impaction aerodynamic diameter fmcro fig relationship between particle size and lung deposition pulmonary drug delivery devices the origin of inhaled therapies can be traced back years ago to india, where people smoked the leaves of the atropa belladonna plant to suppress cough in the th and early th centuries, asthmatics smoked asthma cigarettes that contained stramonium powder mixed with tobacco to treat the symptoms of their disease modern inhalation devices can be divided into three different categories fig , the refinement categories fig , the refinement of the nebulizer and the of compact portable devices, the pressurized metered dose inhaler pmdi, and the dry powder inhaler dpi the advantages and disadvantages of each are summarized in table nebulizers nebulizers have been used for many years to treat asthma and other respiratory diseases there are basic types of nebulizers, jet and ultrasonic nebulizers the jet nebulizer functions by the bernoulli principle by which compressed gas air or oxygen passes through a narrow orifice, creating an area of low pressure at the cyclosporine impact bodybuilding outlet of the adjacent liquid feed tube this results in the drug solution being drawn up from the fluid reservoir and shatter into droplets in the gas stream the ultrasonic nebulizer uses a piezoelectric crystal, vibrating at a high frequency usually to mhz, to generate a fountain of liquid in the nebulizer chamber the higher the frequency, the smaller the droplets produced nebulizers can aerosolize glass nebulizer late � century addon devices dry powder inhaler dpi hand bulb nebulizer adaptive aerosol delivery metered dose liquid inhalers breathactuated mdi cfcfree mdi metered dose inhalers mdi , cfc prqpeliant passive active fig evolution of pulmonary delivery devices most drug solutions and provide large doses with very little patient coordination or skill however, treatments using these nebulizers can be time consuming and inefficient, with large amounts of drug wastage eg loss with continuously operated nebulizers most of the prescribed drug never reaches the lung with neb ulization the majority of the drug is either retained within the nebulizer referred to as residual or cyclosporine impact bodybuilding dead volume or released into the environment during expiration on average, only of the dose placed in a continuous output jet nebulizer is actually deposited in the lungs advances in technology have led to the development of novel nebulizers that reduce drug wastage and improve delivery efficiency breathenhanced jet nebulizers such as the pari lc star, pari, germany increase aerosol output by directing auxiliary air, entrained during inspiration, through the nebulizer, causing more of the generated aerosol to be swept out of the nebulizer and available for inhalation drug wastage during exhalation is reduced to the amount of aerosol produced by the jet airflow rate that exceeds the storage volume of the nebulizer adaptive aerosol delivery halolite, medicaid, bognor regis, uk monitors a patients breathing pattern in the first breaths and then targets the aerosol delivery into the first of each inhalation this ensures that the aerosol is delivered to the patient during inspiration only, thereby eliminating drug loss during expiration that occurs with continuous output nebulizers a number cyclosporine impact bodybuilding of metered dose liquid inhalers, including aerx aradigm, hay ward, ca, aero dose aerogen, sunnyvale, ca and respimat boehringer ingelheim, ingelheim rhein, germany, have been developed to produce a fine aerosol in the respirable aerosols as drug carriers table advantages and disadvantages of inhalation devices inhalation device advantages disadvantages nebulizers jet, ultrasonic no specific inhalation time consuming technique or coordination bulky required nonportable aerosolizes most drug contents easily solutions contaminated delivers large doses relatively expensive suitable for infants and poor delivery efficiency people too sick or drug wastage physically unable to use wide performance other devices variation between models and operating conditions pressurized metered dose compact inhalation technique inhalers pmdi portable and patient coordination multidose required doses high oral deposition inexpensive maximum dose of mg sealed environment no limited range of drugs degradation of drug available reproducible dosing dry powder inhalers dpi compact respirable dose portable dependent on ifr breath actuated humidity may cause easy to use powders to aggregate no handmouth and capsules to soften coordination required dose cyclosporine impact bodybuilding lost if patient inadvertently exhales into the dpi most dpis contain lactose ifr = inspiratory flow rate range by forcing the drug solution through an array of nozzles, using vibrating mesh or electronic micropump platforms with to of the emitted dose being deposited in the lungs metereddose inhalers the pressurized metereddose inhaler pmdi was a revolutionary invention that overcame the problems of the handbulb nebulizer, and it is the most widely used aerosol delivery device today the pmdi emits a drug aerosol driven by propellants, such as chlorofluorocarbons cfc and more recently, hydrofluoroalka nes hfas through a nozzle at high velocity msec pmdis deliver only a small fraction of the drug dose to the lung typically, only to of the emitted dose is deposited in the lung the high velocity and large particle size of the spray causes approximately to of the drug aerosol to impact in the oropharygeal region handmouth discoordination is another obstacle in the optimal use of the pmdi crompton and colleagues found of patients experienced cyclosporine impact bodybuilding problems coordinating the actuation of the device with inhalation, of patients halted inspiration upon firing the aerosol into the mouth, and inspired through the nose instead of the mouth when the aerosol was actuated into the mouth the delivery efficiency of a pmdi depends on a patients breathing pattern, inspiratory flow rate and handmouth coordination the studies by bennett and dolovich demonstrated that for any particle size between to im mass median aerodynamic diameter mmad, deposition was more dependent on inspiratory flow rate than any other variable fast inhalations lmin result in a reduced peripheral deposition because the aerosol is more readily deposited by inertial impaction in the conducting airway and oropharyngeal regions when aerosols are inhaled slowly, deposition by gravitational sedimentation in peripheral lung regions are enhanced peripheral deposition has also been shown to increase with an increase in tidal volume and a decrease in respiratory frequency as the inhaled volume is increased, aerosols are able to penetrate more distally into the lungs a period of breath holding cyclosporine impact bodybuilding on completion of inhalation enhances deposition of particles in the periphery, thus preventing the particles from being exhaled during the expiratory phase thus, the optimal conditions for inhaling pmdi aerosols are from a starting volume equivalent to the functional residual capacity, the actuation of the device at the start of inhalation, inspiratory flow rate of lmin, followed by a second breathhold at the end of inspiration spacer tubes, valved holding chambers and mouthpiece extensions have been developed to eliminate coordination requirements and reduce the amount of drug deposited in the oropharynx, by decreasing the particle size distribution and slowing the aerosols velocity spacer geometry and materials of manufacture influence the quality and quantity of aerosol available the aerosols from a pmdi and the holding chamber are finer than that with the pmdi alone, with an approximate decrease in the mass median aerodynamic diameter mmad, compared with the original aerosol, this finer aerosol is more uniformly distributed in the normal lung, with increased delivery to the peripheral airway however, in cyclosporine impact bodybuilding patients with airway obstructions, the addition of a holding chamber to the pmdi may not change the distribution of the aerosol dry powder inhalers dry powder inhalers dpis were designed to eliminate the coordination difficulties associated with the pmdi there are a wide range of dpi devices on the market from singledose devices loaded by the patient eg aerolizer from novartis, rotahaler from gsk, ware uk to multi unit dose devices provided in a blister pack eg diskhaler, gsk, ware uk, multiple unit doses sealed in blisters on a strip that moves through the inhaler eg diskus, gsk, ware uk or reservoirtype bulk powder systems eg turbuhaler, astrazeneca, lund sweden lung deposition varies among the different dpis approximately to of the emitted dose is delivered to the lungs with to of the drug being retained within the device, poor drug deposition with dpis can be attributed to inefficient deaggregation of the fine drug particles from coarser carrier lactose particles or drug pellets slow inspiratory flow rate, high humidity and cyclosporine impact bodybuilding rapid, large changes in temperature are known to affect drug deaggregation and hence the efficiency of pulmonary drug delivery with dpis, with most dpis, drug delivery to the lungs is augmented by fast inhalation borgstrom and colleagues demonstrated that increasing inspiratory flow from lmin to lmin through the turbuhaler, increased the total lung dose of terbutaline from of nominal dose to this is in contrast to the mdi which requires slow inhalation and breath holding to enhance lung deposition of the drug each dpi has a different air flow resistance that governs the required inspiratory effort, the higher the resistance of the device, the more difficult it is to generate an inspiratory flow great enough to achieve the maximum dose from the inhaler however, deposition in the lung tends to increase when using high resistance inhalers active dpis are being investigated to reduce the importance of a patients inspiratory effort by adding either a battery driven propeller that aids in the dispersion of the powder spiros, elan pharmaceuticals, san cyclosporine impact bodybuilding diego, ca, or using compressed air to aerosolize the powder and converting it into a standing cloud in a holding chamber, the generation of a respirable aerosol becomes independent of a patients inspiratory effort inhance pulmonary delivery system, nektar therapeutic, san carlos, ca aerosol particle size aerosol particle size is one of the most important variables in defining the dose deposited and the distribution of drug aerosol in the lung fig fine aerosols are distributed on peripheral airways, but deposit less drug per unit surface area than larger particle aerosols which deposit more drug per unit surface area, but on aerodynamic diameter jim aerodynamic dtameter �� fig frequency a and cumulative b distribution curves for beclovent mdi used with an aerochamber, in terms of number of particles and volume mass of particles vs particle aerodynamic diameter the volume distribution curves are displaced to the right of the number distribution curves the smaller number of large particles within the aerosol carry the greater mass of the drug this is reflected cyclosporine impact bodybuilding in the larger, second peak of the volume distribution curve, which corresponds to the smaller second peak of the number distribution curve mmad is read from the cumulative distribution curve at the point and if the distribution is lognormal, the gsd can be calculated as the ration of the diameter at the point to the mmad particle distribution was measured using the anderson cascade impactor the larger, more central airways most therapeutic aerosols are nearly always het erodisperse, consisting of a wide range of particle sizes these aerosols are described by the lognormal distribution, with the log of the particle diameters plotted against particle number, surface area or volume mass on a linear or probability scale and expressed as absolute values or cumulative since delivered dose is very important when studying medical aerosols, particle number may be misleading as smaller particles contain less drug than larger ones particle size is defined from this distribution by several parameters mass median diameter of an aerosol refers to the particle diameter that cyclosporine impact bodybuilding has of the aerosol mass residing above and of its mass below it the aerodynamic diameter relates the particle to the diameter of a sphere of unit density that has the same settling velocity as the particle of interest, regardless of its shape or density mmad is read from the cumulative distribution curve at the point fig geometric standard deviation gsd is a measure of the variability of the particle diameters within the aerosol, and is calculated from the ratio of the particle diameter at the point on the cumulative distribution curve to the mmad for a lognormal distribution, the gsd is the same for the number, surface area or mass distributions a gsd of indicates a monodispersed aerosol, while a gsd of indicates a heterodispersed aerosol particles can be deposited by inertial impaction, gravitational sedimentation or diffusion brownian motion, depending on their size while deposition occurs throughout the airways, inertial impaction usually occurs