feet ion with igml psvjsgalactosidase vectors magnification x of dna were delivered into the cytoplasm of each cardiocytes, whereas cationic liposomes delivered approximately x tg dna per cell yet, by increasing the dna content by times in the csils, the intensity of �galactosidase expression was increased to the level of cationic liposome transfection, with at least times more cells transfected conclusion � the application of nanoparticles in the cardiovascular system is finally color chart for levothyroxine becoming desirable as this chapter has shown, the initial foray into this field occurred in , even though the term nanotechnology was not coined for at least a decade nevertheless, its potential as drug delivery and targeting for therapy and diagnosis were recognized earlier on to date, the application of targeted nanoparticles in the cardiovascular system has included targeting the endothelium of atherosclerotic lesions and other inflammatory processes, gene delivery to ischemic cardiocytes and color chart for levothyroxine cell membrane lesion sealing with cytoskeletalantigen specific immunoliposomes other applications such as targeted drug release from nanoparticles, after targeted drug localization in the cardiovascular system, is envisioned for future therapy references allen tm, cullis pr drug delivery systems entering the mainstream science hoet phm, bruskehohlfeld i, salta ov nanoparticlesknown and unknown health risks ] nanobiotechnol hood jd, bednarski m, frausto r, guccione s, reisfeld r, xiang and cheresh da tumor regression by targeted color chart for levothyroxine gene delivery to the neovasculature science kralj m and pavelic � medicine on a small scale europena molecular biology organization reports caride vj and zaret bl liposome accumulation in regions of experimental myocardial infarction science torchilin vp, khaw ba, smirnov vn and haber e preservation of antimyosin antibody activity after covalent coupling to liposomes biochem biophys res comm khaw ba, torchilin, vp, berdichevskii vr, barsukov aa, klibanov al, smirnov vn and haber e color chart for levothyroxine enhancing specificity and stability of targeted liposomes by coincor poration of sialoglycoprotein and antibody on liposomes bull expt biol med translated from russian klibanov al, maruyama k, torchilin vp and huan l amphipathic poly ethyleneglycols effectively prolonged the circulation time of liposomes febs lett torchilin vp, klibanov al, huang l, odonnell s, nossiff nd and khaw ba targeted accumulation of pegcoated immunoliposomes in infarcted myocardium in rabbits faseb torchilin vp, narula j, halpern e color chart for levothyroxine and khaw ba poly ethylene glycolcoated anticardiac myosin immunoliposomes factors influencing targeted accumulation in the infarcted myocardium bioehim biophys acta lanza gm, yu x, winter pm, abendschein dr, karukstis kk, scott mj, chinen lk, fuhrhop rw, scherrer de and wickline sa targeted antiproliferative drug delivery to vascular smooth muscle cellls with a magnetic resonance imaging nanoparticle contrast agent circulation lanza gm, wallace kd, scott mj, cacheris wp, abendschein dr, christy dh, sharkey am, color chart for levothyroxine miller jg, gaffney pj and wickline sa a novel sitetargeted ultrasonic contrast agent with broad biomedical application circulation spragg dd, alford dr, greferath r, larsen ce, lee kd, gurther gc, cybulsky mi, tosi pf, nicolau � and gimbrone jr ma immunotargeting of liposomes to activated vascular endothelial cells a strategy for siteselective delivery in the cardiovascular system proc natl acad sci usa bloeman pg, henricks pa, van bloois l, van den tweel mc, color chart for levothyroxine bloem ac, nijkamp fp, crommelin dj and strom g adhesion molecules a new target for immunoliposomemediated drug delivery febs lett hamilton aj, huang sl, warnick d, rabbat m, kane b, nagaraj a, klegerman m and mcpherson dd intravascular ultrasound molecular imaging of atheroma components in vivo j am coll cardiol khaw ba, torchilin vp, vural i and narula j plug and seal prevention of hypoxic cell death by sealing membrane lesions with cytoskeletonspecific color chart for levothyroxine immunoliposomes nat med shi r, qiao x, emerson n and malcom a dimethylfulfoxide enhances cns neuronal plasma membrane resealing after injury in low temperature or low calcium j neu rocytol mcneil pl repairing a torn cell surface make way, lysosomes to the rescue j cell sci upt togo t, alderton jm and steinhardt ra longterm potentiation of exocytosis and cell membrane repair in fibroblasts mol biol cell mcneil pl and ito s gastrointestinal cell color chart for levothyroxine plasma membrane wounding and resealing in vivo gastroenterology walev i, hombach m, bobkiewicz w, fenske d, bhakdi s and husmann m reseal ingoflarge transmembrane pores produced by streptolysin � in nucleated cells is accompanied by nfkappa � activation and downstream events