idc a nanoparticles in comparison to uncoated or poloxamer or polysorbate coated [c]poly hexadecyl cyanoacrylate nanoparticles [c]phdca nanoparticles surprisingly, coating with polysorbate and also with poloxamer led to lower brain concentrations than uncoated particles in both species in addition, a speciesdependent influence of the surfactants on the brain concentrations lithium cr2 battery specifications was observed in mice, the brain concentrations of the [c]phdca nanoparticles were higher after coating with polysorbate than with poloxamer , whereas this order was reversed in rats it is important to further note that after reduction of the nanoparticle dose, while maintaining the same total polysorbate concentration, higher [c] brain levels lithium cr2 battery specifications were observed with the polysorbate coated nanoparticles than with the pegylated [c]pegphdca particles the authors suggested that these higher brain concentrations were caused by a higher bbb permeability as a result of higher free blood polysorbate concentrations at the lower nanoparticle dose, and tried to support their assumption by another experiment lithium cr2 battery specifications injecting iv [c]sucrose in a polysorbate solution in saline, which also led to higher [c]sucrose levels in the brain however, this assumption that free polysorbate concentrations up to leads to an increased bbb permeability resulting in a larger drug transport, is contradicted by pharmacological studies with drugs in all of these lithium cr2 battery specifications studies, polysorbate , containing drug solutions without nanoparticles that were used as controls, were unable to achieve any significant pharmacological effects interestingly, in the body distribution study of calvo et alil the brain concentration pattern was not mirrored in the other organs and tissues the highest blood concentrations were obtained in mice lithium cr2 battery specifications and rats with the poloxamer coated particles, followed by the pegphdca particles the poloxamer coated nanoparticles also yielded the lowest total uptake in the res organs in rats but not in mice in the latter, the pegphdca particles achieved the lowest total res organ uptake similar results as those of calvo lithium cr2 battery specifications et alir were also obtained with solid lipid nanoparticles, consisting of stearic acid nonstealth sln or stearic acid, ie peg stealth sln, epicuron� , and taurocholate sodium, after intravenous injection to rats and rabbits doxorubicin was bound to these particles using hexadecylphosphate as a counterion in the rabbit study, the amount of lithium cr2 battery specifications the stealth agent stearic acidpeg was systematically increased in steps from to all nanoparticles achieved much higher and prolonged plasma concentrations than the doxorubicin solution the increase in the stearic acidpeg contents was mirrored by an increase and prolongation of the doxorubicin plasma concentrations a comparable increase was observed in the lithium cr2 battery specifications brain reaching a doxorubicin concentration of ngg after administration of mgkg doxorubicin after only hrs with the pegylated solid lipid nanoparticles with the highest stearic acid peg content, doxorubicin was still detectable no doxorubicin was found in the brain after administration of the doxorubicin solution as in the abovementioned studies, the lithium cr2 battery specifications nanoparticles decreased the heart concentration, and in addition, the liver and other organ concentrations of the doxorubicin the biodistribution of the pegylated [c]pegphdca nanoparticles was also tested by calvo et al in darj rats with experimental allergic encephalitis eae and compared with [c]phdca nanoparticles the pegylated nanoparticles achieved much higher brain lithium cr2 battery specifications and spinal cord concentrations than the normal particles the concentration of the pegphdca nanoparticles was significantly higher in the pathological situation, where the bbb permeability was increased and was especially pronounced in the white matter an enhanced macrophage infiltration with macrophages containing nanoparticles was observed at the eae lesions, confirming earlier lithium cr2 battery specifications results of merodio et al after intraperitoneal injection of albumin nanoparticles this transport within macrophages could augment the overall nanoparticle transport across the bbb coating of the nonpegylated [c] phdca nanoparticles with poloxamine resulted in very low and insignificant brain and spinal cord concentrations, although this surfactant again achieved very high lithium cr2 battery specifications nanoparticle plasma levels consequently, the pegylated poly cyanoacrylate nanoparticles may represent promising brain