in the first generations of the lung, where air velocity is high and airflow is cyclosporine impact bodybuilding turbulent most particles above tx m are deposited in the oropharyngeal region with a large amount impacting on the larynx, particularly when the drug is inhaled from devices requiring a high inspiratory flow rate dpis or when the drug is dispensed from a device at a high forward velocity mdis, the large particles are subsequently swallowed and contributed minimally, if at all, to the therapeutic response in the tracheobronchial region, inertial impaction also plays a significant role in the deposition of particles, particularly at bends and airway bifurcations deposition by gravitational sedimentation predominates in the last to generation of airways smaller bronchi and bronchioles, where air velocity is low in the alveolar region, air velocity is negligible and thus the contribution to deposition by inertial impaction is also negligible particles in this region have a longer residence time and are deposited by both sedimentation and diffusion particles not deposited during inhalation are exhaled deposition due to sedimentation affects particles down to �m in diameter, whereas below xm, the main cyclosporine impact bodybuilding mechanism for deposition is by diffusion targeting the aerosol to conducting or peripheral airways can be accomplished by altering the particle size of the aerosol it is difficult to predict the actual site of deposition, since airway calibre and anatomy differ among people however, in general, aerosols with a mmad of to �� are mainly deposited in the large conducting airways and the oropharyngeal region particles to zm in diameter are deposited in the small airways and alveoli with greater than of the xm diameter particles being deposited in the alveolar region in the case of pulmonary drug delivery for systemic absorption, aerosols with a small particle size would be required to ensure peripheral penetration of the drug particles xm have approximately chance of reaching the lower airways, with to being deposited in the alveoli, nanoparticles nm are deposited mainly in the alveolar region targeting drug delivery in the lung the therapeutic effect of aerosolized therapies is dependent on the dose deposited and its distribution within the lung if cyclosporine impact bodybuilding a drug aerosol is delivered at a subopti mal dose or to a part of the lung, devoid of the targeted disease or receptors, the effectiveness of therapy may be compromised for example, the receptors for the agonist, salbutamol and the muscarinic m agonist, ipratropium bromide, are not uniformly distributed throughout the lung autoradiographic studies have shown � adrenergic receptors are present in high density in the airway epithelium from the large bronchi to the terminal bronchioles airway smooth muscle has a lower �receptor density, greater in the bronchioles than bronchi however, greater than of all p receptors are located in the alveolar wall, a region where no smooth muscle exists and whose functional significance is unknown another autoradiographic study has shown a high density of m receptors in submucosal glands and airway ganglia, and a moderate density in smooth muscles throughout the airways, nerves in intrapulmonary bronchi and in alveolar walls the location of these receptors in the lung suggests that ipratropium bromide needs to be delivered to cyclosporine impact bodybuilding the conducting airways, while salbutamol requires a more peripheral delivery to the medium and small airways to produce a therapeutic effect since particle size affects the lung deposition of an aerosol, it can also influence the clinical effectiveness of a drug rees et al reported the varying clinical effect of xg of aerosolized terbutaline from a pmdi, given in three different particle sizes of xm, to im, and to xm in asthmatics, the greatest increase in forced expiratory volume in one second fevi was found with the smallest particle size xm, suggesting that the smaller particle aerosol was considerably more effective than larger particle size aerosols in producing bronchodilation, since it has the best penetration and retention in the lungs in the presence of airway narrowing using three monodisperse salbutamol aerosols mmad of xm, xm, xm, zanen and colleagues demonstrated in patients with mild to moderate asthma that the xm particle size aerosol produced a superior bronchodilation, compared with the other two aerosols in patients with severe airflow obstruction cyclosporine impact bodybuilding fevi , zanen et al demonstrated that the optimal particle size for fi agonist or anticholinergic aerosols is approximately xm they examined the effect on lung function of equal doses of three different sizes of monodisperse aerosols, xm, xm and xm, of salbutamol and ipratropium bromide their findings suggest that small particles penetrate more deeply into the lung and more effectively dilate the small airways than larger particles, which are filtered out in the upper airways the xm aerosol induced significantly less bronchodilation than the xm aerosol, suggesting that this fine aerosol may be deposited too peripherally to be effective, since smooth muscle is not present in the alveolar region the optimal site of deposition in the respiratory tract for aerosolized antibiotics depends on the infection being treated pneumonias represent a mixture of purulent tracheobronchitis and alveolar infection successful therapy would theoretically require the antibiotic to be evenly distributed throughout the lungs however, those confined to the alveolar region would most likely benefit from a greater peripheral deposition pneumocystis carinii cyclosporine impact bodybuilding pneumonia, the most common lifethreatening infection among patients infected with hiv, is found predominately within the alveolar spaces, with relapses occurring in the apical region of the lung after treatment with inhaled pentamidine given as a fim mmad aerosol the mechanism suggested for this atypical relapse is the poorer apical deposition of the aerosol regional changes in intrapleural pressure result in the lower lung regions receiving relatively more of the inspired volume than the upper lung, when sitting in an upright position or standing this influence on deposition has been shown to occur in an experimental lung model, analyzing sites of aerosol deposition in a normal lung the experiment showed a ratio in the overall deposition for a xm aerodynamic diameter aerosol between the lower and upper lobes when in the upright position chronic lung infection with pseudomonas aeruginosa, in patients with cystic fibrosis or noncf bronchiectasis, resides in the airway lumen with limited invasion of the lung parenchyma infection starts in the smaller airways, the bronchioles, and moves cyclosporine impact bodybuilding into the larger airways the optimal site of deposition for inhaled antimicrobial therapy would, therefore, be a uniform distribution on the conducting airways mucus plugs in the bronchi and bronchioles may prevent deposition of even small particle aerosols in regions distal to the airway obstruction, possibly the regions of highest infection, and thereby limiting the therapeutic effectiveness of the aerosolized antibiotic until recently, aerosol drug delivery has been limited to topical therapy for the lung and nose the major contributing factor to this restriction was the inefficiencies of available inhalation devices that deposit only to of the emitted dose in the lungs while appropriate lung doses of steroids and bronchodilators can be achieved with these devices, for systemic therapies, large amounts of the drug are necessary to achieve therapeutic drug levels systemically recent advances in aerosol and formulation technologies have led to the development of delivery systems that are more efficient and that which produce small particle aerosols, allowing higher drug doses to be deposited in the alveolar region cyclosporine impact bodybuilding of the lungs, where they are available for systemic absorption most macromolecules cannot be administered orally because proteins are digested before they are absorbed into the bloodstream in addition, their large size prevents them from naturally passing through the skin or nasal membrane therefore, they cannot be administered intranasally or transdermally without the use of penetration enhancers thus, the easiest route of administration for proteins has been through intravenous or intramuscularsubcutaneous injection it has been known for many years that proteins can be absorbed from the lung as demonstrated with insulin in macromolecules kilodaltons kda nm in diameter appear rapidly in the blood following inhalation into the airways insulin which has a molecular weight mw of kda and a diameter of nm peaks in the blood to min after inhalation macromolecules kda nm in diameter are slowly absorbed over many hours inhaled albumin kda and alphai antitrypsin kda have a tmax of hrs and between to hrs respectively the lung is the only organ through which the entire cardiac cyclosporine impact bodybuilding output passes before the inhaled drug can be absorbed into the blood from the lung periphery, it has several barriers to overcome such as lung surfactant, surface lining fluid, epithelium, interstitium and basement membrane, and the endothelium drug absorption in the lung periphery is regulated by a thin alveolarvascular permeable barrier an enormous alveolar surface area with epithelium, consisting of a thin single cellular layer to xm thickness, promotes efficient gas exchange through passive transport, but also provides a mechanism for efficient drug delivery into the bloodstream although the mechanism of absorption is unknown, it has been hypothesized that macromolecules either pass through the cells via absorptive transcytosis adsorptive or receptor mediated, paracellular transport between bijunctions or trijunctions or through large transitory pores in the epithelium caused by cell injury or apoptosis thus, the high bioavailability of macromolecules deposited in the lung to times greater than nasal and gastrointestinal values may be due to its enormous surface area, very thin diffusion layer, slow surface clearance and antiprotease defense system cyclosporine impact bodybuilding clearance of particles from the lung like all major points of contact with the external environment, the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the body airway geometry, humidity and clearance mechanisms contribute to this filtration process the challenge in developing therapeutic aerosols is to produce an aerosol that eludes the lungs various lines of defense airway geometry and humidity progressive branching and narrowing of the airways encourages impaction of particles the larger the particle size, the greater the velocity of incoming air, while the greater the bend angle of bifurcations and the smaller the airway radius, the greater the probability of deposition by impaction drug particles are known to be hygroscopic and grow in size in high humidity environments, such as the lung which has a relative humidity of approximately the addition and removal of water can significantly affect the particle size and thus deposition of a hygroscopic aerosol a hygroscopic aerosol that is delivered at relatively low temperature and humidity cyclosporine impact bodybuilding into one of high humidity and temperature would be expected to increase in size when inhaled into the lung the rate of growth is a function of the initial diameter of the particle, with the potential for the diameter of fine particles less than xm to increase fold, compared with to fold for particles greater than xm the increase in particle size above the initial size should affect the amount of drug deposited, and particularly, the distribution of the aerosolized drug within the lung ferron and colleagues have predicted that for initial sizes between xm and xm, total deposition of hygroscopic aerosols increases by a factor of for particles with an initial size of fim, xu and yu were able to predict changes in the distribution pattern due to particle growth the calculations showed a shift from deposition due to sedimentation to primarily impaction on more central airways lung clearance mechanisms once deposited in the lungs, inhaled drugs are either cleared from the lungs, absorbed into the circulatory or cyclosporine impact bodybuilding lymphatic systems, or metabolized drug particles deposited in the conducting airways are primarily removed through mucociliary clearance, and to a lesser extent, are absorbed through the airway epithelium into the blood or lymphatic system ciliated epithelium extends from the trachea to the terminal bronchioles the airway epithelial goblet cells and submucosal glands secrete mucus forming a twolayer mucus blanket over the ciliated epithelium a lowviscosity periciliary or sol layer covered by a highviscosity gel layer insoluble particles are trapped in the gel layer and moved towards the pharynx and ultimately to the gastrointestinal tract by the upward movement of mucus generated by the metachronous beating of cilia in the normal lung, the rate of mucus movement varies with the airway region and is determined by the number of ciliated cells and their beat frequency