faseb khaw � a, da silva j, vural i, narula j, torchilin vp intracy toplasmic gene delivery for in vitro transfection with cytoskeletonspecific immunoliposomes j control rel khudairi t and khaw ba color chart for levothyroxine preservation of ischemic myocardial function and integrity with targeted cytoskeletonspecific immunoliposomes } amer college cardiol asahi m, rammohan r, sumii t, wang x, pauw rj, weissig v, torchilin vp and lo eh antiactintargeted immunoliposomes ameliorate tissue plasminogen activator induced hemorrhage after focal embolic stroke } cerebral blood flow metabolism khaw ba, vural i, da silva j, torchilin vp use of cytoskeletonspecific immunoliposomes for preservation of cell viability and gene delivery stp pharma sciences color chart for levothyroxine this page is intentionally left blank nanocarriers for the vascular delivery of drugs to the lungs thomas dziubla and vladimir muzykantov the lungs perform a vital multifunctional physiological role yet, the pulmonary vasculature is susceptible to a host of pathologies, which contribute to morbidity and mortality many medical interventions can improve the course and outcome of these disease conditions, provided they can be delivered in an effective, localized and safe manner venous administration color chart for levothyroxine is a suitable route for drug delivery to the pulmonary vasculature, but most drugs do not have the pharmacokinetic features required for optimal pulmonary delivery in theory, this problem may be overcome through the use of nanocarriers, which can act to improve the localization of drugs in the pulmonary vasculature and allow for a more controled releaseactivity profile for drugs that are otherwise cleared or inactivated rapidly several types of nanocarriers are potentially useful color chart for levothyroxine for this purpose including protein conjugates, liposomes and polymer nanocarriers stealth coats improve carrier circulation, while affinity ligands provide targeting yet, despite these promises and many experimental advances, significant obstacles must be overcome to permit clinical utility this chapter gives a background of the biomedical aspects of lung targeting, introduces basic elements of current design of systems for vascular drug delivery to the lungs, and discusses specific applications where nanocarriers can improve current color chart for levothyroxine therapies, as well as the limitations of existing nanocarrier technologies in this context introduction due to its critical, diverse physiological roles and high vulnerability to pathological processes, the pulmonary vasculature represents an important pharmacological target in order to manage lung pathologies, a plethora of diagnostic and therapeutic treatments including contrast agents, isotopes, antiinflammatory, antithrombotic and antioxidant agents, anticancer and antiproliferative agents, enzyme replacement therapies ert, has been proposed yet, due to unfavorable natural color chart for levothyroxine pharmacokinetic properties, many of these strategies are currently not in use for instance, despite the diversity of the chemical classes of these therapeutic agents, many of which are biotherapeutics, eg proteins, most of them do not naturally accumulate in the lungs after intravascular injection, thereby greatly limiting their effectiveness and specificity many of these limitations may be overcome by the use of nanocarriers, which can improve drug delivery to the therapeutic site by color chart for levothyroxine passive and active targeting furthermore, nanocarriers can optimize the pharmacokinetic properties of drugs by increasing the delivery potential of poorly watersoluble drugs providing extended release of drug in localized areas enhancing the circulation lifetime and isolating sensitivebioactive drugs from the blood, protecting from premature inactivation and systemic adverse effects this chapter focuses on nanocarriers designed for drug delivery to the pulmonary vasculature it begins with a brief background of the lungs as a therapeutic color chart for levothyroxine target and describes nanocarriers design, potential applications, current limitations and avenues for optimization and translation into the clinical domain biomedical aspects of drug delivery to pulmonary vasculature while gas exchange, providing blood oxygenation in the vascular system, is the most important pulmonary function, the lungs serve a variety of other vital functions for instance, the pulmonary vasculature, a unique anatomical and functional compartment itself, acts as an anatomical filter for thrombi, aggregates activated color chart for levothyroxine or damaged blood cells and other types of emboli eg lipid, gas in the venous blood, which would otherwise embolize cerebral vasculature, resulting in stroke in addition, with enzymes exposed on the luminal side of the vascular walls, it functions as a reactor bed for the