drug delivery systems for neuroin flammatory diseases pharmacology as mentioned above, dalargin was the first drug that was transported across the bbb using the polysorbate coated nanoparticles besides polysorbate , coating of the polybutyl cyanoacrylate nanoparticles with polysorbate and lithium cr2 battery specifications also enabled a transport of the nanoparticlebound dalargin across the bbb, whereas coating with other surfactants such as poloxamers poloxamine , cremophor� ez, cremophor� rh , and polyoxyethylenelaurylether brij� achieved no effects table , clearly demonstrating the importance of the surface properties of the nanoparticles for brain drug delivery dalargin was then followed by lithium cr2 battery specifications other antinociceptive drugs such as the opioid loperamide and the metenkephalin kyotorphin, both showing similar effects unlike dalargin and kyotorphin, loperamide is not a peptide and is very lipophilic in contrast to these compounds however, it is a strong pgp substrate, and for this reason, it normally cannot cross the bloodbrain lithium cr2 battery specifications barrier in contrast to binding to polybutyl cyanoacyrylate nanoparticles, this drug was not able to induce any antinociceptive response after binding to polylactic acid nanoparticles, neither after coating with polysorbate nor after preparation of the polylactic acid table maximal possible antinociceptive effect mpe [] obtained after intravenous injection of dalarginloaded surfactantcoated lithium cr2 battery specifications poly butyl cyanoacrylate nanoparticles and amount of apolipoprotein e apo e adsorbed on the surface of these particles in percent of the total amount of adsorbed plasma proteins adapted from kreuter et ali and from luck surfactant mpe [] apo e adsorbed [] uncoated � polysorbate � polysorbate � polysorbate � lithium cr2 battery specifications polysorbate � poloxamer � poloxamer � cremophor� el � cremophor� rh � nanoparticles in the presence of this surfactant unpublished results, although particles with a large variety of compositions with different release characteristics were manufactured, these observations clearly demonstrate that the ability of nanoparticles to enable a delivery of nanoparticles across lithium cr2 battery specifications the bbb, in addition to the surface properties, also depends on the core polymer tubocurarine normally also cannot cross the bbb it induces epileptic spikes after direct intraventricular injection of tubocurarine into the brain this drug was bound to the polybutyl cyanoacrylate nanoparticles and used in brain perfusion experiments in rats, lithium cr2 battery specifications in which the development of epileptic spikes in the eec was recorded addition of the polysorbate overcoated tubocurarineloaded nanoparticles to the perfusate induced frequent severe spikes in the eec that were comparable to direct intraventricular injection of the drug into the brain whereas a normal eec was obtained after a solution lithium cr2 battery specifications of tubocurarine, the turbocurarine solution combined with polysorbate or uncoated tubocurarineloaded nanoparticles were added to the perfusate the novel nmdareceptor antagonists mrz chlorohydroxyloxo l,dihydropyridazino[,b]quinolineoxide choline salt is a potent but rather shortacting min anticonvulsant after intravenous administration this short action is most likely caused by the rapid elimination of the drug from the central nervous system by efflux pumpmediated transport processes accordingly, these efflux processes can be inhibited by pretreatment with probenecid probenecid pretreatment prolongs the anticonvulsive action of mrz from about min to min intravenous injection of mrz bound to polybutyl cyanoacrylate nanoparticles coated with polysorbate , led to an lithium cr2 battery specifications even more prolonged duration of the anticonvulsive activity in mice of up to min, and in combination with probenecid up to min in contrast to mrz , the nmdareceptor antagonist mrz chloro l,dioxol,tetrahydropyridazino[,b]quinoline choline salt is not able to cross the bbb at all however, again after binding to lithium cr2 battery specifications the polysorbate coated nanoparticles, mrz also yielded similar anticonvulsive effects two other drugs, amitriptyline, a tricyclic antidepressant, and valproic acid, a first line antiepileptic drug, were also bound to polysorbate coated nanoparticles while the brain auc of amitriptyline was increased after intravenous injection of the polysorbate coated nanoparticles which was accompanied lithium cr2 battery specifications by a reduction in serum auc, no brain concentration increase was observable with valproic acid as mentioned above under sec , some indications exist that surfactant coated nanoparticles