trends biotechnol harada a and kataoka � pronounced activity of enzymes through the incorporation into the core of polyion complex micelles made from charged ridgid lithium ion batteries block copolymers control rel godbey wt, wu kk and mikos ag polyethylenimine and its role in gene delivery } control rel kopecek j, kopeckova p, ridgid lithium ion batteries minko t, lu zr and peterson cm water soluble polymers in tumor targeted delivery ] control rel hoste k, de winne � and schacht e polymeric prodrugs int j pharm ulbrich � and subr v polymeric anticancer drugs with phcontrolled activation adv drug del rev shuvaev w, dziubla t, wiewrodt r and muzykantov vr streptavidinbiotin crosslinking of therapeutic enzymes with carrier antibodies nanoconjugates for protection against endothelial oxidative stress meth mol biol dziubla td and ridgid lithium ion batteries lowman am gels, in schwartz m ed encyclopedia of smart materials wiley and sons new york lowman am, dziubla td, bures p and peppas na structural and dynamic response of neutral and intelligent networks in biomedical environments, in peppas na and sefton mv eds advances in chemical engineering molecular and ridgid lithium ion batteries cellular foundations of biomaterials academic press new york wiewrodt r, thomas ap, cipelletti l, christofidousolomidou m, weitz da, feinstein si, schaffer d, albelda sm, koval ridgid lithium ion batteries m and muzykantov vr size dependent intracellular immunotargeting of therapeutic cargoes into endothelial cells blood torchilin vp immunoliposomes and pegylated immunoliposomes possible use for targeted delivery of imaging agents immunomethods hermanson gt bioconjugate techniques acedemic press san diego, ca olivier jc, huertas r, lee hj, calon f and pardridge wm synthesis of pegylated immunonanoparticles pharm res tessmar j, mikos a and gopferich a the use of polyethylene glycolblock polylactic acid derived copolymers for the rapid creation of biomimetic surfaces biomaterials nanoparticulate carriers for delivery to the brain jorg kreuter introduction drug the following chapter deals with a subject that according ridgid lithium ion batteries to the journals science or nature, is of no general interest, namely the brain or to be more specific, drug delivery to the brain personal communication ridgid lithium ion batteries the brain is one of the best protected organs of the body, to the outside by the skull and towards the blood circulation by the bloodbrain barrier bbb the purpose of the bbb is to maintain the homeostasis of the brain, and to allow the creation of a unique extracellular fluid environment within the central nervous system cns, whose composition can as a consequence be precisely controlled the extracellular fluid compartments of the cns comprise of the brain, the spinal cord parenchymal interstitial fluid and the cerebrospinal fluid contained within the ventricles of the brain, as well as the cerebral ridgid lithium ion batteries and spinal subarachnoid spaces the structural bbb is created by the endothelial cells forming the capillaries of the brain and the spinal cord these endothelial cells are characterized by having tight continuous circumferential junctions between them, thus abolishing any aqueous paracellular pathways between these cells the presence of the tight junctions and the lack of aqueous pathways between cells greatly restricts the movement of polar solutes across the cerebral endothelium certain substances may diffuse passively ridgid lithium ion batteries across the brain endothelial cells this diffusion is dependent on lipophilicity and molecular weight drugs with a molecular weight above da are normally excluded from ridgid lithium ion batteries a passive diffusional transport across the bbb however, a large number of drugs that would possess a favorable lipophilic ity and molecular weight, which should normally enable an easy transport across the bbb, are rapidly pumped back into the blood stream by extremely effective efflux pumps these pump systems include among others, pglycoprotein pgp, also referred to as multidrug resistance protein mdr, as well as moat multiple organic anion transporter since the brain is dependent ridgid lithium ion batteries on the blood to deliver substrates as well as to remove metabolic waste, the endothelial cells are also required to maintain a high level of carriermediated transport systems that enable the entry or the elimination of a variety of endogenous compounds including hydrophilic substances such as hexoses, amino acids, purine compounds, and monocarbonic substances, as well as lipoproteins including ldl low density lipoprotein, some of these transporters are unidirectional and some bidirectional in their transport of ridgid lithium ion batteries solutes across the cell membrane this polarization means that some solutes can be preferentially transported into or out of the brain as a consequence, the bbb presents a huge challenge for the effective delivery of a large number of therapeutics to the brain, and, therefore, many attempts have been made to overcome this barrier for instance, these attempts include the osmotic opening of the tight junctions use of prodrugs or carrier systems such as antibodies liposomes, and nanoparticles opening of the tight junctions by osmotic pressure, however, is a very invasive procedure that also enables the entry of unwanted substances ridgid lithium ion batteries into the brain the employment of prodrugs may yield a higher lipophilicity, enabling a better permeation and transport into and across the lipophilic endothelial barrier, ridgid lithium ion batteries andor these prodrugs may use the membrane associated carrier systems in many cases, however, a suitable prodrug cannot be synthesized, or the resulting molecular weight is too large colloidal carriers also can take advantage of these carrier systems present in the bbb these systems, for instance, include the lipoprotein receptors and the transferrin transcytosis systems, and may be employed in the delivery of drugs by the above particulate colloidal drug