blood, converting circulating agents eg peptides, mediators and hormones, and thereby affecting systemic signaling and physiology the pulmonary vasculature is the primary interface between the systemic circulation color chart for levothyroxine and the exterior environment hence, it is vulnerable to the damaging effects of extraneous eg inhaled pollutants, particulates, and pathogens and endogenous pathological factors eg circulating thrombi, pathogens, tumor metastases in particular, the pulmonary vascular endothelium, a cellular monolayer lining the luminal surface of blood vessels, is involved in many pathological conditions, local and systemic, and represents an important target for diverse diagnostic, prophylactic and therapeutic interventions this chapter will focus on advanced color chart for levothyroxine drug delivery systems designed to achieve this specific goal routes for pulmonary drug delivery intratracheal vs vascular drugs can easily reach lung tissue through either intratracheal it or intravenous iv administration upon considering pulmonary drug delivery, it administration eg aerosols, inhalants is the first to come to mind it provides a route for noninvasive means of drug delivery to airway compartments eg bronchial epithelium and interstitium and beyond, into the systemic circulation as such, color chart for levothyroxine this is an ideal situation for drugs such as asthma medications, where bronchiolar delivery is required, or for systemic delivery of drugs eg hormones, which can pass via the epithelial cells and other components of gasblood barrier however, for diseases where delivery to pulmonary endothelial cells is needed, it administration effectiveness is limited this route provides patchy delivery with inconsistent alveolar reach since the alveoli are the area of greatest vasculature density with color chart for levothyroxine slowest perfusion, it is the key, yet relatively difficult to reach, site for the transport of drugs from the airways to circulation furthermore, once transport to the vascular space does occur, nothing keeps drugs from fleeing into the systemic circulation, thereby resulting in insufficient local residence time and concentration, thus limiting therapeutic effects in the pulmonary endothelium in contrast to the intratracheal route, iv is naturally designed to aid the delivery of circulating color chart for levothyroxine compounds to the pulmonary endothelium the pulmonary vasculature is the first major microvascular network, which represents one third of the entire vascular surface area, encountered by iv injected drugs in addition, the lungs receive half of the cardiac output at each systole ie entire venous blood, whereas all the other organs share the other half ie arterial blood also, the rate of blood perfusion through the highcapacity, low pressure vascular system in the color chart for levothyroxine lungs is relatively slow see below, favoring interactions of circulating ligands with pulmonary endothelium for these reasons, this review will focus on vascular targeting of the pulmonary endothelium by iv injection pulmonary vasculature as a target for drug delivery to design systems for pulmonary vascular drug delivery, one has to know pertinent features of lung vasculature physiology for example, in order to cope with bouts of high cardiac blood output and to satisfy oxygen color chart for levothyroxine demands, the lungs possess a high transient perfusion capacity hence, blood pressure and the rate of perfusion in the lungs are significantly lower, compared with systemic vasculature several mechanisms regulate perfusion via pulmonary vasculature to adjust to changing cardiac blood output and ventilation rate the lower lobes of both left and right lungs are perfused more effectively than the apical lobes this inequity is matched by a similar ventilation pattern that exists between color chart for levothyroxine basal and apical areas of the lungs hence, lower lobes will receive more injected or inhaled drugs fig a substantial fraction of pulmonary capillaries are only transiently perfused and they get recruited in physical stress for a greater blood volume exchange, optimizing the rate of gas exchange these transiently perfused vessels, forming a reserve perfusion capacity to suit physical stress, can also be recruited to cope with the redistribution of blood flow in color chart for levothyroxine cases of localized and systemic pathologies eg heart diseases for instance, when vessels are partially or fully occluded eg by fibrin thrombi or activated white blood cells, the adjacent vasculature is distribution of drug delivery areas of inflammation enhanced drug localization fig normal and pathological pulmonary blood perfusion patterns affect distribution of delivered nanoparticles under normal conditions, due to preferential perfusion and ventilation of lower lobes, this area of lungs will accumulate higher color