or solid lipid nanoparticles may also increase the distribution of some drugs into the brain after oral administration, and may even lead to pharmacological lithium cr2 battery specifications effects coating of poly butyl cyanoacrylate nanoparticles with polysorbate yielded antinociceptive effects with dalargin via the oral route, although these effects were not as pronounced but rather prolonged as after the iv injection brain tumors brain tumors, especially malignant gliomas, belong to the most aggressive human cancers despite numerous advances lithium cr2 battery specifications in neurosurgical operative techniques, adjuvant chemotherapy, and radiotherapy the prognosis for patients remains very unfavorable, these tumors are characterized by a rapid proliferation, diffuse growth, and invasion into distant brain areas, in addition to extensive cerebral edema and high levels of angiogenesis nevertheless, the disruption of the blood brain barrier bbb lithium cr2 battery specifications remains a local event, which is evident in the tumor core, but absent at its growing margins for this reason, anticancer drugs can penetrate into necrotic tumor areas, while the drug levels in peritumoral regions were reported to remain low or nondetectable for this reason, very efficient anticancer drugs such as lithium cr2 battery specifications doxorubicin cannot cross the intact bbb and reach only the necrotic but not the peritumoral areas as noted above sec , however, this drug reached very high brain concentrations of about xgg, after binding to polybutyl cyanoacrylate nanoparticles these nanoparticles were then tested in rats with intracranially implanted glioblastoma in contrast to lithium cr2 battery specifications many experimental tumors such as rg and l which are characterized by a nodular growth, this tumor has a stable monomorphous structure and shows the characteristic histological picture of aggressive glioblastomas with fast diffuse growth in the brain parenchyma and a rather low tendency towards necrosis therefore, it is morphologically very lithium cr2 battery specifications similar to human glioblastomas doxorubicin bound to the polysorbate coated polybutyl cyanoacrylate nanoparticles injected at a dose level of mgkgday at days , and after tumor transplantation, increased the mean survival time by and repeatedly led to the survival of to of the animals for days from repetitions of unpublished results after lithium cr2 battery specifications this time, the animals were sacrificed, and the absence of tumors was demonstrated by histology in these animals in contrast, the controls, empty polysorbate coated polybutyl cyanoacrylate nanoparticles, doxorubicin solution, doxorubicin solution plus polysorbate , and doxorubicin bound to polybutyl cyanoacrylate nanoparticles without polysorbate , led to no or much shorter increases in lithium cr2 battery specifications survival times or number of longtime survivers table no indications of neurotoxicity were observable by histology with the nanoparticles also, the toxicity against other organs appeared to be reduced by binding to nanoparticles, in comparison to the doxorubicin solution brigger et al showed an accumulation of clabelled pegphdca and phdca nanoparticles lithium cr2 battery specifications after intravenous injection to fischer rats bearing an intrac erebrally transplanted l glioblastoma this accumulation was accompanied by a pronounced tumor retention effect the tumor concentrations of the pegylated nanoparticles were about times higher than with the normal phdca particles, and about times higher than in the adjacent brain areas interestingly, lithium cr2 battery specifications in the table increases in survival times st [] and longterm survivors survival days of rats with intracranially transplanted glioblastoma after intravenous injection of doxorubicin mgkgday or mgkgday on days and after tumor transplantation adapted from steiniger et al x mgkg n st [] survival days control empty nanoparticles ns doxorubicin lithium cr2 battery specifications solution doxorubicin solution polysorbate doxorubicin bound to nanoparticles doxorubicin bound to nanoparticles polysorbate x mgkg control doxorubicin solution doxorubicin solution polysorbate doxorubicin bound to nanoparticles doxorubicin bound to nanoparticles polysorbate statistically difference to controls p ns not statistically different from control tumorbearing rats, the brain concentrations in the areas adjacent to the tumor as well as in the controlateral brain hemisphere were also increased significantly compared with normal animals without tumor, indicating a generally higher permeability in the diseased animals this was supported by coinjection of [h]sucrose together with the nanoparticles the [h]sucrose