movement is faster in the trachea than in the small airways, and is affected by factors influencing ciliary functioning and the quantity and quality of the mucus for normal mucociliary clearance to occur, airway epithelial cyclosporine impact bodybuilding cells must be intact, ciliary structure and activity normal, the depth and chemical composition of the sol layer optimal, and the rheology of the mucus within the physiological range mucociliary clearance is impaired in lung diseases such as immotile cilia syndrome, bronchiectasis, cystic fibrosis and asthma in immotile cilia syndrome and bronchiectasis, the ciliary function can be either impaired or nonexistent in cystic fibrosis, the ciliary structure and function are normal, however, the copious amounts of thick, tenacious mucus present in the airways impairs their ability to clear the mucus effectively in these diseases, clearance of aerosolized drugs deposited in the conducting airways is generally decreased and secretions are cleared from the lung by cough in addition to mucociliary clearance, soluble particles can also be removed by absorptive mechanisms in the conducting airways lipophilic molecules pass easily through the airway epithelium via passive transport hydrophilic molecules cross via extracellular pathways such as tight junctions or by active transport via endocytosis and exocytosis from the submucosal region, particles are absorbed cyclosporine impact bodybuilding either into systemic circulation, bronchial circulation or lymphatic systems drugs deposited in the alveolar region may be phagocytosed and cleared by alveolar macrophages or absorbed into the pulmonary circulation alveolar macrophages are the predominant phagocytic cell for the lung defense against inhaled microorganisms, particles and other toxic agents there are approximately to alveolar macrophages per alveolus in the lungs of healthy, nonsmokers macrophages phagocytose insoluble particles deposited in the alveolar region are either cleared by the lymphatic system or moved into the ciliated airways along currents in alveolar fluid and then cleared via the mucociliary escalator this process can take weeks or months to complete as discussed above, soluble drug particles deposited in the alveolar region can be absorbed into the systemic circulation the pulmonary epithelium appears to be more resistant to soluble particle transport than to the endothelium or the interstitium the lungblood barrier may behave as a molecular sieve, allowing the passage of small solutes but restricting the passage of macromolecules conhaim and colleagues proposed that the cyclosporine impact bodybuilding lung barrier was best fitted to a three pore size model, including a small number of largesized pores nm pore radius, of mediumsized pores nm radius and of smallsized pores nm the rate of protein absorption from the alveoli is size dependent effros and mason demonstrated an inverse relationship between alveolar permeability and molecular weight in rats, after intratracheal instillation of ddavp desamino darginine vasopressin mw = kda, peak serum ddavp levels occurred at hr compared with to hrs after the intratracheal instillation of albumin mw = kda however, some proteins are cleared from the lung more rapidly than expected for their size after intratracheal instillation or aerosolization of human growth hormone mw = kda, peak serum levels were observed between to hrs, indicating a rapid, saturable clearance from the lung that is suggestive of receptormediated endocytosis vasoactive intestinal polypeptide vip is believed to be completely degraded during the passage across the pulmonary epithelium and into the bloodstream nanoparticles can pass rapidly into the systemic circulation the distribution of cyclosporine impact bodybuilding radioactivity, after the inhalation of a m technetium tclabeled ultrafine carbon particles to nm, was detected in the blood one min postinhalation and peaked between and min this blood radioactivity level was sustained up to min of the initial lung radioactivity was measured in the liver min post administration and remained stable over time the rapidity of the appearance of radioactivity systemically makes the translocation from the lung unlikely due to phagocytosis, by macrophages or endocytosis by epithelial and endothelial cells, but by passive diffusion nanoparticle formulations for inhalation delivery of nanosized aerosols to the lung may result in very little drug being deposited in the lung the majority of particles nm inhaled will not have enough residence time in the lung to deposit, and therefore will be exhaled fig however, if the nanoparticles were delivered in larger carrier particles, they could be sufficiently deposited in the lung the carrier particle would dissolve after contact with the lung surface fluid, releasing the nanoparticle at the target tissue or cells cyclosporine impact bodybuilding sham and colleagues demonstrated that nanoparticles to nm could be delivered into the lung in larger respirable lactose carrier particles produced by spraydrying the dry powder containing the nanoparticles had a mmad of xm pmdi formulations are typically micronized drugs in the to xm range suspended in a hydrofluoroalkane hfa propellant solution pmdi such as qvar produce smaller drug particles on propellant evaporation, resulting in better deposition and distribution than a micronized formulation however, for insoluble drug particles in the propellant, the efficiency of pmdi is limited a study by dickinson et al proposed the use of nanoparticles suspended in propellant as a method of increasing the delivery efficiency of insoluble drugs in pmdis they produced hydrophilic nanoparticles using a reverse phase microemulsion technique that captures nanoparticles by snap freezing, followed by freezedrying the nanoparticles of pure drug salbutamol and the drug in a nonpolymer matrix lecithinbased, with and without lactose, were dispersed in hfa and in aerosol performance assessed by cascade impaction the size of the salbutamol nanoparticles cyclosporine impact bodybuilding ranged from to nm dispersion of the nanoparticles in a hfahexane vv blend resulted in a homogeneous fine suspension that showed no signs of sedimentation or creaming over several months rapid release of salbutamol from the nanoparticle was observed approximately min as expected from the large surface area of the particles and the high water solubility of the drug a high fine particle fraction exdevice, xm of to and a low mmad to um were observed with the nanoparticle formulations this data suggests that a high fraction of the nanoparticles would be distributed in the alveolar region of the lung and represents the best aerosol that can be produced using a pmdi budesonide is a potent corticosteroid used as an inhaled anti inflammatory agent to treat asthma it is available as a dry powder inhaler and as a suspension for inhalation with a nebulizer a new formulation for nebulization has been developed that contains nanocrystals of budesonide that give the suspension solutionlike qualities the particles are to nm in cyclosporine impact bodybuilding diameter, compared with nm for the marketed budesonide suspension pulmicort respules, astrazeneca in a randomized crossover study, healthy volunteers were given the nanocrystal budesonide formulation mg and mg doses, pulmicort respules and placebo via nebulization using a pari lc jet nebulizer nebulization times were shorter for the nanocrystal formulation, compared with pulmicort respules min vs min similar aucs were observed with the formulations, suggesting similar pulmonary absorption however, a higher cmax pgml vs pgml and shorter tmax min vs min for nanocrystal budesonide compared with the same dose of pulmicort, suggests a more rapid drug delivery or absorption with the nanocrystal formulation diagnostic imaging radiolabeled nanoparticles have been used for many years in pulmonary ventilation studies ultrafine mtc labeled carbon particles technegas is a relatively new advance in ventilation scintigraphy technegas vita medical ltd, sydney australia consists of nanoparticles of carbon with a diameter of approximately nm, that behaves more like a tm particle technegas is generated by the electrostatic heating of a graphite crucible to � � in cyclosporine impact bodybuilding which a saline solution of mtcpertechnetate had been placed and dried the aerosol is dispersed in a leadlined chamber in an atmosphere of argon gas that is then inhaled by the patient it is deposited in alveoli by inhalation and distributes similarly as the inert gas radioisotopes once they are inhaled, the particles adhere to the alveolar structures without appreciable movement for at least min pulmonary delivery of nanoparticles is also being investigated for lymphoscintigraphy to assess the spread of or the staging of lung cancer lung cancer usually exhibits metastasis proliferation, spreading through the lymphatic system and the blood circulation lymphatic drainage is responsible for the alveolar clearance of the deposited particulates and drugs up to a certain particle diameter nm thus, radiolabeled nanoparticles could be used to visualize the lymph nodes to determine the presence of tumors the lymphatic uptake of solid lipid nanoparticles has also been studied as an imaging method to stage lung cancer the lipid nanoparticles were radiolabeled with the lipophilic tracer, d,lhexamethylpropylene cyclosporine impact bodybuilding amine oxime hmpao, tagged with mtc the lipid nanoparticles were prepared by the melted homogenization method and had a mean diameter of nm the radiolabeled nanoparticles were aerosolized using an ultrasonic nebulizer and delivered to rats until , cpm was achieved over the lung after inhalation, the total activity in the lung was observed, followed by a fast clearance rate ti = min that decreases activity in the lung to of the total dose a significant uptake was detected in the regional lymph nodes during the first to min, suggesting that aerosol delivery to the lungs of solid lipid nanoparticles could be used as an effective colloidal carrier for lymphoscintigraphy drainage into the lymph nodes following the lung instillation of nanoparticles of insoluble iodinated ct xray contrast agents was studied in beagle dogs nanoparticles of the contrast agent were prepared by microfluidization a particle size of to nm was achieved the nanoparticles were suspended in different surfactant solutions ml of the suspension was instilled using a fiber optic bronchoscope at cyclosporine impact bodybuilding specific sites in the small airways and alveoli the nanoparticles were transported from the lung to the draining lymph nodes, to days post instillation as visible on the ct radiographs no adverse clinical signs were observed in the dogs however, microscopic lung lesions were observed at the instillation sites for both formulations and vehicle the lesions consisted of inflammatory infiltrates, mainly macrophages, in intraalveolar, interstitial and perivascular locations a few small sites had fibrosis and granulomatous nodules with the destruction of the lung parenchyma the presence of foamy macrophages was observed in the lymph nodes the microscopic findings suggest that instillation of these nanoparticles of contrast agent may be harmful to the lung the authors suggested that administering the nanoparticles as an aerosol, rather than by instillation, would prevent high concentrations in focal areas believed to be responsible for these lesions vaccine delivery mucosal vaccine administration is an attractive method of inducing an immune response, since many pathogens invade the body through mucosal surfaces in the nose, lung and cyclosporine impact bodybuilding gut as it is the first contact point, the mucosa has developed barriers to protect the body the mucosa associated lymphoid tissue malt is one of these barriers it contributes of the immunocytes and secretes more immunoglobulins than any other organs in the body antigens are delivered locally in the respiratory tract to nasalassociated and bronchusassociated lymphoid tissues nalt and balt, respectively and a mucosal immunity is induced using nanoparticles, systemic immunity may also be induced several studies have investigated the use of nanoparticles as carriers for the nasal delivery of vaccines using tetanus toxoid as a model antigen, vila and colleagues have studied the use of chitosan nanoparticles as well as polyethyleneglycol and polylactic acid pegpla nanoparticles as nasal vaccine carriers, they compared pegpla nanoparticles with pla alone tetanus toxoid was entrapped in the hydrophobic pla core and protected from interacting with enzymes such as lysozymes, by a hydrophilic peg coating upon incubation with lysozymes in vitro, pla particles aggregate and do not reach the epithelium, whereas pegpla cyclosporine impact bodybuilding nanoparticles remain stable and size unmodified the nanoparticles were produced using a double emulsion technique pegpla tetanus toxoid nanoparticles had a similar diameter to the pla particles nm vs nm, but had a lower loading efficiency of compared with with pla the igg antibody response induced by pegpla was superior at weeks to , after intranasal instillation of fig of tetanus toxoid � per nostril on days , and in male