chart for levothyroxine loads of nanocarriers left enhanced permeability of pulmonary vasculature will drive preferential delivery of nanoparticles to sites of acute inflammation, hence passive targeting right areas of inflammation may be reached by epr effects or by active targeting of nanocarriers with coated with antibodies to cell adhesion molecules expressed preferentially in areas of inflammation this allows for both the treatment of lung inflammation and noninvasive visualization areas of lung pathology recruited to meet perfusion color chart for levothyroxine demand and compensate for the pathological deficit this ability to rapidly respond and alter flow patterns, allows the lungs to function as a filter for debris that would otherwise embolize the brain and the other organs pulmonary perfusion changes under pathological conditions, thus affecting drug delivery in addition to focal perfusion changes caused by thrombosis or inflammation fig , generalized pulmonary vascular pathologies markedly alter hemodynamics in this organ for example, primary pulmonary hypertension, depending color chart for levothyroxine on the phase of the disease, might lead to either acceleration or deceleration of pulmonary perfusion congestive heart disease, defects of the right heart valves and the insufficiency of pumping function of the right ventricle, may all result in blood pooling and stagnation in the pulmonary vasculature all these factors may affect pulmonary delivery of injected drugs pulmonary targeting of nanocarriers selective localization of drugs in the site of interest can be achieved color chart for levothyroxine by passive andor active targeting passive targeting refers to the accumulation of carriers not involving specific recognition of the target compartment in the body, and includes mechanical and charge retention, and the enhanced permeation and retention epr effect in most cases, active targeting that employs recognition moieties possessing specific affinity to target determinants eg antigenantibody or receptor ligand, affords greater specificity of drug delivery this section reviews these strategies for delivery nanocarriers to color chart for levothyroxine the pulmonary vasculature effects of carrier size on circulation and tissue distribution whether passive or active targeting is used, nanocarrier size can affect its distribution, circulation and subcellular localization fig when carrier size is nm, permeation across endothelial and epithelial barriers is possible via transcellular and pericellular pathways submicron carriers are less likely to pass through intercellular junctions in endothelial and epithelial cells, with the exception of organs with fenestrated endothelium having large, color chart for levothyroxine few micron openings, such as in the liver and the spleen however, even relatively large carriers of nm in diameter, are still capable of being internalized either via receptormediated eg endocytosis or constitutive eg macropinocytosis pathways cellular internalization allows for a more precise level of control of subcellular destinations including lysosomes, other intracellular compartments and cytosol, or even beyond the endothelial cells micron carriers still allow circulation without embolism, although the likelihood of either color chart for levothyroxine barrier penetration or cellular internalization is greatly limited =zse nm nm nm fig effect of carrier size on transport through vascular endothelium nanocarriers nm diameter are capable of passing though certain endothelial barrier either between the cells or via transcellular mechanisms involving endocytosis nanocarriers nm poorly transport between endothelial cells in the lungs, yet they are still capable of being internalized by endothelium particles larger than ��, may still be capable of circulating color chart for levothyroxine and being targeted, yet they are unlikely to leave vascular lumen in the lung unless pathological factors induce abnormally high vascular permeability leakiness, not shown such size ranges provide a mechanism for maintaining targeted drug carriers to reside on the luminal side of the endothelium, an ideal situation for drugs that require bloodplasma contact for therapeutic activity size also determines the carriers fate in the circulation despite the fact that submicron size range color chart for levothyroxine permits unimpeded vascular circulation, nanocarriers are cleared from the bloodstream within minutes via uptake by reticuloendothelial system ie res, including hepatic and spleenic resident macrophages available to the blood, via openings in the vessels in mice, this can result in clearance of the injected dose in the first instance grafting the surface of nanocarriers with large molecular weight hydrophilic polymers, negative or neutral, the primary example being polyethylene glycol peg, greatly extends the color chart for levothyroxine