level ratios between tumor, adjacent brain area, and the lithium cr2 battery specifications adjacent brain area obtained with the two types of nanoparticles were similar to the cnanoparticle level ratios, and much lower levels again resulted without tumors unfortunately, these nanoparticles did not increase the survival of fisher rats bearing the same tumor, l, after intracranial transplantation biodistribution studies revealed that the binding of lithium cr2 battery specifications doxorubicin to the nanoparticles decreased the tumor accumulation of the particles by a factor of , which may be the cause for the lack of efficacy of these particles against l the loss of wild type tumor suppressor genes like p function renders many tumors resistant to the induction of apoptosis by lithium cr2 battery specifications drugs such as doxorubicin therefore, the delivery of wild type suppressor genes across the bbb is of enormous importance for the therapy with highly active chemotherapeutic drugs the possibility of suppressor gene delivery into the brain with nanoparticles was evaluated in rats with an intracranially implanted f rat glioblastoma five days lithium cr2 battery specifications after tumor implantation, these rats received an intravenous injection of a sgalactosidase reporter bound to polybutyl cyanoacrylate nanoparticles coated with polysorbate the animals were sacrificed and hrs after nanoparticle injection, and a time dependent transport of the gene across the endothelial cells and glial cells was obtained, showing the strongest gene lithium cr2 battery specifications expression in the experimental tumors, whereas injection of naked control dna did not render any expression at all toxicology the acute toxicity of empty polybutyl cyanoacrylate nanoparticles as well as of the above polybutyl cyanoacrylate nanoparticle formulations, doxorubicin solution in saline, doxorubicin solution plus polysorbate in saline, doxorubicin bound to nanoparticles, lithium cr2 battery specifications and doxorubicin bound to nanoparticles coated with polysorbate , was assessed by gelperina et al in normal and glioma bearing rats doses up to mgkg of empty nanoparticles did not cause any mortality within the period of observation days, nor did they affect body weight or weight of internal organs after intravenous lithium cr2 battery specifications injection higher doses cannot be administered intravenously because of biological and technical limitations no significant difference in toxicity occurred between the groups obtaining iv the four doxorubicin formulations in healthy as well as in the tumorbearing animals the results indicated that the toxicity of doxorubicin bound to nanoparticles is similar or lithium cr2 battery specifications may even be lower than that of free doxorubicin in the above described chemotherapy study of steiniger et al with doxorubicin bound to the polysorbate coated polybutyl cyanoacrylate nanoparticles, similar toxicological results were obtained alimited dosedependent systemic toxicity was found in the group treated with doxorubicin in saline autopsy of the lithium cr2 battery specifications whole body in healthy animals in this study revealed an empty gastrointestinal tract only in all animals treated with doxorubicin the healthy animals treated with doxorubicin solution also showed slight signs of lung edema, which was confirmed by histology these changes were not observed in animals treated with doxorubicin bound to lithium cr2 battery specifications the nanoparticles indications of shortterm neurotoxicity, such as increased apoptosis in areas distant from the tumor, increased expression of gfap or ezrin on distant astrocytes or degenerative morphological changes of neurons, were entirely absent in treated animals on day , as well as in longterm survivors in addition, there was no indication lithium cr2 battery specifications of chronic glial activation in areas distant from the tumor site in longterm surviving rats moreover, longterm survivors did not exhibit any obvious neurological symptoms mechanism of the delivery of drug across the bloodbrain barrier with nanoparticles presently, the mechanism of the delivery of drugs with nanoparticles across the bbb is lithium cr2 battery specifications not totally elucidated a number of possibilities were suggested for this mechanism the nanoparticles with bound drugs could be transcytosed through the endothelial cell layer all these mechanisms could also work in combinations mechanisms and appear to be unlikely for the following reasons if the drugloaded nanoparticles would have merely created lithium cr2 battery specifications a high drug concentration gradient by adherence to the inner surface of the blood capillary walls mechanism , the diffusing drug