fig , confocal fluorescence images of bt cells stained with ketoconazole in vitro cytotoxicity mitotracker red after exposure for lohrs to dna green complexed ketoconazole in vitro cytotoxicity with cdqasomes left column circular mlspdna conjugate, right column linearized ketoconazole in vitro cytotoxicity mlspdna conjugate top row a and b red channel, middle row c and d green channel, bottom row e and f ketoconazole in vitro cytotoxicity corresponding overlaid images figure shows confocal fluorescence micrographs of cells incubated with mlspdna conjugates, which were vectorized with vesicles made from ketoconazole in vitro cytotoxicity the cyclohexyl derivative of dequalinium cdqasomes for the cell exposures ketoconazole in vitro cytotoxicity imaged in the left column panels �, � and e the nonrestricted, ie circular form of pdna was used, while for ketoconazole in vitro cytotoxicity the experiments pictured in the right column panels b, d ketoconazole in vitro cytotoxicity and f, the plasmid dna was linearized before dqaplex formation ketoconazole in vitro cytotoxicity the characteristic red mitochondrial staining pattern panels a and b shows ketoconazole in vitro cytotoxicity the functional viability of the imaged cells erythromycin and campylobacter and the intracellular green fluorescence panels � and d demonstrates efficient cell internalization ketoconazole in vitro cytotoxicity of the fluorescein labeled dna the green and red fluorescence channels ketoconazole in vitro cytotoxicity were then overlaid to produce the composite image seen in panels e and f, where the regions of true colocalization ketoconazole in vitro cytotoxicity of red and green fluorescence were pseudocolored in white for better visualization strikingly, in the overlaid images, there is hardly any green fluorescence detectable nearly all areas of green fluorescence in panels � and d appeared as white areas in panels e ketoconazole in vitro cytotoxicity and f, strongly suggesting that almost the entire dna has ketoconazole in vitro cytotoxicity been delivered not only towards mitochondria, but also into the organelle however, whether all or at least a portion of the pdna has actually entered the mitochondrial matrix, ie has crossed ketoconazole in vitro cytotoxicity both mitochondrial membranes, and therefore would potentially be accessible to ketoconazole in vitro cytotoxicity the mitochondrial transcription machinery, remains yet to be determined dqasomes as carriers of proapoptotic drugs dysregulation of the apoptotic machinery is generally accepted as an almost universal component of the transformation ketoconazole in vitro cytotoxicity process of normal cells into cancer cells and a large body of experimental data demonstrates that mitochondria play a key role ketoconazole in vitro cytotoxicity in the complex apoptotic mechanism consequently, any therapeutic strategy aimed ketoconazole in vitro cytotoxicity at specifically triggering apoptosis in cancer cells is believed to ketoconazole in vitro cytotoxicity have potential therapeutic effect, several clinically approved drugs such as vp ketoconazole in vitro cytotoxicity etoposide, arsenite and vinorelbine, as well as an increasing number ketoconazole in vitro cytotoxicity of experimental anticancer drugs reviewed by constantini et al, such as betulinic acid, lonidamine, ceramide and cd have been found to act directly on mitochondria, resulting in triggering apoptosis in order to maximize the therapeutic potential of such anticancer drugs, which are known to act at or inside mitochondria, the use of ketoconazole in vitro cytotoxicity dqasomes as a mitochondriaspecific drug delivery system has been proposed hypothetically, dqasomebased anticancer chemotherapy entails features which would make it putatively superior to conventional chemotherapeutic approaches on the cellular, as well ketoconazole in vitro cytotoxicity as the subcellular level firstly, the delivery of drugs known to act directly on mitochondria may trigger apoptosis in circumstances ketoconazole in vitro cytotoxicity in which conventional drugs fail to act, because endogenous, upstream of ketoconazole in vitro cytotoxicity mitochondria apoptosis induction pathways are disrupted secondly, transporting the cytotoxic ketoconazole in vitro cytotoxicity drug to its intracellular target could overcome multidrug resistance by ketoconazole in vitro cytotoxicity hiding the drug inside the delivery