circulation time peg modified carriers stealth have a hydrophilic molecular brush that repels cellular and protein interactions, thus reducing recognition and uptake by res tissue uptake of pegcoated carriers depends more on mechanical retention than on active recognition and phagocytosis by res hence smaller, carriers circulate for longer duration than large ones there is growing evidence that carrier geometry is critical to circulation and cellular localization effects for instance, wormlike micelles have been reported color chart for levothyroxine to align with flow, a feature that has been hypothesized to extend and prolong the circulation of stealth carriers also, liposomes containing polymerized micelles possessed both an elongated, ellipsoidal shape, as well as a greatly enhanced circulation profile, it is not clear whether these effects are a result of improved fluid dynamics or phagocytic evasiveness however, this effect allows for additional levels of designcontrol of circulation, and perhaps other pharmacokinetic features of nanocarrier color chart for levothyroxine systems passive targeting mechanical retention microspheres larger than the precapillaries ie micron diameter injected into the venous system, embolize the downstream capillary bed thus, the site of injection dictates the localization site hence, targeting lung vasculature can be achieved by simply injecting into a pulmonary artery or an upstream femoral vein since embolism occurs at the first bifurcation that is too small for carrier passage, targeting is limited to the arterioles delivery to color chart for levothyroxine the venous sites occurs only in a form of released drug passage through this downstream vascular compartment furthermore, while pulmonary vasculature can tolerate low levels of embolism, it is not a fully benign process, resulting in ischemic vascular pockets losing contact with the blood flow and the nutrient exchange yet, mechanical retention of degradable microcarriers in the pulmonary vasculature has medical utility, eg for visualization of the lung blood vessels and perfusion patterns color chart for levothyroxine using radiolabeled microspheres furthermore, newer treatments for massive hemoptysis the coughing up of blood have focused on the embolization of the bronchial arteries while microspheres embolize vasculature, nanocarriers size allows for unobstructed flow throughout all vessels yet, nanocarriers can also be designed to associate into micronsized aggregates, prior to or upon injection, which are then delivered and mechanically retained in the capillary bed fig through the proper selection of nanocarrier size and rate of color chart for levothyroxine aggregate breakup, either subcellular or transcellular compartments can be reached, disconnecting embolism and drug delivery, and allowing for shorter durations of ischemia with a longer term drug delivery phase further, nm diameter nanocarriers may provide a more favorable degradation pattern, compared with solid microspheres degrading via either surface erosion or bulk degradation for a more detailed discussion, see the reviews at refs since surface erosion results in the overall shrinking of a particle, color chart for levothyroxine the remnant microspheres will eventually be washed away from the delivery site, prematurely terminating local effects bulk degradation is more suitable for a stable deposition of microspheres, since the overall structure remains intact until the polymer has degraded to the point where structural integrity is completely lost yet, under a continuous back pressure in the vasculature, particle disintegration can result in highly disordered debris of various sizes, geometry and surface roughness that can color chart for levothyroxine induce local and systemic damage in the case of aggregated nanocarriers, such hazardous debris is likely to be avoided, since individually released nanocarriers possess designed nanoscale geometry, permitting nonobtrusive behavior in the circulation fig mechanical retention of nanocarriers in the pulmonary vasculature a in the presence of crosslinking stimuli eg plasma opsonins or circulating ligands in biood, large � xm aggregates of nanocarriers will form after injection and embolize the pulmonary capillary bed, color chart for levothyroxine thus creating a high local concentration of a drug and ceasing blood flow b as the aggregate disintegrates, released individual nanocarriers can diffuse into the surrounding tissue via interendothelial gaps orand transcellular pathways, allowing them to accumulate in the pulmonary mterstitium disintegration of emboli initiates reperfusion of blood c as disintegration proceeds and blood flow is reestablished, released nanocarriers will be washed away drugs delivered by and released from aggregated nanoparticles will be eliminated color chart for levothyroxine by the restored flow chargemediated retention and nonviral