trends biotechnol harada a and kataoka � pronounced activity of enzymes through the incorporation into the core of polyion complex micelles made from charged side effects of pseudoephedrine block copolymers control rel godbey wt, wu kk and mikos ag polyethylenimine and its role in gene delivery } control rel kopecek j, kopeckova p, side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine liposomes, and side effect from levitra nanoparticles opening of the tight junctions by osmotic pressure, however, is a very invasive procedure that also enables the entry of unwanted substances 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, side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine and early s � dal ps mgkg dalnp mgkg dalnp ps mgkg dalnp ps mgkg dalnp ps mgkg fig antinociceptive effects after intravenous injection of side effects of pseudoephedrine different dalargin dal formulations into mice mpe = maximal possible effect np = nanoparticles ps = polysorbate dal saline mgkg the possibility to use nanoparticles side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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, side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine the slns, and no doxorubin was detectable in the brain of rats after iv administration of the solution through the jugular vein with tobramycin mgkg, the 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 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 side effects of pseudoephedrine 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 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 were then loaded with paclitaxel and tested in the u and hct cell lines and by rat brain perfusion entrapment zelnorm tummy of paclitaxel in the solid side effects of pseudoephedrine 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, 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 side effects of pseudoephedrine 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 side effects of pseudoephedrine 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 mice and rats that the cconcentration in different brain tissues was also significantly enhanced after intravenous injection of pegylated [c]poly[methoxy poly ethylene glycol cyanoacrylatecohexadecyl cyanoacrylate] nanoparticles [c]pegp!