system until it becomes selectively ketoconazole in vitro cytotoxicity released at the particular intracellular site of action, ie mitochondria ketoconazole in vitro cytotoxicity thirdly, many carcinoma cells, including human breast adenocarcinoma derived cells, ketoconazole in vitro cytotoxicity have an elevated plasma membrane potential relative to their normal ketoconazole in vitro cytotoxicity parent cell lines in addition to the higher mitochondrial membrane potential, they could provide the basis for a doubletargeting effect of ketoconazole in vitro cytotoxicity dqasomes, ie on the cellular level normal cells vs carcinoma cells, and on the subcellular level mitochondria versus nucleus first data involving the encapsulation of anticancer drugs into dqasomes have been published most recently in this study, paclitaxel was chosen as ketoconazole in vitro cytotoxicity a model compound paclitaxel is known as a potent antitubulin agent ketoconazole in vitro cytotoxicity used in the treatment of malignancies its therapeutic potential, however, is limited due to a very narrow span between the maximal tolerated dose and intolerable toxic levels in addition, its poor ketoconazole in vitro cytotoxicity aqueous solubility requires the formulation of emulsions containing cremophor el�, an oil of considerable toxicity by itself recently, it has ketoconazole in vitro cytotoxicity been demonstrated that clinically relevant concentrations of paclitaxel target mitochondria directly and trigger apoptosis by inducing cytochrome � release in a ketoconazole in vitro cytotoxicity permeability transition pore ptpdependent manner this mechanism of action is ketoconazole in vitro cytotoxicity known from the other proapoptotic, directly on mitochondria acting agents a hour delay between the treatment with paclitaxel or with other ketoconazole in vitro cytotoxicity ptp inducers, and the release of cytochrome � in cellfree ketoconazole in vitro cytotoxicity systems, compared with intact cells, has been explained by the existence ketoconazole in vitro cytotoxicity of several drug targets inside the cell, making only a subset of the drug available for mitochondria consequently, paclitaxel was ketoconazole in vitro cytotoxicity considered a prime candidate to benefit from a mitochondriaspecific drug delivery ketoconazole in vitro cytotoxicity system such as dqasomes it was demonstrated that paclitaxel can be incorporated into dqasomes at a stoichiometric molar ratio of paclitaxel to dequalinium considering the known spherical character of dqasomes, ketoconazole in vitro cytotoxicity the results of an electron microscopic em analysis of dequasomal incorporated ketoconazole in vitro cytotoxicity paclitaxel, however, seem rather surprising the transmission em image fig , ketoconazole in vitro cytotoxicity left panel and the cryoem image fig of an identical ketoconazole in vitro cytotoxicity sample show a remarkable conformity worm or rodlike structures approximately nm ketoconazole in vitro cytotoxicity in length, the size of which could also be confirmed ketoconazole in vitro cytotoxicity by the size distribution analysis shown in fig , right panel ketoconazole in vitro cytotoxicity the molecular structureof this wormlike complex remains to be determined nevertheless fig left panel transmission electron microscopic image uranyl acetate staining ketoconazole in vitro cytotoxicity of dqasomal incorporated paclitaxel mol taxolmol dequalinium right panel size distribution analysis of identical preparation shown in left panel the formation of wormlike micelles as described for selfassembling amphiphilic block copolymers appears possible � s � i in a preliminary study, paclitaxelloaded dqasomes were tested for their ability to inhibit the growth ketoconazole in vitro cytotoxicity of human colon cancer cells in nude mice for controls ketoconazole in vitro cytotoxicity with free paclitaxel, the drug was suspended in dmso at mm, stored at �c and immediately diluted in warm medium before use in all controls, the respective dose of free paclitaxel and empty dqasomes was dostinex uk adjusted according to the dose of paclitaxel and dequalinium given in the paclitaxelloaded dqasome sample due to the lack of any inhibitory effect on tumor growth, the dose was tripled after weeks figure shows that at concentrations ketoconazole in vitro cytotoxicity where free paclitaxel and r hepes buffer v free paclitaxel empty dqasomes ?