balbc mice in a similar study, the same group compared radiolabeled pegpla, pegpla with gelatin stabilizer to radiolabeled pla encapsulated tetanus toxoid they reported that hr after intranasal administration, pegpla nanoparticles produced a radioactivity level fold higher in the blood than pla which remained constant for hrs the radioactivity detected in the lymph nodes, lungs, liver and spleen was to fold higher for pegpla than pla nanoparticles hrs post instillation the results of this work suggest that the pegpla nanoparticles are partially taken up by the m cells of the nalt, as well as being transported to the submucosa and cyclosporine impact bodybuilding drained into the lymphatic system and blood stream recent work by the same group has investigated the potential use of chitosan nanoparticles for nasal administration of vaccines chitosan is a hydrophilic natural polysaccharide that is biodegradable and has mucoadhesive properties the nanoparticles are formed spontaneously by adding the counter anion sodium tpp into the chitosan solution, without the use of energy sources or organic solvents required for the production of pegpla nanoparticles again, using tetanus toxoid as the model antigen, the investigators studied the effect of chitosan dose �g and fig and molecular weight , or kda on the efficacy of the nanoparticles the nanoparticles produced were to nm and had a positive surface charge mv the loading efficiency of tetanus toxoid was to , irrespective of the molecular weight of chitosan in vitro, the formulations exhibited a rapid release over the initial hrs followed by a slow release for days, with the greater initial release at lower molecular weights of chitosan or jig of antigen associated with and jg of cyclosporine impact bodybuilding chitosan was given intranasally to balbc mice on days , and the igg levels induced by the nanoparticles were significantly higher than those elicited by free tetanus toxoid the response lasted for the weeks studied with the igg titres increasing over time antitetanus iga titers were detected in the saliva, bronchoalveolar and intestinal lavage fluids weeks post administration the results were independent of the administered dose and were significantly higher for the nanoparticle than the free tetanus toxoid jung and colleagues evaluated tetanus toxoidloaded polymer nanoparticles as potential nasal vaccine carriers in mice the nanoparticles were produced with various diameters nm, nm using a novel polyester, sulfobutylated poly vinyl alcoholgraftpolylactidecoglycolide, sbpvalgplga the surface charge was � to mv mice were immunized with tetanus toxoid nanoparticles or free toxoid in solution at weeks , and , either by oral, intranasal or intraperitoneal administration four weeks after the first intranasal immunization, igg and iga titers were significantly higher than baseline oral immunization with the nanoparticles produced a weak igg antibody response only of the cyclosporine impact bodybuilding oral dose was administered to the nose vs mg, however, intranasal immunization appeared to be more effective in inducting an immune response particle size had an effect on the titer levels particles �� did not induce an immune response, but no difference was observed between the nm and nm nanoparticles which both induced significantly levels of igg and iga these studies suggest that nasal delivery of vaccines using biodegradable nanoparticles are a promising method of inducing mucosal and systemic immunity anti tuberculosis therapy intracellular bacterial infections caused by pathogens such as mycobacterium tuberculosis are difficult to eradicate because they are generally inaccessible to free antibiotics by loading antibiotics into nanoparticles, it is expected that delivery to the infected cells would improve since nanoparticles have been shown to localize preferentially in organs with high phagocytic activity and in circulating macrophages as well the encapsulation of antibiotics has several advantages it modifies their pharmacokinetic characteristics by prolonging the antibiotics halflife and increasing the area under the concentration time curve auc, while cyclosporine impact bodybuilding decreasing its apparent volume of distribution it improves the targeting of the drug to the phagocytic cells it reduces toxicity of the antibiotics, such as the hepatotoxicity of anti tuberculosis drugs and the nephrotoxicity of aminoglycosides antibiotics encapsulated in nanoparticles have been shown to be superior at treating intracellular infections when administered intravenously however, the pulmonary delivery of these nanoparticles have only been investigated recently although effective therapy for tuberculosis is available, treatment failure and drug resistance is typically the result of patients noncompliance to improve compliance, investigators have been studying ways to reduce the dosing frequency of the drugs poly lactidecoglycolide plg nanoparticles as an aerosolized sustained release formulation for anti tuberculosis drugs, isoniazid, rifampicin and pyrazinamide, has been investigated since pulmonary tuberculosis is the most common form of the infection the majority of the nanoparticles were to nm in diameter drug encapsulation efficiency was to aerosolized nanoparticles had a mmad of ��, with of the particles in the respirable range im a single nebulization to guinea pigs cyclosporine impact bodybuilding resulted in sustained plasma drug concentrations for to days and in the lung for days the halflife and mean residence time of the drugs was significantly prolonged, compared with the oral free drugs nebulizing the nanoparticles every days to guinea pigs infected with mycobacterium tuberculosis resulted in no detectable bacilli in the lung after doses of treatment, compared with daily doses of orally administered drug to achieve the equivalent efficacy the use of lectinbased plg nanoparticles as an aerosolized sustained release formulation of isoniazid, rifampicin and pyrazinamide has also been studied in guinea pigs mucoadhesive drug delivery systems such as chitosan have been previously investigated as a method of prolonging residence at a site of absorption the main drawback of mucoadhesive systems is that its residence time is limited by the turnover time of the mucous gel layer, which is only a few hrs attaching the polymeric nanoparticles to cytoadhesive ligands such as lectins could prolong the duration of adhesion, thereby prolonging residence time lectins bind to epithelial surfaces cyclosporine impact bodybuilding via specific receptors wheat germ agglutinin wga is the least immunogenic lectin and has known receptors on the alveolar epithelium as well as the intestinal wall wga lectinplg nanoparticles were prepared by a twostep car bodiimide procedure their size ranged from to nm with drug encapsulation efficiency between and the nanoparticles were delivered via nebulization to guinea pigs of the aerosol was in the respirable range im with a mmad of xm gsd of three doses of nanoparticles were administered every days for days the wgaplg nanoparticles resulted in a prolonged tmax increased auc and mean residence time after inhaled delivery all three drugs were present in the lungs, liver and spleen at concentrations above the minimum inhibitory concentration days post dosing, compared with orallyadministered free drug chemotherapeutic studies in guinea pigs infected with mycobacterium tuberculosis showed that doses administered every days for days yielded undetectable mycobacterial colony forming units, which was only achievable with doses of the oral free drugs the study results suggest that wgabased plg nanoparticles cyclosporine impact bodybuilding could be potential drug carriers for anti tuberculosis through aerosol delivery, reducing the drug dosing frequency gene therapy pulmonary gene delivery and dna vaccinations are attractive therapies for a variety of lung diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, lung cancer and infections caused by mycobacterium tuberculosis, influenza or sarsassociated coronavirus gene delivery requires carriers to transfer dna into the nuclei of cells there are two approaches for delivery viral and non viral carriers viral delivery systems, although very efficient at transfection, are problematic due to their inherent immunogenicity non viral are safer but their transfection efficiency is low recently, biodegradable polymerbased nanoparticles have been investigated as a non viral pulmonary gene delivery system, taking advantage of their prolonged residence time in the lung and ability to be taken up by macrophages and dendritic cells, and to escape degradation by lysosomes asthma is characterized by elevated eosinophilic inflammation in the airway and increased airway hyperresponsiveness chronic inflammation can lead to structural damage and airway remodeling ifny cyclosporine impact bodybuilding is a cytokine that promotes thelper type thl responses which down regulates the th immune responses present in asthma recombinant ifny has been shown to reverse inflammation in murine models of asthma however, its short halflife and severe adverse effects at high doses have prevented its therapeutic use an intranasal ifny gene therapy had been developed as an attempt to circumvent the drawbacks to its use kumar and colleagues studied the effects of a chitosanifny plasmid dna nanoparticle in a balbc mouse model of allergic asthma using ovalbuminsensitization mice treated with the chitosan nanoparticles exhibited a significantly lower airway hyperresponsiveness to methacholine challenge, reduced number of eosinophils and a significant decrease in epithelial denudation, mucus cell hyperplasia and cellular infiltration production of ifny was increased posttreatment while il and il and ovalbuminspecific ige were reduced chitosan ifny nanoparticles induced ifny gene expression predominately in epithelial cells and worked within to hrs after intranasal administration poly d,llactidecoglycolide plgapolyethyleneimine pei nanoparticles are also being investigated for pulmonary gene delivery plga cyclosporine impact bodybuilding had been extensively evaluated for its sustainedrelease profile and ability to be taken up by macrophages pei is a cationic polymer its high positive charge density suggests that it would be a promising candidate as a non viral vector plga nanoparticles with pei on their surface had a mean particle diameter between and nm, surface charge mv and a dna loading efficiency of internalization of the nanoparticles in the human airway submucosal epithelial cell line, calu, was observed and dna detected hrs after administration however, in vivo efficiency of this system still needs to be studied respiratory syncytial virus rsv infection is a major cause of respiratory tract infections and is associated with approximately deaths annually on a worldwide basis, with no anti viral therapy or vaccine available rsv ns protein appears to antagonize the host type interferonmediated response zhang and colleagues hypothesized that blocking the ns gene expression might inhibit rsv replication and thus provide effective antiviral therapy small interfering rna sirna targeting the ns gene sinsl were cyclosporine impact bodybuilding encapsulated in chitosan nanoparticles balbc mice were intranasally treated with sinsl chitosannanoparticles before or after rsv infection a significant decrease in virus titers in the lung was observed, in addition to a decrease in inflammation and airway hyperresponsiveness, compared with controls the effect of sinsl lasted at least days the data show that sinsl nanoparticles may be a promising anti viral therapy against rsv infection conclusion innovations in the biotechnology and pharmaceutical industries have led to novel approaches for delivering drugs more efficiently and to specific targets in the lung and the body one of the growth areas is the development of nanoparticles as carriers of active pharmaceutical agents for diagnosis and treatment aerosol delivery systems, discussed at the beginning of this chapter, are the current technologies for delivering therapies to treat respiratory diseases and some systemic diseases the accepted philosophy, and one based on sound in vitro and in vivo clinical data, is that the optimal size of aerosol needed to target the distal lung is of the cyclosporine impact bodybuilding order of �� this size is times greater than the nanoparticles being considered in the design of agents including antibiotics, vaccines and gene therapies for inhaled delivery novel techniques and formulations are being studied to produce successful vehicles for delivering these types of products in vivo positive outcomes using animal models to test these new aerosol formulations have been reported however, clinical studies still need to be conducted to determine their efficacy in humans as with any new technology, there will be benefits and risks associated with its use the use of nanotechnology to provide improved targeting of drugs via the inhaled route is an exciting development that has the potential to yield novel treatments for many diseases in the near future references horsfield k, dart g, olson de, filley gf and cumming g models of the human bronchial tree j appl physiol kreuter j drug targeting with nanoparticles