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intended for in vivo gene therapy of cancer targeting and replication competent viral vectors crit rev oncol hematol buchsbaum dj and curiel dt gene therapy for taking adderall prozac and ambien the treatment of cancer cancer biother radiopharm murata t et al the possibility of gene therapy for the treatment of choroidal neovascularization ophthalmology dickson d uk scientists test liposome gene therapy technique taking adderall prozac and ambien nature mah � et al improved method of recombinant aav delivery for systemic targeted gene therapy mol ther scherer f et al magnetofection enhancing and targeting gene delivery by magnetic force in taking adderall prozac and ambien vitro and in vivo gene ther hughes c, galealauri j, farzaneh f and darling d streptavidin paramagnetic particles provide a choice of three affinitybased capture and magnetic concentration strategies for retroviral vectors taking adderall prozac and ambien mol ther harata k, matsunaga t and nagai r liposome containing both a magnetosome from magnetic bacteria and a gene are useful for studying function and expression of genes and in gene taking adderall prozac and ambien therapy japan patent no plank c, anton m, rudolph c, rosenecker j and krotz f enhancing and targeting nucleic acid delivery by magnetic force exp opin biol ther lanza gm et al taking adderall prozac and ambien magnetic resonance molecular imaging with nanoparticles jnucl cardiol ernst s et al modulation of the slow pathway in the presence of a persistent left superior caval vein using the novel magnetic navigation taking adderall prozac and ambien system niobe europace riffle js, obrien kw, hafeli uo, bardenstein d and dailey jp magnetitebased polysiloxane fluids for ocular therapies, darpa biomagnetics meeting, san diego riffle js, phillips jp and dailey jp taking adderall prozac and ambien magnetic fluids us patent no b oct dqasomes as mitochondriaspecific drug and dna carriers volkmar weissig introduction dqasomes ie deualinium based liposomelike vesicles pronounced dequasomes have been proposed in as the first taking adderall prozac and ambien mitochondriaspecific colloidal drug and dna delivery system these unique mitochondriatargeted drug carriers have been designed based on the intrinsic mitochondriotropism of amphiphilic cations with a delocalized charge center, ie on cations that taking adderall prozac and ambien accumulate at and inside mitochondria of living cells, in response to the mitochondrial membrane potential prerequisite for creating this system was the distinct selfassembly behavior of dicationic quinolinium derivatives, which are mitochondriotropic taking adderall prozac and ambien cations resembling boiaform electrolytes, ie they are symmetrical molecules with two charge centers separated by a hydrophobic chain at a relatively large distance such bola form like amphiphiles form upon sonication of taking adderall prozac and ambien aqueous suspensions cationic vesicles bolasomes are termed dqasomes when prepared from dequalinium salts the need for mitochondriaspecific delivery systems arises from the central role mitochondria play in a multitude of metabolic pathways mitochondria taking adderall prozac and ambien are vital for the cells energy metabolism and for the regulation of programmed cell death in addition, mitochondria are critically involved in the modulation of intracellular calcium concentration and the mitochondrial respiratory taking adderall prozac and ambien chain is the major source of damaging reactive oxygen species consequently, mitochondrial dysfunction either causes or at least contributes to a large number of human diseases malfunctioning mitochondria are found in several taking adderall prozac and ambien adultonset diseases including diabetes, cardiomyopathy, infertility, migraine, blindness, deafness, kidney and liver diseases and stroke the accumulation of somatic mutations in the mitochondrial genome has been suggested to be involved in aging, agerelated neurodegenerative diseases, neuromuscular diseases, as well as in cancer consequently, mitochondria are increasingly recognized as a prime target for pharmacological intervention the development of methods for selectively delivering biologically active molecules taking adderall prozac and ambien to the site of mitochondria, along with the identification of new mitochondrial molecular drug targets, will potentially launch new therapeutic approaches for the treatment of mitochondriarelated diseases, based on either the selective taking adderall prozac and ambien protection, repair or eradication of cells the self assembly behavior of bis quinolinium derivatives monte carlo computer simulations dequalinium salts fig a are dicationic mitochondriotropic compounds resembling bola form electrolytes, ie they taking adderall prozac and ambien are symmetrical molecules with two charge centers separated at a relatively large distance such symmetric bolalike structures are known from archaeal lipids, which usually consist of two glycerol backbones connected by two taking adderall prozac and ambien hydrophobic chains the selfassembly behavior of bipolar lipids from archaea has been extensively studied reviewed by gambacorta et al} it has been shown that these symmetric