would still have been subjected to the highly efficient efflux transporters in the membranes of the endothelial cells oh the other hand, if the polysorbate would have inhibited these efflux transporters lithium cr2 battery specifications mechanism , injection of polysorbate coated empty nanoparticles or min before injection of dalargin, should also have induced antinociceptive effects, which was not observed in this case the view that mechnisms and are unlikely are additionally supported by the brain perfusion experiments of koziara et al olivier et al postulated that lithium cr2 battery specifications the enhanced drug transport across the bbb was caused by a toxic effect by the polysorbate coated nanoparticles, resulting in the permeabilization or disruption of the bloodbrain barrier mechanisms andor pointing in the same direction, calvo et al tried to explain the higher [c]sucrose levels that they observed in the brain lithium cr2 battery specifications after iv injection of [c]sucrose in a polysorbate solution in saline with bbb permeabilization caused by unbound free polysorbate present in the nanoparticle formulations mechanism however, both hypotheses can be refuted by the abovementioned experiment, where no antinociceptive effects were obtained after preinjection of the polysorbate coated empty nanoparticles in addition, no antinociceptive responses were observed after the injection of dalargin nanoparticles coated with other surfactants such as poloxamers poloxamine , cremophor� ez, cremophor� rh , and polyoxyethylenelaurylether brij� , further out ruling mechanism , a general membrane fluidization this opinion that toxicity is not the mechanism for the nanoparticlemediated drug transport across the bbb was lithium cr2 battery specifications also substantiated by the experiments of sun et al and of koziara et al partial coverage of the particles by polysorbate was sufficient for brain delivery, and the brain perfusion experiments showed that the nanoparticles did not induce any statistically significant changes in barrier integrity, membrane permeability or facilitated choline transport lithium cr2 battery specifications finally, opening of the tight junctions as the underlying mechanism mechanism can be refuted by the findings that no major increase in the inulin spaces was observable in rat brain perfusion experiments additionally, electron microscopical studies also did not find any evidence for an opening of the tight junctions therefore, the lithium cr2 battery specifications most likely mechanism appears to be mechanism , endocytotic uptake of the nanoparticles carrying the drug this mechanism was already shown in vitro in tissue cultures of brain endothelial cells of human, bovine, porcine, mice, and rat origin, at an incubation temperature of �c, a significant and rapid uptake was observed with lithium cr2 battery specifications the polysorbate coated nanoparticles, whereas without coating, this uptake was minimal and it was inhibited at �c, a temperature at which phagocytosis does not occur, or after treatment with cytochalasin b, a potent phagocytic uptake inhibitor mechanism is further supported by the observation that, in contrast to the abovementioned surfactants, poloxamer lithium cr2 battery specifications etc, besides polysorbate , polysor bates and were also able to induce antinociceptive effects after the coating of dalarginloaded nanoparticles and injection to mice in addition, all polysor bates, and , and not the other surfactants, were able to adsorb apolipoprotein e apo e on the surface of the nanoparticles after their incubation lithium cr2 battery specifications in blood plasma table kreuter et ali then showed that the dalargin nanoparticles were also able to induce antinociceptive effects after the adsorption of apolipoproteins e and b these effects were even much higher after polysorbate preincubation therefore, the following scenario can be suggested due to the polysorbate on their surface, lithium cr2 battery specifications the nanoparticles adsorb apolipoproteins e andor � from the blood after injection the particles, thus seem to mimic lipoprotein particles, and are taken up by the brain endothelial cells that express numerous lipoprotein receptors via receptormediated endocytosis since the efflux transporters are mainly located in the luminal membrane, the drug can lithium cr2 battery specifications then be transported into the brain by diffusion, after release from the very rapidly biodegrading nanoparticle polymer it is also possible that the nanoparticles are transcytosed mechanism , although no concrete evidence for this mechanism exists at present the nanoparticles, therefore, seem to act as a trojan horse this hypothesis that drug lithium cr2 battery specifications