eur j drug met pharmacol ghirardelli r, bonasoro f, porta � and cremaschi d identification of particular epithelial areas and cyclosporine impact bodybuilding cells that transport polypeptidecoated nanoparticles in the nasal respiratory mucosa of the rabbit biochim biophys acta huang m, ma z, khor e and lim ly uptake of fitcchitosan nanoparticles in a cells pharm res russelljones gj, veitch h and arthur l lectinmediated transport of nanoparticles across caco and ok cells int j pharm brigger i, dubernet � and couvreur p nanoparticles in cancer therapy and diagnosis adv drug del rev martonen �� mathematical model for the selective deposition of inhaled pharmaceuticals } pharm sci ocallaghan � and barry pw the science of nebulized drug delivery thorax suppl ss denyer j, dyche t, nikander k, newman sp, richards j and dean a halolite a novel liquid drug aerosol delivery system thorax suppl dolovich m new propellantfree technologies under investigation ] aerosol med suppl issl smaldone gc, agosti j, castillo r, cipolla d and blanchard jd deposition of radiolabeled protein from aerx in patients with asthma aerosol med newman sp and clarke sw inhalation devices and techniques, in clark tjh, godfrey cyclosporine impact bodybuilding s and lee th eds, asthma chapman & hall, london, pp newman sp, pavia d, moren f, sheahan nf and clarke sw deposition of pressurized aerosols in the human respiratory tract thorax crompton gk problems patients have using pressurized aerosol inhalers european journal of respiratory diseases � supplement bennett wd and smaldone gc human ventilation in the peripheral airspace deposition of inhaled particles am } physiol dolovich m, ryan g and newhouse mt aerosol penetration into the lung influence on airway responses chest suppl newman sp, pavia d, garland n and clarke sw effects of various inhalation modes on the deposition of radioactive pressurized aerosols eur } respir dis suppl pavia d, thomson ml, clarke sw and shannon hs effects of lung function and mode of inhalation on penetration of aerosol into the human lung thorax dolovich m, ruffin re, roberts r and newhouse mt optimal delivery of aerosols from metered dose inhalers chest dolovich mb characterization of medical aerosols physical and clinical requirements for new inhalers aerosol sci cyclosporine impact bodybuilding technol dolovich m, chambers c, mazza m and newhouse mt relative efficiency of four metered dose inhaler mdi holding chambers hc compared to albuterol mdi j aerosol med dolovich m, ruffin r, corr d and newhouse mt clinical evaluation of the aerochamber a simple demand inhalation mdi delivery device chest newman sp, moren f, trofast e, talaee n and clarke sw deposition and clinical efficacy of terbutaline sulphate from turbohaler, a new multidose inhaler eur respir f pedersen s inhalers and nebulizers which to choose and why respiratory medicine newhouse mt and kennedy a condensation due to rapid, large temperature t changes impairs aerosol dispersion from turbuhalert am j respir cell mol biol a newhouse mt and kennedy a inspiryl turbuhaler ith dpi vs ventolin mdi aerochamber ac aerosol dispersion at high and low flow and relative humiditytemperature rht in vitro am } respir crit care med a borgstrom l, bondesson e, moren f, trofast e and newman sp lung deposition of budesonide inhaled via turbuhaler a comparison with terbutaline cyclosporine impact bodybuilding sulphate in normal subjects euro respir } richards r and saunders m need for a comparative performance standard for dry powder inhalers thorax everard ml, devadason sg and le souef pn flow early in the inspiratory manoeuvre affects the aerosol particle size distribution from a turbuhaler respir med newman sp, hollingworth aand clark ar effect of different modes of inhalation on drug delivery from a dry powder inhaler int j pharma newman sp, moren f, trofast e, talaee n and clarke sw terbutaline sulphate turbuhaler effect of inhaled flow rate on drug deposition and efficacy int j pharma clark ar and hollingworth am the relationship between powder inhaler resistance and peak inspiratory conditions in healthy volunteers � implications for in vitro testing aerosol med svartengren k, lindestad pa, svartengren m, philipson k, bilin g and camner p added external resistance reduces oropharyngeal deposition and increases lung deposition of aerosol particles in asthmatics am respir crit care med melchor r, biddiscombe mf, ��� vh, short md and spiro sg lung cyclosporine impact bodybuilding deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow obstruction thorax vidgren m, paronen p, vidgren p, vainio p and nuutinen j in vivo evaluation of the new multiple dose powder inhaler and the rotahaler using the gamma scintigraphy acta pharma nordica borgstrom l and newman sp total and regional lung deposition of terbutaline sulphate inhaled via a pressurised mdi or via turbuhaler int ] pharma ruffin re, dolovich mb, wolff rk and newhouse mt the effects of preferential deposition of histamine in the human airway am rev respir dis lourenco rv and cotromanes e clinical aerosols i characterization of aerosols and their diagnositic uses arch intern med heyder j particle transport onto human airway surfaces eur j respir dis suppl brain jd and blanchard jd mechanisms aerosol deposition and clearance, in moren f, newhouse mt and dolovich mb eds, aerosols in medicine principles, diagnosis and therapy elsevier science publishers, new york, pp gerrity tr pathophysiological and disease constraints on aerosol deposition, in cyclosporine impact bodybuilding byron pr ed, respiratory drug delivery boca raton, crc press, inc, florida effros rm and mason gr measurements of pulmonary epithelial permeability in vivo am rev respir dis supplss folkesson hg, westrom br and karlsson bw permeability of the respiratory tract to differentsized macromolecules after intratracheal instillation in young and adult rats acta physiol scand patton js mechanisms of macromolecule absorption by the lungs adv drug del rev carstairs jr, nimmo aj and barnes pj autoradiographic visualization of beta adrenoceptor subtypes in human lung am rev respir dis ��� jcw and barnes pj autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung am rev respir dis rees pj, clark tj and moren f the importance of particle size in response to inhaled bronchodilators european journal of respiratory diseases � supplement zanen p, go lt and lammers jwj the optimal particle size for adrenergic aerosols in mild asthmatics int j pharma zanen p, go lt and lammers jwj optimal particle size for fc agonist and anticholinergic aerosols cyclosporine impact bodybuilding in patients with severe airflow obstruction thorax baskin ml, abd ag and ilowite js regional deposition of aerosolized pentamidine effects of body position and breathing pattern ann int med gerrity tr, garrard cs and yeates db theoretical analysis of sites of aerosol deposition in the human lung chest suppl baltimore rs, christie cdc and walker smith gj immunohistopathologic localization of pseudomonas aeruginosa in lungs from patients with cystic fibrosis implications for the pathogenesis of progressive lung deterioration am rev respir dis potts sb, roggli vl and spock a immunohistologic quantification of pseudomonas aeruginosa in the tracheobronchial tree from patients with cystic fibrosis pediatric pathol lab med alderson po, seekerwalker rh, stominger db et al pulmonary deposition of aerosols in children with cystic fibrosis j pediatr ilowite js, gorvoy jd and smaldone gc quantitative deposition of aerosolized gentamicin in cystic fibrosis am rev respir dis anderson pj, blanchard jd, brain jd, feldman ha, mcnamara jj and heyder j effect of cystic fibrosis on inhaled aerosol boluses am rev respir dis cyclosporine impact bodybuilding wolff rk safety of inhaled proteins for therapeutic use aerosol med farr st, gonda i and licko v physicochemical and physiological factors influencing the effectiveness of inhaled insulin, in dalby rn, byron pr and farr st eds, in respiratory drug delivery vi, interpharm press inc, buffalo grove, il, pp laube bl, georgopoulos a and adams gki preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients jama jendle jh and karlberg be effects of intrapulmonary insulin in patients with noninsulindependent diabetes scand } clin lab invest jendle jh and karlberg be intrapulmonary administration of insulin to healthy volunteers} int med laube bl, benedict gw and dobs as time to peak insulin level, relative bioavailability, and effect of size of deposition of nebulized insulin in patients with noninsulin dependent diabetes mellitus aerosol med byron pr and patton js drug delivery via the respiratory tract } aerosol med l ma jkh, bhat m and rojanasakul y drug metabolism and enzyme kinetics in the lung, in lenfant cyclosporine impact bodybuilding � ed, inhalation aerosols physical and biological basis for therapy marcel dekker new york, ny folkesson hg, matthey ma, westrom br, kim kj, karlsson bw and hastings rh alveolar epithelial clearance of protein } appl physiol newman sp aerosol deposition considerations in inhalation therapy chest suppl sl s phipps pr, gonda i, anderson sd, bailey d and bautovich g regional deposition of saline aerosols of different tonicities in normal and asthmatic subjects euro respir j swift dl aerosols and humidity therapy generation and respiratory deposition of therapeutic aerosols am rev respir dis ferron ga, oberdorster g and henneberg r estimation of the deposition of aerosolized drugs in the human respiratory tract due to hygroscopic growth, f aerosol med xu gb and yu cp theoretical lung deposition of hygroscopic nacl aerosols aerosol sci technol smaldone gc, perry rj, bennett wd, messina ms, zwang j and ilowite j interpretation of hour lung retention in studies of mucociliary clearance j aerosol med houtmeyers e, gosselink r, gayanramirez g and decramer m regulation cyclosporine impact bodybuilding of mucociliary clearance in health and disease eur respir } rossman cm, lee rmkw, forrest jb and newhouse mt nasal ciliary ultra structure and function in patients with primary ciliary dyskinesia compared with that in normal subjects and in subjects with various respiratory diseases am rev respir dis rossman cm, waldes or, sampson d and newhouse mt effect of chest physiotherapy on the removal of mucus in patients with cystic fibrosis am rev respir dis robinson m bye ptb mucociliary clearance in cystic fibrosis pediatric pulmonol isawa t, teshima t, hirano t, anazawa y, miki m, konno � and motomiya m mucociliary clearance and transport in bronchiectasis global and regional assessment jnuclmed edsbacker s uptake, retention and biotransformation of corticosteroids in the lung and airways, in schleimer rp, obyrne pm, szefler sj and brattsand r eds, inhaled steroids in asthma optimizing effects in the airways, marcel dekker, inc, new york, pp summers qa inhaled drugs and the lung clin exp allergy stone ��, mercer rr, gehr p, stockstill � cyclosporine impact bodybuilding and crapo id allometric relationship of cell numbers and size in the mammalian lung am j respir cell mol biol conhaim rl, eaton a, staub nc and heath td equivalent pore estimate for the alveolarairway barrier in isolated dog lung appl physiol barrowcliffe mpa, jones jg and sever ps pulmonary clearance of vasoactive intestinal peptide thorax nemmar a, hoet phm, vanquickenborne b, dinsdale d, thomeer m, hoylaerts mf, vanbilloen h, mortelmans l and nemery � passage of inhaled particles into the blood circulation in humans circulation sham joh, zhang y, finlay wh, roa wh and lobenberg r formulation and characterization of spraydried powders containing nanoparticles for aerosol delivery to the lung int j pharma leach cl, davidson pj and boudreau rj improved airway targeting with the cfcfree hfabeclomethasone metered dose inhaler compared with cfc beclomethasone eur respir f dickinson pa, howells sw and kellaway iw novel nanoparticles for pulmonary drug administration j drug targ kraft wk, steiger b, beussink d, quiring jn, fitzgerald n, greenberg he and waldman sa cyclosporine impact bodybuilding the pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers } clin pharma l kramer elanddivgicrpulmonary applications of nuclear medicine clin chest med l satoh k, takahashi k, sasaki m, kobayashi t, honjo n, ohkawa m, tanabe m, fujita j and miyawaki h comparison of mtctechnegas spect with xe dynamic spect in pulmonary emphysema ann nuclear med isawa t, teshima t, anazawa y, miki m and motomiya m technegas for inhalation lung imaging nucl med commun videira ma, botelho mf, santos ac, gouveia lf, pedrosos de lima jj and almeida aj lymphatic uptake of pulmonary delivered radiolabeled solid lipid nanoparticles j drug targ mclntire gl, bacon er, toner jl, cornacoff jb, losco pe, illig kj, nikula kj, muggenburg ba and ketai l pulmonary delivery of nanoparticles of insoluble, iodinated ct xray contrast agents to lung draining lymph nodes in dogs j pharma sci lamm me interactions of antigens and antibodies at mucosal surfaces ann rev microbiol vila a, sanchez a, janes k, behrens i, kissel t, vila jato j cyclosporine impact bodybuilding and alonso mj low molecular weight chitosan nanoparticles as new carriers for nasal vaccine delivery in mice eur j pharmaceut biopharmeut vila a, sanchez a, evora c, soriano i, vila jato j