bipolar archaeal lipids can selfassociate into taking adderall prozac and ambien mechanically very stable monolayer membranes the most striking structural difference between dequalinium and archaeal lipids lies in the number of bridging hydrophobic chains between the polar head groups contrary to the common taking adderall prozac and ambien arachaeal lipids, in the dequalinium molecule, there is only one alkyl chain that connects the two cationic hydrophilic head groups monte carlo simulations were applied to a system of bola form amphiphiles taking adderall prozac and ambien in a coarsegrained model, in which the amphiphilic molecules consist of connected segments with each segment of the chain representing several atoms of a real amphiphilic molecule all segments of the coarse taking adderall prozac and ambien grained model are therefore either headlike hydrophilic or taillike hydrophobic as shown in fig ib the formation of molecular aggregates was studied by employing a sequence of lattice simulations in an nvt taking adderall prozac and ambien ensemble constant number of particles, n, constant volume, v, constant temperature, t, starting from an isotropic threedimensional distribution of model molecules the unoccupied lattice sites were considered waterlike, ie hydrophilic all computer taking adderall prozac and ambien simulations were done at reduced temperatures t = kgt� and interactions were modeled based on nearest neighbor repulsions e in units of kbt between hydrophobic tail segments and hydrophilic iix fig, a taking adderall prozac and ambien chemical structure of dequalmium b dequalinium after coarse graining, c snapshot from monte carlo computer simulation left, whole vesicle left right, cross section d possible conformation of singlechain bola amphiphiles left, stretched taking adderall prozac and ambien bola right, bended horse shoe heads at t � and at voi amphiphiles ie of all lattice sites were occupied with amphiphilic molecules, selfassembled vesicular structures could be found, as shown in the snapshot in fig � monte carlo simulations were also used to predict the conformational state of dequalinium within a selfassembled structure while the stretched conformation fig id, left would give rise taking adderall prozac and ambien to the formation of a monolayer, assuming the horseshoe conformation fig, id, right, it would result in the formation of a bilayer it was found that both conformations could theoretically coexist, although taking adderall prozac and ambien the balance between them appeared to be temperature dependent physicochemical characterization the selfassembly behavior, as predicted by monte carlo computer simulation, was confirmed by electron microscopy fig and photon correlation spectroscopy fig taking adderall prozac and ambien it was found that dequalinium forms upon sonication spheric appearing aggregates with a diameter between approximately and nm freeze fracture images fig , panel c show both convex and concave fracture faces these taking adderall prozac and ambien images fig electron photomicrograph of dqasomes panel a, negatively stained panel b, rotary shadowed panel c, freeze fractured fig size distribution of dqasomes strongly indicate the liposomelike aggregation of dequalinium negatively stained taking adderall prozac and ambien samples fig , panel a demonstrate that the vesicle is impervious to the stain and appears as a clear area surrounded by stain with no substructure visible rotary shadowed vesicles fig , panel b taking adderall prozac and ambien appeared very electron dense without showing any substructure structure activity relationship studies to define relationships between the structure of dequaliniumlike bola amphiphiles and their ability to form bolasomes, the selfassembly behavior of taking adderall prozac and ambien nine dequalinium derivatives with varying hydrophilic head groups and different hydrophobic tail segments was evaluated it was found that the methyl group in ortho position to the quaternary nitrogen at the quinolinium taking adderall prozac and ambien ring system seems to play an essential role in the selfassembly behavior of these bola amphiphiles this seems surprising, considering the bulky and hydrophobic nature of this group while the removal of this methyl group significantly impairs the stability of formed vesicles, replacing the methyl group by an aliphatic ring system fig confers unexpected superior vesicle forming properties to this bola amphiphile vesicles made from taking adderall prozac and ambien this cyclo hexyl derivative of dequalinium are contrasted with vesicles made from dequalinium, with a very narrow size distribution of � nm which hardly changes at all, even after storage at room taking adderall prozac and ambien temperature for over months in contrast to vesicles made from dequalinium, bolasomes made from the cyclohexyl derivative are also stable upon dilution of the original vesicle preparation while dequalinium based bolasomes, slowly taking adderall prozac and ambien disintegrate over a period of several hours upon dilution, bolasomes made from the cyclohexyl compound do not show any change in size distribution following dilution it appears that bulky aliphatic residues, attached taking adderall prozac and ambien to the quinolinium