gene delivery nanocarriers possessing a positive surface charge accumulate in the first vascular bed, similar to the targeting behavior of mechanical retention, although the mechanism of retention is different the highly anionic glycocalyx covering the endothelium binds cationic molecules and particles in cell cultures, such binding has resulted in the internalization and enhanced levels of transfection by nonviral dna delivery means, eg cationic liposomes yet, color chart for levothyroxine many blood components are also negatively charged hence, the aggregation of serum components andor the thrombus formation resulting in embolism may also occur high levels of lung targeting due to charge retention in the pulmonary vasculature have been displayed by iv injected cationic liposomes and carriers decorated with either cationic polymers eg polylysine or peptides eg tat sequences while it is not clear if in vivo localization is due to particleendothelium association or color chart for levothyroxine aggregation, it does provide an interesting mechanism for the internalization and cytosolic delivery of dna for gene delivery interestingly, in many instances, chargemediated retention of the nonviral gene delivery means in the pulmonary vasculature results in transgene expression in cells underlying endothelium eg vascular smooth muscle cells, but not in endothelial cells per se pulmonary enhanced permeationretention epr effect the enhanced permeation and retention effect was originally described when long circulating stealth liposomes color chart for levothyroxine were found to accumulate into vascularized solid tumors, due to the erratic, highly permeable nature of the tumor vasculature, as nanocarriers circulate and encounter this area, characterized also by poor lymphatic drainage, leakage into and retention in the interstitium resulted in gradual accumulation epr targeting improved with increased circulation times, and when nanocarrier size is small enough to pass through the pores in the leaky vessels of nm a similar mechanism has been found color chart for levothyroxine to enhance the delivery into the sites of inflammation, where the vasculature is also highly permeable since the pulmonary vascular bed receives the entire venous blood flow and is highly susceptible to enhanced vascular permeability under pathological conditions, it is plausible that eprrelated accumulation in the lungs might occur this mechanism might permit the visualization of inflammation sites in the lungs and provide a means of treating localized pulmonary inflammation and edema fig color chart for levothyroxine active targeting active targeting involves the engagement of specific recognition ligands with surface determinants present in the site of interest this can be achieved by either using immunoglobulins raised against target antigens, affinity peptides or using a native ligand receptor pair for a review of endothelial determinants used as targets and antibodies, and other affinity ligands used as vectors for active drug targeting into the pulmonary vasculature, please see reviews at refs and color chart for levothyroxine a brief list of the key guidelines in pulmonary target selection includes the following factors the target should be present on the luminal surface of pulmonary endothelium, accessible spatially and temporally, and should not be down regulated or masked in disease states for example, adhesion of activated blood cells and accelerated shedding inhibit targeting to some constitutive endothelial determinants on the other hand, determinants exposed on the endothelial cells under pathological conditions eg color chart for levothyroxine selectins have a distinct transient surface expression profile, which may permit selective drug delivery to pathologically altered endothelium, but require exact timing of administration to match the duration of target availability the target should not be present in nonendothelial counterparts that are accessible to the circulating nanocarriers for example, endothelial cells have transferrin receptors, which are also abundantly exposed in hepatic cells that are accessible to the bloodstream as a result, transferrintargeted drugs color chart for levothyroxine accumulate in the liver with minimal delivery to the lungs also, analogues of the target determinants circulating in the blood eg soluble forms of transmembrane glycoproteins or pselectin on platelets will compete with endothelial counterparts, compromising targeting targeting should not cause harmful side effects in the vasculature binding of targeted drugs may cause shedding, internalization, or inhibition of endothelial determinants, which may be detrimental for example, thrombomodulin, a surface protein responsible for thrombosis containment, color chart for levothyroxine is abundantly expressed in the pulmonary vasculature, providing high pulmonary targeting specificity yet, its