and alonso mj pegpla nanoparticles as carriers for nasal vaccine delivery ] aerosol med tobio m, gref r, sanchez a, langer r and alonso mj stealth pla peg nanoparticles as protein carriers for nasal administration pharma res jung t, kamm w, breitenbach a, hungerer kd, hundt e and kissel t tetanus toxoid loaded nanoparticles from sulfobutylated polyvinyl alcoholgraft polylactidecoglycolide evaluation of antibody response after oral and nasal application in mice pharma res pintoalphandary h, andremont a and couvreur p trgeted delivery of antibiotics using liposomes and nanoparticles research and applications int j antimicrobial agents pandey r, sharma a, zahoor a, sharma s, khuller gk and prasad � poly dl lactidecoglycolide nanoparticlebased inhalable sustained drug delivery system for experimental tuberculosis } antimicrob chemother sharma a, sharma s and khuller gk lectinfunctionalized poly lactideco glycolide nanoparticles as oralaerosolized antitubercular cyclosporine impact bodybuilding drug carriers for treatment of tuberculosis j antimicrob chemother yoshida m, leigh r, matsumoto k, wattie j, ellis r and obyrne pm effect of interferongamma on allergic airway responses in interferongammadeficient mice am } respir crit care med kumar m, kong x, behera ak, hellermann gr, lockey rf and mohapatra ss chitosan ifnypdna nanoparticle cin therapy for allergic asthma gen vacc ther bivasbenita m, romeijn s, junginger he and borchard g plgapei nanoparticles for gene delivery to pulmonary epithelium eur j pharmaceut biopharmeut thompson ww, shay dk, weintraub e, brammer l, cox n, anderson lj and fukuda � mortality associated with influenza and respiratory syncytial virus in the united states jama zhang w, yang h, kong x, mohapatra s, juanvergara hs, hellermann g, behera s, singam r, lockey rf and mohapatra ss inhibition of respiratory syncytial virus infection with intranasal sirna nanoparticles targeting the viral ns gene nat med lll dolovich mb and newhouse mt aerosols generation, methods of administration, and therapeutic applications in asthma, in middleton e jr, cyclosporine impact bodybuilding reed ce, ellis ef, adkinson nf jr, yunginger jw and busse ww eds, allergy principles and practice, mosby � year book, inc, st louis this page is intentionally left blank magnetic nanoparticles as drug carriers urs o hafeli and mathieu chastellain magnetic nanoparticles possess many characteristics that make them promising as drug carriers and for use in biomedical applications they can be attracted or magnetically guided by strong magnetic fields, thus acting as drug carriers they can also be used for hyperthermia applications, due to the heat they produce in an alternating magnetic field the resulting temperature increase can be used to modify or inhibit specific cell activities locally, or even to release drugs in a precisely controlled, temperatureincrease activated manner magnetic nanoparticles can also serve as contrast agents for diagnostic applications such as magnetic resonance imaging introduction magnetic nanoparticles occur frequently in nature they are found not only in the mineral world but also in living organisms well known examples are magnetotactic bacteria, which are believed to navigate cyclosporine impact bodybuilding the waters they live in, by using internal magnetic crystals aligned in chains that function as a compass higher forms of life, such as humans, also employ iron as an essential metal in order to ensure a constant supply of iron, the body stores it within the welldefined protein shell ferritin as a to nm hydrous ferric oxide nanoparticle the use of magnetic powders in medical applications was already conceptualized by ancient greek and roman scientists however, magnetic nanoparticles have only been used since the mid s in the area of biological and medical sciences a wide range of in vivo as well as in vitro applications have been or are currently being developed these applications include magnetic drug delivery, magnetic fluid hyperthermia, magnetic cell separation and extraction when an external magnetic field is applied, and contrast enhancement for diagnostic imaging procedures, as the magnetic nanoparticles own magnetic field influences their surrounding from a practical point of view, magnetic nanoparticles are thus versatile tools that enhance yields for many cyclosporine impact bodybuilding in vitro processes such as cell purifications in addition, in general, no invasive procedures are required when they are used for in vivo therapies definitions the development of nanoparticles for biomedical applications requires contributions from the basic to the medical sciences such interdisciplinary interactions can sometimes lead to communication problems for example, the term magnetic nanoparticle has a different meaning for a physician and a biochemist, and might have no meaning at all for a physicist for this reason, definitions satisfying all partners involved in the present research field are required with the following simplified definitions, we attempt to provide a universal starting point properties of magnetic ma terials the magnetic properties of materials are mainly related to electrons, with all materials showing some kind of magnetic behavior materials can be classified according to their response to external magnetic solicitations magnetic susceptibility is defined by the initial slope of the magnetic curve, presenting the magnetization m response as a function of an applied magnetic field h solicitation fig the cyclosporine impact bodybuilding observed behavior of different materials can be explained in terms of their magnetic structure at the atomic level, and can be summarized as diamagnetism, paramagnetism, and ferromagnetism diamagnetic materials consist of atoms with no net magnetic moment nevertheless, they tend to oppose any external magnetic field change due to induced dipoles in the material for this reason, they are characterized by a slight negative magnetic susceptibility paramagnetic materials are made of atoms showing a net magnetic moment the random orientation of these moments is responsible for a slight positive magnetic susceptibility and no magnetization remains when the external magnetic field is switched off see fig ferromagnetic materials react strongly to external magnetic fields, unlike dia and paramagnetic materials they can be viewed as paramagnetic materials with an organized domain structure see fig within a domain, all atomic magnetic moments are parallel when submitted to an external magnetic field, the different domains, initially in a random orientation, tend to align according to the size increase temperature increase paramagnetism ferro or cyclosporine impact bodybuilding ferrimagnetism superparamagnetism f j thermal activation h m atomic magnetic moment m magnetisation h applied magnetic field mr remanent magnetisation hc coercive field ms saturation magnetisation fig atomic magnetic moment structure upper drawings and corresponding magnetization curves lower graphs paramagnetic materials show random atomic moment orientation which is responsible for their weak response to magnetic solicitations and no remanence a typical ferro or ferrimagnetic material shows a characteristic domain structure with associated hysteresis magnetization curve superparamagnetic materials present a thermally induced oscillating magnetic moment and a strong magnetic response to external magnetic fields red curve their saturation magnetization is comparable to ferro or ferrimagnetic materials black curve, but without remanence as in the case of paramagnetic materials blue curve for a given particle composition, all three behaviors might be encountered, depending on temperature or particle size upper arrows external field this alignment requires domain wall motions and results in hysteresis of the magnetization curve after the external field is switched off, a remaining or remanent magnetization mr can be cyclosporine impact bodybuilding observed again, in order to achieve a random domain orientation, more energy must be provided by means of an external magnetic field applied in the opposite direction a coercive field he is defined as the value of the external field necessary to misalign the domains to a random state more detailed information is available in the literature magnetic materials can be composed of different atoms and ions with various magnetic moments the most well known example is magnetite fecu, which consists of fe and fe ions the crystallographic structure of such materials determines whether or not antiferromagnetic or ferrimagnetic properties are present for magnetic drug targeting, only ferro and ferrimagnetic materials are of interest, as they react strongly to external magnetic fields due to their nonzero atomic or lattice unit magnetic moment and the domain structure temperature also plays a role in the magnitude of magnetic response, as high thermal energy can disturb the atomic moment orientation within the domains, leading to paramagnetic behavior when ferro or ferrimagnetic materials cyclosporine impact bodybuilding are divided, the obtained nanoparticles can become small enough to show single domain structure with a nonzero magnetic moment depending on the particle size, the thermal energy might be high enough to have the particles magnetic moment switch between energetically favorable or easy directions these directions are defined by the particle structure, especially the crystallography, the shape and the surface as a result of the moment oscillation, the net particle magnetization is zero and no remanent magnetization is observed, but the particles still strongly react to external magnetic solicitations see fig this behavior, called superparamagnetism, is generally encountered for particles that are a few nanometers in size superparamagnetism can be influenced by magnetic interparticle interactions, which lead to collective behavior of several particles acting as one bigger particle the observation time is also important and must be longer than the particle relaxation time, necessary to switch from one to the other easy direction nanoparticles no single definition exists to describe a nanoparticle most of the time, an arbitrary size cyclosporine impact bodybuilding range is used nanometer sized, from to m in view of the recent developments in nanotechnology, some people now use the drastic behavior changes arising below a critical size such as the superparamagnetic state described earlier to define nanoparticles when reducing nanoparticle size, not only does the surface over volume ratio increase gradually, but a complete modification of the material properties may also occur this is of primary importance in the biomedical field, where a change in size can lead to toxic effects many unanswered questions remain in this field and legal aspects related to nanoparticles are currently under discussion for use in biomedical applications, ferro, ferri or superparamagnetic particles must be coated to ensure colloidal stability, increased circulation time in the body, functional surfaces, and appropriate diagnostic properties in this regard, the term magnetic nanoparticle not only refers to an inorganic core responsible for magnetic properties, but also to a composite structure with one or several cores coated or embedded in a matrix coatings are reviewed elsewhere in cyclosporine impact bodybuilding this book in addition to a compatible coating, magnetic nanoparticles used in clinical applications must form stable aqueous suspensions suspensions are complex dynamic systems their equilibrium is influenced by the forces present, including van der waals, electrostatic, steric, and magnetic forces, as well as by brownian motion on this account, it is crucial to realize that solvent modifications can drastically influence the behavior of the system the term ferrofluid is correctly used only in the case of a colloidal stable suspension of single domain nanoparticles magnetic nanoparticles in general, a single particle type cannot be used for all applications instead, the composition, size and production route of synthesized magnetic nanoparticles is determined by the target application although superparamagnetic, ferro and ferri magnetic particles can all be used for magnetic drug carrier applications, superparamagnetic particles are favored for biomedical applications, due to the fact that they behave nonmagnetically when they are not under the influence of an external magnetic field, thus preventing undesired magnetic agglomeration to further assist in preventing cyclosporine impact bodybuilding agglomerations, to optimize biointeractions with the host environment and to maximize biocompatibility, the choice of appropriate surface chemistries and functionalizations is also important many magnetic nanoparticles are available with different surface chemistries, and details about the properties of these chemistries are given elsewhere in this book the following subsections provide an overview of magnetic nanoparticles as drug carriers, classified according to magnetic composition the final subsection deals with the general biocompatibility issues of magnetic nanoparticles iron oxide based magnetic nanoparticles in biomedical applications, the most commonly used magnetic nanoparticles