transport via endocytotic uptake of the nanoparticles represents the underlying pathway was also supported by sun et al, koziara et al, and gessner et al since the lipoprotein receptors are overexpressed in brain tumors, the above suggested scenario, lipoprotein receptor interaction, would also be an explanation for the good efficacy of lithium cr2 battery specifications the polysorbate coated doxorubicinloaded polybutyl cyanoacrylate nanoparticles summary a number of drugs that normally cannot cross the bloodbrain barrier bbb, or only in insufficient amounts, can be transported across this barrier after binding to polysorbatecoated polybutyl cyanoacrylate nanoparticles or to solid lipid nanoparticles, and achieve significant brain drug concentrations and pharmacological effects in the brain after intravenous injection these drugs include the hexapeptide dalargin and the dipeptide kyotorphin, loperamide, tubocurarine, amitriptyline, the nmda receptor antagonists mrz and mrz , doxorubicin, idarubicin, campthothecin, paclitaxel, as well as tobramycin doxorubicin bound to polysorbate coated polybutyl cyanoacrylate nanoparticles was able to strongly improve the survival time lithium cr2 battery specifications of rats with intracranially transplanted glioblastoma , an extremely aggressive tumor the general toxicity of this drug was not increased by binding to the nanoparticles pegylation of poly cyanoacrylate nanoparticles prolonged their blood circulation time after intravenous injection and strongly increased their concentration in the intracranially transplanted glioblastoma l, but failed to lithium cr2 battery specifications prolong the survival of these rats the mechanism of the nanoparticlesmediated drug transport across the bbb after intravenous injection seems to be the adsorption of apolipoproteins from the blood, leading to receptormediated endocytotic uptake of the particles into the brain capillary endothelial cells via lipoprotein receptors the nanoparticles can then release lithium cr2 battery specifications the drugs within these cells, followed by the diffusion into the brain, or the access to the brain by transcytosis conclusions poly cyanoacrylate nanoparticles or solid lipid nanoparticles sln can enable the transport of many essential drugs across the bloodbrain barrier bbb that normally cannot cross this barrier the nanoparticles may lithium cr2 battery specifications be even useful for the delivery of larger and complex molecules such as proteins nucleic acids and genes across this barrier they may also improve the treatment of brain tumors, since after binding to nanoparticles coated with polysorbates, antitumor drugs are also transported across the intact bbb thereby accessing sites that lithium cr2 battery specifications cannot be reached by most anticancer drugs although the mechanism for the transport of nanoparticlebound drugs across the bbb is not fully elucidated presently, binding of apolipoproteins after their injection into the blood stream, followed by receptormediated endocytotic uptake of the particles into the brain capillary endothelial cells, seems to be lithium cr2 battery specifications the most likely mechanism thus, the nanoparticles would act as a trojan horse which can then release the drugs within these cells, or after transcytosis into the brain references begley dj delivery of therapeutic agents to the central nervous system the problems and possibilities pharmacol ther brightman m ultrastructure of the lithium cr2 battery specifications brain endothelium bradbury mwb ed physiology and pharmacology of the bloodbrain barrier handbook of experimental pharmacology springer berlin, heidelberg, pp begley dj the bloodbrain barrier principles for targeting peptides and drugs to the central nervous system ] pharm pharmacol kreuter j nanoparticulate systems for brain delivery of drugs adv drug del lithium cr2 battery specifications kreuter j transport of drugs across the bloodbrain barrier by nanoparticles curr med chem � central nervous syst agents begley dj and brightman mw structural and functional aspects of the blood brain barrier prokai l and prokaitatrai � eds peptide transport and delivery into the central nervous system progress in drug lithium cr2 battery specifications delivery birkhauser verlag basel, pp rapoport si modulation of the bloodbrain barrier permeability } drug targ dehouck b, fenart l, dehouck mp, pierce a, torpier g and cecchelli r a new function for the ldl receptor transcytosis of ldl across the bloodbrain barrier j cell biol gummerloch mk and neuwelt ea lithium cr2 battery specifications drug entry into the brain and its pharmacologic manipulation bradbury mwb ed physiology and pharmacology of the blood brain barrier handbook of experimental pharmacology