delivery systems nanoparticles nanoparticles for ridgid lithium ion batteries pharmaceutical purposes as defined by the encyclopedia of pharmaceutical technology are solid colloidal particles ranging in size from to nm fim, consisting of macromolecular materials in which the active principle drug or biologically active material is dissolved, entrapped, or encapsulated, or to which the active principle is adsorbed or attached the use of nanoparticles for the transport of drugs across the bbb was already suggested in the early s by prof speiser at the eth swiss ridgid lithium ion batteries federal institute of technology in zurich personal communication, who was also the first to systematically develop nanoparticles for drug delivery purposes in the late s and early s � dal ps mgkg dalnp mgkg dalnp ps mgkg dalnp ps mgkg dalnp ps mgkg fig antinociceptive effects after intravenous injection of different dalargin dal formulations into mice mpe = maximal possible effect np = nanoparticles ps = polysorbate dal saline mgkg the possibility to use nanoparticles ridgid lithium ion batteries for the transport of drugs into the brain across the bbb was first shown with the hexapeptide dalargin tyrdalaglyphe leuarg, a leuenkephalin analogue with opioid ridgid lithium ion batteries activity, this drug was bound to nanoparticles of a size of about nm, made of the very rapidly biodegradable polymer poly butyl cyanoacrylate this material ridgid lithium ion batteries is one of the most rapidly biodegradable nanoparticle materials the nanoparticles were incubated with this drug for hrs, yielding the sorptive binding of of the initial amount of dalargin overcoating of these particles with the surfactant polysorbate tween� was then achieved by further incubation for another min with this surfactant, ridgid lithium ion batteries resulting in an equilibrium between surfacebound polysorbate and polysorbate in solution a dosedependent antinociceptive analgesic effect was observed using the tailflick test, after intravenous injection ridgid lithium ion batteries to mice fig which was later repeated by other research groups with the hot plate test, the antinociceptive effect was accompanied by a pronounced straub effect and could be totally inhibited by injection of the �opiate receptor antagonist naloxone min before the injection of the nanoparticle preparation both results indicate ridgid lithium ion batteries a central action of dalargin on the cns, demonstrating that it was indeed transported across the bbb and that the observed antinociceptive effects were not ridgid lithium ion batteries due to peripheral activity in contrast to the polysorbate coated nanoparticles, none of the controls including a solution of dalargin, a solution of polysorbate , a suspension of poly butyl cyanoacrylate nanoparticles, a mixture of dalargin with polysorbate , dalargin with nanoparticles or a mixture of all three components, dalargin, polysorbate , and nanoparticles, mixed immediately before injection, as well as dalargin bound to nanoparticles without polysorbate coating, were able to exhibit any antinociceptive action fig the antinociceptive effects also showed circadian phaseday timedependency, as well as a shift of the minima and maxima of the nociceptive reactions of the mice of almost hrs ridgid lithium ion batteries compared with the controls and the dalargin solution biodistribution influence of surfactants on the biodistribution of nanoparticles fundamental biodistribution studies of troster et al with clabelled polymethyl methacrylate nanoparticles demonstrated that the coating of these nanoparticles with certain surfactants increased the whole brain concentrations of the nanoparticles in rats after ridgid lithium ion batteries intravenous injection however, at that time, the authors were convinced that the nanoparticles were not taken up by any brain associated cells, including the brain capillary endothelial cells, nor were transported across the bbb, but rather remained in the blood lumen adhering to the luminal surface of the endothelial cells in addition, it has to be noted that some surfactants in trosters experiments led to high [c] brain concentrations, which were unable to achieve any ridgid lithium ion batteries antinociceptive effects with dalargin bound to the nanoparticles these important antinociceptive effects in the cns with the polysorbate coated dalargin nanoparticles reported above sec led to the investigation of the biodistribution of this drug after intravenous injection to mice, using h labelled dalargin in the form of [leucyl,h]dalargin as well as of [htyr] dalargin up to fold higher concentrations in brain homogenates were found with the polysorbate coated nanoparticles than with dalargin solution these ridgid lithium ion batteries concentration differences were statistically different at most time points, although smaller than expected from the huge difference in the pharmacological responses however, it has to ridgid lithium ion batteries be considered that the determination of the hradioactivity in brain homogenates cannot discriminate between drug that has and drug that has not actually crossed the bbb in addition, the observed concentration differences between different brain homogenate fractions may be the reason for the lack of efficient bbb crossing of dalargin in ridgid lithium ion batteries solution form much larger and important brain concentration differences were obtained after intravenous injection of polybutyl cyanoacrylate nanoparticles loaded with doxorubicin in this case, the drug was added during polymerization four doxorubicin formulations, doxorubicin solution in saline, doxorubicin solution plus polysorbate in saline, doxorubicin bound to nanoparticles, or doxorubicin bound ridgid lithium ion batteries to nanoparticles coated with polysorbate , were injected into the tail vein of rats at a doxorubicin dosage of mgkg in the brain, the polysorbate coated ridgid lithium ion batteries nanoparticles yielded high doxorubicin concentrations of xgg tissue between and hrs after injection the brain