are superparamagnetic magnetite fe and maghemite yfe this is due to their ease of synthesis using chemical or physical approaches, as well as their general biocompatibility and fda approval massarts aqueous coprecipitation method, which leads to particles easily dispersible in water, is the most cited method of magnetic nanoparticle preparation the particle size can be tuned in the to nm size range and the particles usually show an ellipsoidal shape the stoichiometry ranges from magnetite to maghemite, the two crystallographic cyclosporine impact bodybuilding structures being very similar the size distribution is about to [see fig a] time consuming size sorting procedures allow for further narrowing of the size distribution to about in the best case a thorough characterization of such particles was carried out by the group of jolivet et ali iron oxide nanoparticles have been synthesized intensively during the past decades, but until recently, phase and size control have been problematic a newly developed twostep approach has allowed for much better control over the particle fig typical ��� bright field pictures of maghemite nanoparticles a classical co precipitation synthesis and b decomposition at high temperature of organic precursors despite its much improved size and shape distribution, the second particle type suffers from two major drawbacks for biomedical applications biocompatibility and the ease of dispersion in water based solvents structure in this approach, metal particles are first obtained and then oxidized in a controlled way size distributions of better than can be achieved in the to nm range, as shown by alivisatos cyclosporine impact bodybuilding et al and hyeon et al [see fig b] these particles are, however, often not appropriate for biomedical applications as they do not disperse easily in water many other magnetite and maghemite nanoparticle synthesis approaches can be found in the literature, but none are significantly different from the ones presented above slightly modified nanoparticles can also be obtained by partly replacing the iron in the magnetite or maghemite structure with cobalt or nickel this in turn changes the magnetic properties of the particles more details are given in a recent and extensive review by tartaj et al cobalt based magnetic nanoparticles from a magnetic point of view, particles showing a stronger reaction to magnetic fields are desirable cobalt achieves this aim, but its toxicity is a major drawback one way of preventing or minimizing this toxicity caused by cobalt ion leakage is the inorganic encapsulation of cobalt with, for example, silica iron based magnetic particles pure iron nanoparticles can be synthesized, but their sensitivity to oxidation is a major cyclosporine impact bodybuilding drawback for biomedical applications thus, a coating, as described for cobalt particles, should be used iron has also been coated or alloyed with platinum, cobalt and carbon encapsulated magnetic nanoparticles depending on the application, magnetic nanoparticles may be combined into larger conglomerates to increase the overall magnetic moment see fig great care should be paid to interparticle magnetic interactions the superparamagnetic behavior of a system might, for example, be lost due to such interactions also, the magnetic core concentration must be kept constant among the magnetic conglomerates to yield homogeneous magnetic moments, and thus a consistent response to an applied magnetic field either a single or a twostep approach can be used to synthesize magnetic particles in the onestep approach, a linker is present while synthesizing the magnetic nanoparticles in the twostep approach, the linker is added subsequently the linker can be organic or inorganic and is chosen for its chemical and biocompatible characteristics for biomedical applications, dextran, starch, polyethylene glycol peg, polyvinyl alcohol pva, silica and gold are cyclosporine impact bodybuilding among the most common compounds biocompatibility issues of magnetic nanoparticles du one of the first papers to discuss the biocompatibility issues of magnetic particles was published in the early s by nakamura et al the authors prepared fine carbonyliron particles and infused them into different animal species in vivo they concluded that to achieve optimal results, the magnetic particles should be coated with a biocompatible material and be as round as possible a liemii i tick fig bright field ��� pictures of different types of magnetic particles a silica magnetite composite and b dextranmagnetite composite the silica layer can be observed easily, whereas dextran does not produce enough contrast to be seen clearly further research showed that pure magnetic metal particles, such as iron, cobalt and nickel particles, should not be used directly in vivo because they oxidize easily and release or charged metal ions that can exert unwanted as well as toxic effects iron ions, for example, are problematic in that they produce and catalyze oxygen radical formation cyclosporine impact bodybuilding cobalt and nickel ions have been found to induce adverse tissue reactions, and to promote infection and metal sensitivity in contrast to pure magnetic particles, iron oxides and superparamagnetic iron oxide nanoparticles spion coated and stabilized with hydrophilic polymers have been found to be quite thermodynamically stable under physiological conditions, not exerting obvious toxic effects in fact, they are similar in size and core composition to the natural nontoxic magnetic nanoparticles found in magnetotac tic bacteria and in human tissue pharmacokinetic studies of small magnetite nanoparticles destined for magnet resonance imaging, have shown that the magnetite nanoparticles are taken up by the cells of the reticuloendothelial system res and are transported intracellularly to lysosomes, where they slowly oxidize at low ph and are then recycled by the body within days, up to of the iron is recovered in the red blood cells, as determined using radiolabeled fe recent discussions have centered on the fate and toxic effects of magnetic nanoparticles in humans after inhalation rodent models have shown the cyclosporine impact bodybuilding potential problematic effects of such particles to include the induction of asthma, inflammation, and potentially even cancer some of these effects might be due to the fact that particles smaller than loonm are not exhaled, but are almost completely retained in the alveoli for this reason, acute effects can rapidly turn into chronic effects another possible cause for concern is the report that small particles have been found behind the blood brain barrier see also chap further research needs to clarify if these particles directly crossed the blood brain barrier or via the nose care must be taken to relate the effects seen in animal models to the human situation, especially since effects seen in rodents do not seem to develop in humans clarification of the short and long term risks of nanoparticle use is the aim of several programs being initiated in by the european, american and canadian governments application of magnetic nanoparticles as drug carriers the following section presents an overview of the use of magnetic nanoparticles cyclosporine impact bodybuilding sized im or less for the delivery of drugs magnetic microspheres of larger than im size are also mentioned in a few places, but for a recent and thorough review, as well as for the history of magnetic drug delivery, the reader is advised to consult a more extensive treaty on this matter such as the recent volume of the mml series in this section, magnetic nanoparticles will be grouped according to their mechanism of action including magnetic hyperthermia the delivery of magnetic nanoparticles that slowly release drugs tumor treatment, thrombolysis, delivery of aritiinfective, antiarthritic, antifungal, and antiscar agents, and local anesthesia or neuroblocking agents or act without drug release radiotherapy or embolization and the improved delivery of peptides gene transfer results from in vitro, in vivo and clinical work will be discussed magnetic hyperthermia magnetic nanoparticles in an alternating current ac magnetic field produce heat by neel and brownian relaxation heat production above a persons normal body temperature is called hyperthermia and can be medically used for the cyclosporine impact bodybuilding eradication of cancer cells temperatures above �c lead to thermoablation once magnetic nanoparticles have successfully reached certain organs or tissues, especially tumors, magnetic hyperthermia can be induced normal tissue nearby, not containing the magnetic nanoparticles, remains at body temperature and is thus spared one of the first to examine this effect was gilchrist who published a seminal paper in on the selective inductive heating of lymph nodes, after injection of maghemite particles sized between and nm diameter directly into the lymph nodes near surgically removed canine tumors using mg of ����� per gram of lymph node and a magnetic field strength of oe, a maximum temperature rise of �c was reached within minutes to prevent a reoccurrence of the cancer, hyperthermia is normally combined with a second treatment modality such as chemotherapy or irradiation twenty years later, rand et al showed that ferrosilicone can induce heat after being infused into a tumors blood supply and placed under the influence of a strong magnetic alternating field rands ferromagnetic silicone microspheres cyclosporine impact bodybuilding were based on turner et als research in , in which magnetic particles of unknown but probably larger size in a silicone fluid were infused into and then clogged embolized the capillary bed of several targeted organs with this technique, the researchers successfully embolized the blood supplies of different tumors no side effects were reported in the patients who had brain tumors, pheochromocytomas, a tongue tumor and a hypernephroma rands socalled magnetic field induced hyperthermia was then further developed by sako et al who showed that heating was reproducible and proportional to the amount of iron used the use of single domain, dextrancoated cipro litigation magnetite nanoparticles for tumor hyperthermia was developed by jordan and chan, and is currently undergoing in vivo and clinical testing jordan reported the optimal nanoparticle core diameter to be in the nm range although type of coating and coating stability also seemed to be important using these nanoparticles, mg of material per gram of tumor was sufficient to increase the tumor temperature by �� to cell toxic cyclosporine impact bodybuilding levels jordan is currently conducting a clinical phase ii trial combining magnetic hyperthermia and radiation therapy, he recently presented the first clinical results from patients at the th international conference on the scientific and clinical applications of magnetic carriers in lyon, france the patients were treated for cervix , rectal, and prostate carcinoma, as well as for a chondrosarcoma, rhabdomyosarcoma, and liver metastasis during the hour sessions, after local injection of the magnetic particles, the tumor temperature increased to � � under the influence of a magnetic field of to kam and a frequency of khz while no additional nanoparticle injections were necessary, the hyperthermia treatment was repeated from times the magnetic fluid hyperthermia was well tolerated two patients showed complete remission and months after treatment, while the other six patients showed local control with no recurrent growth of the tumors these results are very promising another group in germany led by hilger is working on circumventing the drawback of having to directly inject the particles into a tumor, by cyclosporine impact bodybuilding using antibody bound magnetic nanoparticles which are able to target breast cancer, followed by magnetic field hyperthermia although their particles are taken up extensively by tumor cells and show a specific heating power of up to w g, there is still more work needed to increase the number of particles in the tumor and to reach a homogeneous tumor distribution magnetic hyperthermia is also possible with large microspheres that contain magnetic nanoparticles, as an example, moroz et al incorporated nm maghemite particles into xm biocompatible plastic particles and then embolized the arterial blood supply of liver tumors with them in an animal study with rabbits, the vx tumor volumes decreased significantly within weeks the development of maghemite nanoparticles with very high ac losses is ongoing hergt et al are in the process of characterizing the largest, but still superparamagnetic particles, optimizing the coatings such as carboxydextran or polyethylene glycol, and investigating the exact mechanism of heat production in an ac magnetic field magnetic hyperthermia is an exciting cancer treatment cyclosporine impact bodybuilding possibility and is profiting from ongoing research into its mechanism of action and from improved magnetic materials the proof of principle has advanced to the clinical stage with the construction and clinical testing of jordans magnetic field therapy system the targeted cancer cell uptake of sufficient amounts of magnetic nanoparticles from a patients blood supply could make