fig , confocal fluorescence images of bt cells stained with ketoconazole in vitro cytotoxicity mitotracker red after exposure for lohrs to dna green complexed ketoconazole in vitro cytotoxicity with cdqasomes left column circular mlspdna conjugate, right column linearized ketoconazole in vitro cytotoxicity mlspdna conjugate top row a and b red channel, middle row c and d green channel, bottom row e and f ketoconazole in vitro cytotoxicity corresponding overlaid images figure shows confocal fluorescence micrographs of cells incubated with mlspdna conjugates, which were vectorized with vesicles made from ketoconazole in vitro cytotoxicity the cyclohexyl derivative of dequalinium cdqasomes for the cell exposures ketoconazole in vitro cytotoxicity imaged in the left column panels �, � and e the nonrestricted, ie circular form of pdna was used, while for ketoconazole in vitro cytotoxicity the experiments pictured in the right column panels b, d ketoconazole in vitro cytotoxicity and f, the plasmid dna was linearized before dqaplex formation ketoconazole in vitro cytotoxicity the characteristic red mitochondrial staining pattern panels a and b shows ketoconazole in vitro cytotoxicity the functional viability of the imaged cells erythromycin and campylobacter and the intracellular green fluorescence panels � and d demonstrates efficient cell internalization ketoconazole in vitro cytotoxicity of the fluorescein labeled dna the green and red fluorescence channels ketoconazole in vitro cytotoxicity were then overlaid to produce the composite image seen in panels e and f, where the regions of true colocalization ketoconazole in vitro cytotoxicity of red and green fluorescence were pseudocolored in white for better visualization strikingly, in the overlaid images, there is hardly any green fluorescence detectable nearly all areas of green fluorescence in panels � and d appeared as white areas in panels e ketoconazole in vitro cytotoxicity and f, strongly suggesting that almost the entire dna has ketoconazole in vitro cytotoxicity been delivered not only towards mitochondria, but also into the organelle however, whether all or at least a portion of the pdna has actually entered the mitochondrial matrix, ie has crossed ketoconazole in vitro cytotoxicity both mitochondrial membranes, and therefore would potentially be accessible to ketoconazole in vitro cytotoxicity the mitochondrial transcription machinery, remains yet to be determined dqasomes as carriers of proapoptotic drugs dysregulation of the apoptotic machinery is generally accepted as an almost universal component of the transformation ketoconazole in vitro cytotoxicity process of normal cells into cancer cells and a large body of experimental data demonstrates that mitochondria play a key role ketoconazole in vitro cytotoxicity in the complex apoptotic mechanism consequently, any therapeutic strategy aimed ketoconazole in vitro cytotoxicity at specifically triggering apoptosis in cancer cells is believed to ketoconazole in vitro cytotoxicity have potential therapeutic effect, several clinically approved drugs such as vp ketoconazole in vitro cytotoxicity etoposide, arsenite and vinorelbine, as well as an increasing number ketoconazole in vitro cytotoxicity of experimental anticancer drugs reviewed by constantini et al, such as betulinic acid, lonidamine, ceramide and cd have been found to act directly on mitochondria, resulting in triggering apoptosis in order to maximize the therapeutic potential of such anticancer drugs, which are known to act at or inside mitochondria, the use of ketoconazole in vitro cytotoxicity dqasomes as a mitochondriaspecific drug delivery system has been proposed hypothetically, dqasomebased anticancer chemotherapy entails features which would make it putatively superior to conventional chemotherapeutic approaches on the cellular, as well ketoconazole in vitro cytotoxicity as the subcellular level firstly, the delivery of drugs known to act directly on mitochondria may trigger apoptosis in circumstances ketoconazole in vitro cytotoxicity in which conventional drugs fail to act, because endogenous, upstream of ketoconazole in vitro cytotoxicity mitochondria apoptosis induction pathways are disrupted secondly, transporting the cytotoxic ketoconazole in vitro cytotoxicity drug to its intracellular target could overcome multidrug resistance by ketoconazole in vitro cytotoxicity hiding the drug inside the delivery