springer berlin, heidelberg, pp remsen lg, trail pa, hellstrom i, hellstrom ke and neuwelt ea enhanced delivery improves the efficacy of a tumorspecific doxorubicin immunoconjugate in a lithium cr2 battery specifications human brain tumor xenograft model neurosurgery pardridge wm, buciak jl and friden pm selective transport of an antitransferrin receptor antibody through the bloodbrain barrier in vivo pharmacol exp ther huwyler j, wu d and pardridge wp brain drug delivery of small molecules using immunoliposomes proc natl acad sci zhou x lithium cr2 battery specifications and huang l targeted delivery of dann by liposomes and polymers j control rel chen d and lee kh biodistribution of calcitonin encapsulated in liposomes in mice with particular reference to the central nervous system biochem biophys acta kreuter j nanoparticles swarbrick j and boylan jc eds encyclopedia of pharmaceutical technology lithium cr2 battery specifications marcel dekker new york, pp birrenbach g and speiser pp polymerized micelles and their use as adjuvants in immunology j pharm sci h kopf h, joshi rk, soliva m and speiser pp studium der mizellpolymerisa tion in gegenwart niedermolekularer arzneistoffe herstellung und isolierung der nanopartikel, restmonomerenbestimmung, physikalischchemische daten pharm ind alyautdin lithium cr2 battery specifications r, gothier d, petrov v, kharkevich d and kreuter j analgesic activity of the hexapeptide dalargin adsorbed on the surface of polysorbate coated polybutyl cyanoacrylate nanoparticles eur } pharm biopharm kreuter j, alyautdin rn, kharkevich da and ivanov aa passage of peptides through the bloodbrain barrier with colloidal polymer particles nanoparticles lithium cr2 battery specifications brain res grislain l, couvreur p, lenaerts v, roland m, deprezde campenere d and speiser p pharmacokinetics and distribution of a biodegradable drugcarrier int j pharm schroeder u and sabel ba nanoparticles, a drug carrier system to pass the blood brain barrier, permit central analgesic effects of iv dalargin injections brain lithium cr2 battery specifications res ramge p, kreuter j and lemmer � circadian phasedependent antinociceptive reaction in mice after i v injection of dalarginloaded nanoparticles determined by the hotplate test and the tailflick test chronobiol int troster sd, mtiller u and kreuter j modification of the body distribution of polymethyl methacrylate nanoparticles by coating with lithium cr2 battery specifications surfactants int j pharm kreuter j, petrov ve, kharkevich da and alyautdin rn influence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its delivery across the bloodbrain barrier using surfactantcoated nanoparticles j control rel schroeder u, schroeder h and sabel ba body distribution of lithium cr2 battery specifications hlabelled dalargin bound to polybutyl cyanoacrylate nanoparticles after iv injections to mice life sciences alyautdin rn, reichel a, lobenberg r, ramge p, kreuter j and begley dj interaction of polybutylcyanoacrylate nanoparticles with the bloodbrainbarrier in vivo and in vitro, f drug targ gulyaev ae, gelperina se, skidan in, antropov as, kivman lithium cr2 battery specifications gy and kreuter j significant transport of doxorubicin into the brain with polysorbate coated nanoparticles pharm res couvreur p, kante b, grislain l, roland m and speiser p toxicity of polyalkyl cyanoacrylate nanoparticles ii doxorubicinloaded nanoparticles f pharm sci zara gp, cavalli r, fundaro a, bargoni a, caputo � and gasco lithium cr2 battery specifications mr pharmacokinetics of doxorubicin incorporated into solid lipid nanospheres sln pharmacol res zara gp, cavalli r, fundaro a, bargoni a, caputo � and gasco mr pharmacokinetics and tissue distribution of idarubicinloaded solid lipid nanoparticles after duodenal administration to rats j pharm sci bargoni a, cavalli r, zara gp, fundaro a, caputo lithium cr2 battery specifications � and gasco mr transmucosal transport of tobramycin incorporated in solid lipid nanoparticles sln after duodenal administration to rats part ii tissue distribution pharmacol res yang sc, lu lf, cai y, zhu jb, liang bw and yang cz body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting lithium cr2 battery specifications effect on brain } control rel wang jx and zhang zr enhanced brain targeting by synthesis ,dioctanoyl fluorodeoxyuridine and incorporation into solid lipid nanoparticles eur f biopharm lockman pr, koziara j, roder, ke, paulson j, abbruscato tj, mumper rj and allen dd in vitro and in vivo assessment of baseline bloodbrain lithium cr2 battery specifications barrier parameters in the presence of novel nanoparticles pharm res lockman pr, oyewumi mo, koziara j, roder, ke, paulson j, mumper rj and allen dd brain uptake of