concentrations were still at a level of about xgg after ridgid lithium ion batteries hrs, while the three other preparations remained below the detection limit of xgg at all times in contrast, very low concentration differences appeared between all ridgid lithium ion batteries four preparations in the blood only interestingly, the heart concentrations of both nanoparticle formulations remained very low, confirming earlier results of couvreur et al,h whereas the heart concentrations with the two solutions were about times higher than with the nanoparticles since the use of doxorubicin is limited by its cumulative high heart toxicity, this observation is of major significance solid lipid nanoparticles sln were also able to achieve significant brain concentrations after intravenous, and ridgid lithium ion batteries even after duodenal administration slns consisting of stearic acid, the surfactant epicuron� , and taurocholate sodium loaded with doxorubicin, tobramycin, or idarubicin were prepared by dispersing a microemulsion containing the above components in water at a dose of mgkg doxorubicin, brain concentrations of about �gg were obtained after min only with the slns, and no doxorubin was detectable in the brain of rats after iv administration of the solution through the jugular vein with tobramycin terazosin ptsd mgkg, the ridgid lithium ion batteries intravenous route was compared with duodenal administration through a surgically implanted cannula no tobramycin was detectable in the brain after administration of tobramycin solution to ridgid lithium ion batteries the rats however, with the solid lipid nanoparticles, the amount of tobramycin in the brain hrs after duodenal administration xgg was comparable to that after ridgid lithium ion batteries iv administration xgg the tobramycin brain concentration was decreased hrs after duodenal dosing, while the levels after iv administration remained fairly high mgg in all ridgid lithium ion batteries other tissues except the brain, the tobramycin levels were higher after iv administration of the solution than those obtained with the solid lipid nanoparticles duodenal ridgid lithium ion batteries administration of idarubicin, at a dose of lmgkg bound to solid lipid nanoparticles, yielded brain concentrations of about ngg after hrs this concentration was similar to that in the heart ng g and about half of that in the liver no detectable idarubicin nor the metabolit idarubicinol was found in ridgid lithium ion batteries the brain after administration of the solution solid lipid nanoparticles consisting of stearic acid, soybean lecithin, and the surfactant poloxamer pluronic� f loaded with the anticancer drug camp tothecin were produced by high pressure homogenization the in vitro release of the drug lasted for one week after intravenous injections of mgkg camp tothecin to mice, the drug residence time in the body was significantly prolonged by the nanoparticles compared with the solution, and the plasma ridgid lithium ion batteries auc was increased by a factor of , the brain auc even by a factor of , and the auc in other organs by a factor of ridgid lithium ion batteries between lungs and heart an increase of the dose to mgkg camptothecin factor in the nanoparticle formulation further increased the plasma auc by , the brain auc by , and the auc in the other organs by times on the average incorporation of ,dioctanoylfluorodeoxyuridine into solid lipid nanoparticles also increased its brain uptake after iv injection of the slns, its brain auc was increased twofold over the solution of this compound different types of solid lipid nanoparticles with a size of about nm, consisting of emulsifying waxbrij� and out of brij� polysorbate , were made by lockman et al and koziara et al and ridgid lithium ion batteries investigated in rat brain perfusion experiments for both nanoparticle types, a statistically significant uptake was observed compared with [c]sucrose in rat brain perfusion experiments, suggesting ridgid lithium ion batteries central nervous system uptake of the nanoparticles perfusion of the nanoparticles did not induce any statistically significant changes in barrier integrity, membrane permeability, or facilitated ridgid lithium ion batteries choline transport [h]thiamine was then bound to the emulsifying waxbrij� nanoparticles via a pegspacer distearoylphosphatidylethanolamine dspepegnhs to target the particles to the thiamine transporters in the brain although an association with the thiamine transporter occurred, no difference in the brain uptake was observed in balbc mice after iv injection between ridgid lithium ion batteries emulsifying waxbrij� nanoparticles with protruding peg chains on the outside and nanoparticles with thiamine bound to the peg chains the emulsifying waxbrij� solid lipid nanoparticles ridgid lithium ion batteries were then loaded with paclitaxel and tested in the u and hct cell lines and by rat brain perfusion entrapment of paclitaxel in the solid ridgid lithium ion batteries lipid nanoparticles significantly increased its brain uptake and its toxicity towards the pglycoprotein expressing tumor cells influence of pegylation on the biodistribution of nanoparticles besides, ridgid lithium ion batteries by coating with surfactants, the body distribution may also be altered by covalent attachment of polyethylene glycol peg chains to the nanoparticle surface pegylation like a number of surfactants such as poloxamine and , the nanoparticlesurfacebound peg chains can prevent the opsonization and rapid capture and removal of the nanoparticulate carriers ridgid lithium ion batteries by the cells of the reticuloendothelial system res, and consequently, can significantly prolong the blood circulation times of the particles calvo et al showed in ridgid lithium ion batteries mice and rats that the cconcentration in different brain tissues was also significantly leton lithium battery protector enhanced after intravenous injection of pegylated [c]poly[methoxy poly ethylene glycol cyanoacrylatecohexadecyl cyanoacrylate] nanoparticles [c]pegp!