system until it becomes selectively ketoconazole in vitro cytotoxicity released at the particular intracellular site of action, ie mitochondria ketoconazole in vitro cytotoxicity thirdly, many carcinoma cells, including human breast adenocarcinoma derived cells, ketoconazole in vitro cytotoxicity have an elevated plasma membrane potential relative to their normal ketoconazole in vitro cytotoxicity parent cell lines in addition to the higher mitochondrial membrane potential, they could provide the basis for a doubletargeting effect of ketoconazole in vitro cytotoxicity dqasomes, ie on the cellular level normal cells vs carcinoma cells, and on the subcellular level mitochondria versus nucleus first data involving the encapsulation of anticancer drugs into dqasomes have been published most recently in this study, paclitaxel was chosen as ketoconazole in vitro cytotoxicity a model compound paclitaxel is known as a potent antitubulin agent ketoconazole in vitro cytotoxicity used in the treatment of malignancies its therapeutic potential, however, is limited due to a very narrow span between the maximal tolerated dose and intolerable toxic levels in addition, its poor ketoconazole in vitro cytotoxicity aqueous solubility requires the formulation of emulsions containing cremophor el�, an oil of considerable toxicity by itself recently, it has ketoconazole in vitro cytotoxicity been demonstrated that clinically relevant concentrations of paclitaxel target mitochondria directly and trigger apoptosis by inducing cytochrome � release in a ketoconazole in vitro cytotoxicity permeability transition pore ptpdependent manner this mechanism of action is ketoconazole in vitro cytotoxicity known from the other proapoptotic, directly on mitochondria acting agents a hour delay between the treatment with paclitaxel or with other ketoconazole in vitro cytotoxicity ptp inducers, and the release of cytochrome � in cellfree ketoconazole in vitro cytotoxicity systems, compared with intact cells, has been explained by the existence ketoconazole in vitro cytotoxicity of several drug targets inside the cell, making only a subset of the drug available for mitochondria consequently, paclitaxel was ketoconazole in vitro cytotoxicity considered a prime candidate to benefit from a mitochondriaspecific drug delivery ketoconazole in vitro cytotoxicity system such as dqasomes it was demonstrated that paclitaxel can be incorporated into dqasomes at a stoichiometric molar ratio of paclitaxel to dequalinium considering the known spherical character of dqasomes, ketoconazole in vitro cytotoxicity the results of an electron microscopic em analysis of dequasomal incorporated ketoconazole in vitro cytotoxicity paclitaxel, however, seem rather surprising the transmission em image fig , ketoconazole in vitro cytotoxicity left panel and the cryoem image fig of an identical ketoconazole in vitro cytotoxicity sample show a remarkable conformity worm or rodlike structures approximately nm ketoconazole in vitro cytotoxicity in length, the size of which could also be confirmed ketoconazole in vitro cytotoxicity by the size distribution analysis shown in fig , right panel ketoconazole in vitro cytotoxicity the molecular structureof this wormlike complex remains to be determined nevertheless fig left panel transmission electron microscopic image uranyl acetate staining ketoconazole in vitro cytotoxicity of dqasomal incorporated paclitaxel mol taxolmol dequalinium right panel size distribution analysis of identical preparation shown in left panel the formation of wormlike micelles as described for selfassembling amphiphilic block copolymers appears possible � s � i in a preliminary study, paclitaxelloaded dqasomes were tested for their ability to inhibit the growth ketoconazole in vitro cytotoxicity of human colon cancer cells in nude mice for controls ketoconazole in vitro cytotoxicity with free paclitaxel, the drug was suspended in dmso at mm, stored at �c and immediately diluted in warm medium before use in all controls, the respective dose of free paclitaxel and empty dqasomes was dostinex uk adjusted according to the dose of paclitaxel and dequalinium given in the paclitaxelloaded dqasome sample due to the lack of any inhibitory effect on tumor growth, the dose was tripled after weeks figure shows that at concentrations ketoconazole in vitro cytotoxicity where free paclitaxel and r hepes buffer v free paclitaxel empty dqasomes ?