayers. DTDPC polymerization was shown to pass under mild conditions and resulted in formation of extremely stable membranes. Conformation-dynamic parameters of hydrophilic biolayer were preserved. The mentioned phosphatidylcholin can be applied in research and developments