thiaminecoated nanoparticles } control rel koziara mj, lockman pr, allen dd and mumper rj in situ bloodbrain barrier transport of nanoparticles pharm res lithium cr2 battery specifications koziara mj, lockman pr, allen dd and mumper rj paclitaxel nanoparticles for the potential treatment of brain tumors j control rel gref r, minamitake y, peracchia mt, trubetskoy v, torchilin v and langer r biodegradable longcirculating polymeric particles science bazile d, prudhomme c, bassoullet mt, marlard m, spenlehauer g and veillard lithium cr2 battery specifications m ] pharm sci peracchia mt, fattal e, deasmaele d, besnardm, noel jp, gomis jm, appel m, dangelo j and couvreur p stealth pegylated polycyanoacrylate nanoparticles for intrave nous administration and splenic targeting ] control rel calvo p, gouritin b, chacun h, desmaele d, dangelo j, noel jp, georgin d, fatal lithium cr2 battery specifications e, andreux p and couvreur p longcirculating pegylated polycyanoacrylate nanoparticles as new drug cariers for brain delivery pharm res brigger i, morizet j, aubert g, chacun h, terrierlacombe mj, couvreur p and vassal g polyethylene glycolcoated hexadecylcyanoacrylate nanospheres display a combined effect for brain tumor targeting } pharmacol exp ther fundaro lithium cr2 battery specifications a, cavalli r, bargoni a, vighetto d, zara gp and gasco mr nonstealth and stealth solid lipid nanoparticles sln carrying doxorubicin pharmacokinetics and tissue distribution after iv administration to rats pharmacol res zara gp, cavalli r, bargoni a, fundaro a, vighetto d and gasco mr intravenous administration of nonstealth and stealth lithium cr2 battery specifications doxorubicinloaded solid lipid nanoparticles at increasing concentration of stealth agent pharmacokinetics and distribution in brain and other tissue j drug targ alyautdin rn, petrov ve, langer k, berthold a, kharkevich da and kreuter j delivery of loperamide across the bloodbrain barrier with polysorbate coated poly butylcyanoacrylate nanoparticles pharm res schroeder u, lithium cr2 battery specifications sommerfeld p, ulrich s and sabel ba nanoparticle technology for delivery of drugs across the bloodbrain barrier } pharm sci alyautdin rn, tezikov eb, ramge p, kharkevich da, begley dj and kreuter j significant entry of tubocurarine into the brain of rats by absorption to polysorbate coated polybutylcyanoacrylate nanoparticles an in lithium cr2 battery specifications situ brain perfusion study microencapsul friese a, seiler e, quack g, lorenz � and kreuter j enhancement of the duration of the anticonvulsive activity of a novel nmda receptor antagonist using polybutylcyanoacrylate nanoparticles as a parenteral controlled release delivery system eur } pharm biopharm friese a kleinpartikulare tragersysteme nanopartikel als ein lithium cr2 battery specifications parenterales arzneistoff transportsystem zur verbesserung der bioverfugbarkeit znsaktiver substanzen dargestellt am beispiel der nmdarezeptorantagonisten mrz und mrz phd thesis, jw goetheuniversitat frankfurt, frankfurt calvo p, gouritin b, villarroya h, eclancher f, giannavola � klein c, andreux p and couvreur p quantification and localization of pegylated polycyanoacylate nanoparticles in brain and spinal lithium cr2 battery specifications cord during experimental allergic encephalomyelitis in the rat eur j neurosci merdio m, irache jm, eclancher f, mirshadi m and villarroya h distribution of albumin nanoparticles in animals induced with the experimental allergic encephalomyelitis } drug targ ueda m and kreuter j optimization of the preparation of loperamideloaded polyllactide nanoparticles by lithium cr2 battery specifications high pressure emulsificationsolvent evaporation j microencapsul ueda m, iwata a and kreuter j influence of the preparation methods on the drug release behaviour of loperamideloaded nanoparticels j microencapsul darius j, meyer fp, sabel ba and schroeder u influence of nanoparticles on the braintoserum distribution and the metabolism of valproic acid in lithium amlodipine besylate safe in pregnancy cr2 battery specifications mice j pharm pharmacol yang s, zhu j, lu y and yang � body distribution of camptothecin solid lipid nanoparticles after oral administration pharm res schroeder u, sommerfeld p and sabel ba efficacy of oral dalarginloaded nanoparticle delivery across the bloodbrain barrier peptides deangelis lm brain tumors new engl j med lithium cr2 battery specifications steiniger scj, kreuter j, khalansky as, skidan in, bobruskin al, smirnova zs, severin se, uhl r, ���� m, geiger kd and gelperina se chemotherapy of glioblastoma in rats using doxorubicinloaded nanoparticles int ] cancer donelli mg, zucchetti m and dlncalci m do anticancer agents reach the tumor target in the human brain?