materials today february icrp report human respiratory tract model for radiological protection international commission on radiological protection, oxford kreuter j influence of the surface properties on nanoparticlemediated transport of drugs to neurontin pain medication for dog the brain } nanosci nanotechnol hafeli uo magnetic nano and microparticles for targeted drug delivery, in arshady r and kono � eds, smart nanoparticles in nanomedicine � the mml series, vol kentus neurontin pain medication for dog books, london, uk, pp hergt r, hiergeist r, hilger i and kaiser w magnetic nanoparticles for ther moablation, in pandalai sg ed, recent research developments in materials science, vol part , pp gilchrist neurontin pain medication for dog rk et al selective inductive heating of lymph nodes ann surg rand rw, snyder m, elliott d and snow h selective radiofrequency heating of ferrosilicone occluded tissue a preliminary report bull los angeles neurol soc turner rd, rand rw, bentson jr and mosso ja ferromagnetic silicone necrosis of hypernephromas by selective vascular occlusion to the tumor a new technique } urol sako m and neurontin pain medication for dog hirota s embolotherapy of hepatomas using ferromagnetic microspheres, its clinical evaluation and the prospect of its use as a vehicle in chemoembolo hyperthermic therapy gan to kagaku ryoho hase m et al neurontin pain medication for dog experimental study of embolohyperthermia for treatment of liver tumorinduction heating to ferromagnetic particles injected into tumor tissue nippon igaku hoshasen gakkai zasshi jordan a et al inductive heating of ferrimagnetic particles and neurontin pain medication for dog magnetic fluids physical evaluation of their potential for hyperthermia int j hyperthermia chan dcf, kirpotin db and bunn pa synthesis and evaluation of colloidal magnetic iron oxides for the sitespecific radiofrequencyinduced hyperthermia neurontin pain medication for dog of cancer j magn magn mater jordan a, 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hyperthermia hergt r et neurontin pain medication for dog al enhancement of aclosses of magnetic nanoparticles for heating applications j magn magn mater hergt r et al maghemite nanoparticles with very high aclosses for application in rfmagnetic hyperthermia j magn magn neurontin pain medication for dog mater widder k, flouret g and senyei a magnetic microspheres synthesis of a novel parenteral drug carrier j pharm sci senyei ae, reich sd, gonczy � and widder kj in vivo kinetics neurontin pain medication for dog of magnetically targeted lowdose doxorubicin pharm sci widder kj, morris rm, howard dp and senyei ae tumor remission in yoshida sarcomabearing rats by selective targeting of magnetic albumin microspheres containing doxorubicin proc neurontin pain medication for dog natl acad sci usa widder kj, morris rm, poore ga, howards dp and senyei ae selective targeting of magnetic albumin microspheres containing lowdose doxorubicin total remission in yoshida sarcomabearing rats eur j neurontin pain medication for dog cancer clin oncol kuznetsov aa et al ferrocarbon particles preparation and applications, in hafeli u et al eds, scientific and clinical applications of magnetic carriers plenum press, new york, pp goodwin s neurontin pain medication for dog magnetic targeted carriers offer sitespecific drug delivery oncol news int johnson j et al the mtc technology a platform technology for the sitespecific delivery of pharmaceutical agents eur cells mat ibrahim a, neurontin pain medication for dog couvreur p, roland m and speiser p new magnetic drug carrier j pharm pharmacol hassan ee and gallo jm targeting anticancer drugs to the brain, i enhanced brain delivery of oxantrazole following administration in magnetic cationic microspheres f drug targ vyas sp and jaitely v magnetoresponsive solid lipid nanoparticles sln as novel targeting modules for targeting of methotrexate proceed intern symp control rel bioact mater , neurontin pain medication for dog abstract liibbe as et al clinical experiences with magnetic drug targeting a phase i study with epidoxorubicin in patients with advanced solid tumors cancer res liibbe as, alexiou � and bergemann common side effects of seroquel � neurontin pain medication for dog clinical applications of magnetic drug targeting surg res gupta pk and hung ct magnetically controlled targeted chemotherapy, in willmott n and daly j eds, microspheres and regional cancer therapy crc press, boca raton, pp sako m et al transcatheter microembolization with ferropolysaccharide a new approach to ferromagnetic embolization of tumors preliminary report invest radiol sako m, hirota s and ohtsuki s clinical evaluation of neurontin pain medication for dog ferromagnetic microembolization for the treatment of hepatocellular carcinoma ann radiol hafeli uo radiolabeled magnetic microcapsules for magnetically targeted radionuclide therapy, in arshady r ed, microspheres, microcapsules & liposomes radiolabeled and magnetic particulates neurontin pain medication for dog in medicine and biology, vol citus books, london, pp iacob g, rotariu o, strachan njc and hafeli uo magnetizable needles and wiresmodeling an efficient way to target magnetic microspheres in vivo biorheology neurontin pain medication for dog rotariu o, iacob g, strachan njc and chiriac h simulating the embolization of blood vessels using magnetic microparticles and acupuncture needle in a magnetic field biotechnol prog hafeli uo, pauer gj, roberts neurontin pain medication for dog wk, humm jl and macklis rm magnetically targeted microspheres for intracavitary and intraspinal y radiotherapy, in hafeli u, schiitt w, teller j and zborowski m eds, scientific and clinical applications of magnetic neurontin pain medication for dog carriers, st edn plenum, new york yu jf et al radiolabeling of magnetic targeted carriers with several therapeutic and imaging radioisotopes eur cells mat suppl hafeli uo, yu j, farudi f, li neurontin pain medication for dog y and tapolsky g radiolabeling of magnetic targeted carriers mtc with indiumill nucl med biol wang yx, hussain sm and krestin gp superparamagnetic iron oxide contrast agents physicochemical characteristics and applications in neurontin pain medication for dog mr imaging eur radiol polyakov vr et al novel tatpeptide chelates for direct transduction of tcm and rhenium into human cells for imaging and radiotherapy bioconjug chem wunderbaldinger p, josephson l and neurontin pain medication for dog weissleder r tat peptide directs enhanced clearance and hepatic permeability of magnetic nanoparticles bioconjug chem torchilin vp et al magnetically driven thrombolytic preparation containing immobilized streptokinasetargeted transport and action haemostasis yoshimoto t neurontin pain medication for dog et al magnetic urokinase targeting of urokinase to fibrin clot biochem biophys res commun yao f and eriksson e gene therapy in wound repair and regeneration wound repair regen galanis e, vile neurontin pain medication for dog r and russell sj delivery systems 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 neurontin pain medication for dog 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 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 neurontin pain medication for dog 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 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 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 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 neurontin pain medication for dog 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 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 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 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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 neurontin pain medication for dog 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?