magnetic hyperthermia the method of choice for many different kinds of tumors magnetic chemotherapy magnetic drug delivery is able to concentrate drugs in a tumor if the tumor is accessible through the arterial system and has a good supply of blood magnetic drug delivery thus promises to deliver highly effective anticancer drugs with fewer side effects, and with shorter and less toxic treatments most drug release from magnetic particles occurs passively, by desorption from and diffusion out of the particle matrix the main driving forces are ph, osmolarity and concentration differences between particles and the bloodtissue widder and senyei were the first to successfully illustrate this concept with the chemotherapeu tic drug cyclosporine impact bodybuilding doxorubicin encapsulated into albumincoated magnetite particles sized around im targeting a distinct area of a rats tail, they were able to deliver times more of the drug than intravenous application of the same amount of free drug could achieve taking it a step further, they treated yoshida rats with sarcomas in their tails and attained complete remission in of the rats the magnetic albumin microspheres were never tested clinically, likely because the magnetophoretic mobility overall magnetic responsiveness to a magnetic field was considered too low for deeper applications this changed with the introduction of ironcarbon particles originally developed in russia and then brought to clinical trial by the company ferx ferxs irregularlyshaped carboncoated iron particles, of to zm in diameter and with a very high magnetic susceptibility, were loaded with doxorubicin and showed promising results and very low therapyrelated toxicity in the treatment of inoperable liver cancer unfortunately, ferx ceased to exist in when a preliminary analysis of their ongoing clinical trial failed to convince investors of the methods cyclosporine impact bodybuilding superiority over other treatment methods not only doxorubicin, but also many other chemotherapeutic drugs can be and have been adsorbed to magnetic nanoparticles made from many different matrix materials examples of chemotherapeutic magnetic nanoparticles tested in vivo include polyalkylcyanoacrylate nanoparticles of nm diameter filled with adsorbed dactinomycin, chitosan nanoparticles of nm diameter loaded with oxantrazole, solid lipid nanoparticles of nm diameter loaded with methotrexate, and ferro carbon of nm diameter loaded with carminomycine each of these nanoparticles has been tested in animal experiments with positive results specifically, after intravenous injection, the drug concentration tripled in the target organ when a magnet was placed above it, compared with a control without an applied magnet it seems that the intravenous injection of magnetic nanoparticles, even very close to the target region, is not optimal this was well documented in a clinical cancer therapy trial performed by lubbe et al in patients they used magnetic nanoparticles of nm in diameter loaded with epidoxorubicin for the treatment of advanced solid cancer the phase cyclosporine impact bodybuilding i study clearly showed accumulation of magnetic nanoparticles in the target area without toxic effects mri measurements, however, indicated that more than of the magnetic nanoparticles were deposited in the liver this was likely due to the particles low magnetic susceptibility and small size, which limited their ability to be held at the target organ intraarterial injection into the blood supply that leads to the target region might be much more effective for magnetic drug targeting for this reason the above examples of magnetic drug targeting with magnetic nanospheres are only a subset of all the magnetic drug delivery attempts a more complete compilation is given by hafeli in addition, all the important factors in magnetically controlled targeted chemotherapy are extensively described in a review by gupta and hung other magnetic treatment approaches under the influence of a magnetic field, magnetic particles align in chains and eventually agglomerate depending on particle size and shape, this can lead to embolization clogging of the blood vessels and especially of the small cyclosporine impact bodybuilding capillaries of to xm in diameter this accumulation of particles can be used on its own to starve the target tissue of oxygen, produce hypoxia and induce necrosis the magnetic particles used for this approach are generally larger, such as the iron sponge of xm used by sako et � but can also consist of nanoparticles in a more lipophilic solvent such as the ferrosilicone employed by turner et al turner added a catalyst to their ferrosilicone suspension, which resulted in vulcanization of the viscous slurry min after injection into patients with diverse solid tumors magnetic particles can also be used for tumor treatment without releasing any drugs for this purpose, magnetic particles can incorporate radioisotopes either in the matrix or bound to their surface, and then deliver tumor celltoxic radiation doses wherever they accumulate external magnetic fields or internal magnetizable wires, can be used to accumulate radioactive magnetic particles and hold them at the target site the particles irradiate the area within the specific treatment range of the cyclosporine impact bodybuilding isotope initial experiments in mice showed that intraperitoneally injected radioactive polylactic acid based magnetic microspheres x,m in diameter could be concentrated near a subcutaneous tumor in the belly area above which a small magnet had been attached the dosedependent irradiation from the iemitter ycontaining magnetic particles resulted in the complete disappearance of more than half of the tumors iron carbonbased smaller radioactive particles of around xm have been radiolabeled with different diagnostic mtc, in and therapeutic re, y radioisotopes, targeting studies to distinct liver regions in swine by our group unpublished results showed that more than of the injected radioactive magnetic particles were accumulated underneath a strong ndfebmagnet the radioactive particles stayed in the target region for at least days, even after the removal of the magnet magnetic nanoparticles of much smaller diameters are being used clinically for diagnostic purposes, mainly as contrast agents the accumulation of these magnetic particles is, however, based on nonspecific properties such as the tissue specific pore size fenestration or enhanced permeability and cyclosporine impact bodybuilding retention effect epr seen in tumor tissues, but not on magnetic targeting recent examples of nonspecific targeting are the internalization into cells of the positively charged at peptide bound to therapeutic agents, such as radioactively complexed mtc and re, and superparamagnetic iron oxides known as tatclio tatcross linked iron oxides magnetic drug delivery is also able to deliver other types of drugs such as highly potent antiinfective, blood clotdissolving, antiinflammatory, antiarthritic, photodynamic therapy and paralysisinducing drugs, among many others a good example of these applications was reported in in this study, torchilin et al surgically induced a thrombus in both carotid arteries of a dog, fixed a permanent magnet near one of them, and hr later, intravenously injected xmsized dextran microspheres with covalently bound streptokinase the side without the magnet completely occluded within hrs, while the magnet side returned to initial blood flow conditions after about min and appeared completely open at histological examination torchilin noted that these results were achieved using doses times lower than those used when cyclosporine impact bodybuilding streptokinase is directly injected similar results were obtained in the same year by another group using nm pegylated magnetite particles containing urokinase in both cases, the thrombolytic activity remained at background levels outside the targeted region magnetic gene transfer the newest application of magnetic nanoparticles is for targeted and enhanced gene delivery in potential applications such as wound repair and the treatment of cancer eye disease, and cystic fibrosis magnetically enhanced gene transfer may be able to overcome the current lack of selectivity of the existing vectors and low efficiency of gene transfer the mechanisms by which magnetic nanoparticles can improve on transfection rates are by magnetically forced contact and by increasing the plasmid concentration magnetically magnetofection was first described in a japanese patent by harata et al who used magnetic liposomes to transfect cells bergemann et al described the first experiments of transfecting cytokineinduced killer cells cikcells with plasmid dna carrying distinct interleukin genes however, their magnetic nanoparticles were only used as plasmid carriers, not as the driving cyclosporine impact bodybuilding force, which was provided by electroporation using a magnet as the driving force was then described a couple of years later by plank et al, for successful in vitro and in vivo transfections, only very small amounts of plasmid were necessary, and the transfection occurred in a matter of just a couple of minutes this speedy and efficient transfection at low vector doses is the main advantage of magnetofection furthermore, remotely controlled vector targeting in vivo seems possible conclusions the technological advancements in the material and engineering sciences, and especially in the nanotechnology revolution, with its increasing molecular approach to the synthesis, derivatization, combination, selfassembly, and manipulation of materials, will guide improvements in all aspects of magnetic nano and microparticles these advancements include the synthesis of higher magnetic nanophases the increasing availability of stronger magnets and engineered magnetic fields the ability to prepare more uniform particles and the rendering of these particles biocompatible and ultimately biodegradable without toxicity for real therapeutic breakthrough, however, a few challenges in the field cyclosporine impact bodybuilding of magnetic drug delivery still need to be addressed one of the challenges is the difficulty involved in generating the focused field profiles needed to target magnetic nanoparticles deep within the body, due to the speed with which the magnetic fields drop off as their distance from the source increases intensity = � another challenge centers on attaining homogeneous particle distributions given that blood flow in the target region can vary from very fast cms to very slow cms a final challenge is the optimization of magnetic nanoparticles in terms of magnetization and size uniformity all these problematic areas are currently being addressed by multidisciplinary groups worldwide, as evident from a special issue of the j magn magn mater , containing original peerreviewed papers that were submitted at the th international conference on the scientific and clinical applications of magnetic carriers in wwwmagneticmicrospherecom the potential of magnetic drug delivery is great in addition to their magnetic responsiveness, magnetic nanoparticles carry an innate signal that can be used for magnetic resonance cyclosporine impact bodybuilding imaging furthermore, other imaging modalities such as radioisotope or fluorescence imaging can be used after derivatizing the particle surface there is no limitation to the kind of drugs that can be encapsulated or bound to magnetic nanoparticles also, current pharmaceutical techniques allow for the development of drug release profiles for a large group of drugs and diseases magnetic targeting devices such as the recently fda approved niobe system stereotaxis inc, st louis, missouri, usa improve on the precise manipulation of magnetic forces anatomical and physiological conditions in a patient are, however, complicated, and successful therapies will have to be specifically adapted to each disease and ideally applied under imaging control the treatment of cancer is an especially good target for magnetic drug delivery however, any disease that could benefit from precise control over the delivery of highly effective, but potentially toxic substances would also be a good candidate for example, antiangionic drugs could be delivered to the back of the eye to prevent blindness in patients with agerelated macular cyclosporine impact bodybuilding degeneration attempts to develop such a drug delivery system are ongoing references massover wh ultrastructure of ferritin and apoferritin a review micron chasteen nd and harrison pm mineralization of 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elsevier amsterdam tartaj p, del puerto morales m, veintemillasverdaguer s, gonzalezcarreno t and serna cj the preparation of magnetic nanoparticles for applications in biomedicine phys d appl phys rr arshady r microspheres, microcapsules & liposomes magneto and radiopharmaceuticals, st edn citus books, london nakamura t, konno k, morone t, tsuya n and hatano m magnetomedicine biological aspects of ferromagnetic fine particles appl physiol darleyusmar v and halliwell � blood radicals reactive nitrogen species, reactive oxygen species, transition metal ions, and the vascular system pharm res granchi d et al cell death induced by metal ions necrosis or apoptosis?