heterocycle, favor selfassociation of the planar ring system it has therefore been speculated that the bulky group sterically prevents the free rotation of the hydrophilic head of the amphiphile taking adderall prozac and ambien around the ch axis fig , thus contributing to improved intermolecular interactions between the amphiphilic monomers � fig schematic illustration of the stabilizing effect of the cyclohexyl ring system black circles dqasomes as taking adderall prozac and ambien mitochondrial transfection vector the number of diseases found to be associated with defects of the mitochondrial genome has grown significantly since despite major advances in understanding mtdna, defects at the genetic and taking adderall prozac and ambien biochemical level, there is no satisfactory treatment available for a vast majority of patients objective limitations of conventional biochemical treatment, for patients with defects of mtdna, warrant the exploration of gene therapeutic taking adderall prozac and ambien approaches two different strategies for mitochondrial gene therapy are imaginable the first involves expressing a wildtype copy of the defective gene in the nucleus, with cytoplasmic synthesis and subsequent targeting of the taking adderall prozac and ambien gene product to the mitochondria allotopic expression besides the different codon usage in mitochondria, however, there are possibly four major difficulties in adapting this nuclearcytosolic approach for mitochondrial gene therapy to mammalian taking adderall prozac and ambien cells, as recently reviewed by dsouza firstly, the majority of mtdna defects involve trnas, and to date, no natural mechanism has been reported for the mitochondrial uptake of cytosolic trnas in mammalian taking adderall prozac and ambien cells secondly, it is generally agreed that the proteins encoded for by mtdna are very hydrophobic peptides, which would not be readily imported by the mitochondrial protein import machinery however, since the taking adderall prozac and ambien mitochondrial coded proteins are not equally hydrophobic, the allotopic expression of at least some of the peptides appears as possible thirdly, it has been hypothesized that some of the proteins encoded by taking adderall prozac and ambien the mitochondrion may potentially be toxic if synthesized in the cytosol fourthly, according to a hypothesis termed co location for redox regulation, the colocation of mtdna and its products may be essential taking adderall prozac and ambien for the rapid control of gene expression by the redox state in the mitochondrial matrix considering all the problems associated with the nuclear cytosolic approach, the development of methods for the direct taking adderall prozac and ambien transfection of mitochondria as an alternative approach towards mitochondrial gene therapy is warranted based on the intrinsic mitochondriotropism of dequalinium salts and the ability of dequaliniumbased vesicles, ie dqasomes, to bind and taking adderall prozac and ambien condense pdna, a strategy for the direct transfection of mitochondria within living mammalian cells has been proposed, this new strategy involves the transport of a dna mitochondrial leader sequence peptide conjugate to mitochondria using cationic mitochondriotropic vesicles dqasomes, the liberation of this conjugate from the cationic vector upon contact with the mitochondrial outer membrane, followed by dna uptake via the mitochondrial protein import machinery taking adderall prozac and ambien in a series of papers, it was then shown that dqasomes indeed fulfill all prerequisites for dqasomes as mitochondriaspecific drug and dna carriers a mitochondriaspecific dna delivery system dqasomes bind pdna forming taking adderall prozac and ambien socalled dqaplexes and protect the dna from nuclease digestion the cytotoxicity of dqasomes and of dqasomepdna complexes is comparable to nonviral transfection vectors, which are already being used in clinical trials dqasomes taking adderall prozac and ambien mediate the cellular uptake of bound pdna, most probably via nonspecific endocytosis dqasomes are endosomolytically active, thereby presumably contributing to an early endosomal release of the dqasomepdna complex dqaplexes do not release taking adderall prozac and ambien pdna upon contact with anionic phospholipids from the inner cytoplasmic membrane dqaplexes release pdna upon contact with mitochondrialike membranes, as well as upon contact with whole isolated mitochondria tested under identical experimental taking adderall prozac and ambien conditions, dqasomes were shown to transport pdn a as well as oligonucleotides to the site of mitochondria, while lipofectin was demonstrated to deliver pdna and oligonucleotides towards the nucleus plasmid dna dissociates taking adderall prozac and ambien from dqaplexes upon contact with mitochondria within living mammalian cells perhaps the most surprising finding among the above listed results is the selective dna release from dqaplexes upon contact with different membranes taking adderall prozac and ambien why do anionic phospholipids such as phosphatidylserine displace pdna from lipofectin as shown by xu and szoka, but not from dqaplexes, and why do dqaplexes in turn become destabilized upon contact with mitochondrial membranes?