inhibition by antibodies may provoke incidences of thrombosis that prevents clinical potential for drug delivery ideally, engaging of the target should provide therapeutic benefits such as the inhibition of proinflammatory molecules it is ideal for the docking to a surface determinant to result in optimal subcellular addressing of a drug thus, depending on the therapeutic goal, a targeted nanocarrier color chart for levothyroxine should either be retained on the cell surface blood therapies or undergo trafficking to a proper subcellular compartment eg nucleus in the case of dna, or lysosomes in the case of enzyme replacement therapies no single targeting suits all therapeutic needs specific therapeutic goals require different secondary effects mediated by binding to the endothelium, drug targeting to different subpopulations of endothelial cells, and diversifying the cellular compartments a plethora of affinity carriers, sometimes color chart for levothyroxine directed to relatively similar endothelial targets eg cell adhesion molecules or even binding to different domains of the same target molecule, are currently explored to capitalize more fully on unique opportunities offered by vascular targeting strategies for defining molecular determinants targets for affinity delivery of nanocarriers to endothelial cells, include both highthroughput analyses eg in vivo selection of phage display libraries, subtractive proteomics of endothelial plasma membrane and lowthroughput analysis of affinity ligands color chart for levothyroxine to identify endothelial molecules with known functions some of the most promising endothelial determinants for such ligands include constitutive antigens such as angiotensinconverting enzyme ace, cell adhesion molecules of igsuperfamily pecam and icam, inducible adhesion molecules e and pselectins, vcam, aminopeptidases and caveoliassociated glycoproteins carrier design as a whole, nanocarriers require a ground up design approach for each application depending on the particular needs of a given strategy, material selection can vary greatly this color chart for levothyroxine section will outline the general considerations of the design of nanocarriers for pulmonary drug delivery biocompatibility the initial material constraint is biocompatibility, a term that might be misleading, without considering the context of a given application the materials used for nanocarriers should induce no deleterious eg thrombogenic, mutagenic or carcinogenic effects in the body these effects like with any medicines depend on dose, location, structure, and residence time of nanocarriers for this reason, color chart for levothyroxine while prelabeling a material as biocompatible has been used in many papers, it provides rather limited information to specific situations and applications a rigorous reevaluation of carriers biocompatibility for each new indication in a given pathological context likely, even in given patients cohorts, does not seem to be an excessive precaution in a postvioxx era for instance, titanium and titanium oxide coated implants has long been considered a highly inert, biocompatible material in color chart for levothyroxine bone prosthetics and dental implants, yet, kidney stones and caffeine sub nm nanoparticle forms of titanium oxide have highly active surface sites capable of catalyzing the formation of oxygen radicals, which can result in cell and tissue injury as such, the biocompatible label must not simply be given to titanium oxide nanoparticles, although this does not mean that there is no potential therapeutic use of this carrier however, there are settings in which its use is unadvisable, color chart for levothyroxine eg drug delivery into the pulmonary tissue which is prone to oxidative stress, due to high level of oxygen and reactive oxygen species produced by leukocytes and pulmonary endothelial cells on the other hand, some materials that have been previously labeled as non biocompatible may be revisited for use in nanocarriers, having to undergo degradation and excretion pathways unsuitable for larger carriers however, the primary requirement of nanocarrier compatibility is the ability to break color chart for levothyroxine down into nontoxic, plasma soluble components that can be eliminated via renal filtration or hepatic bile excretion for this reason, most carriers under development are composed of either degradable polymers, or possess mws lower than kda material selection by application imaging the lungs are a classically difficult organ for imaging due to lowsignal to noise ratio, multiple airtissue interfaces, and physiological motion such as cardiac and ventilating, of all imaging technologies available, the color chart for levothyroxine most commonly used technology for pulmonary imaging except routine chest xrays is computer tomography ct yet, it is still difficult to properly identify many pulmonary disease pathologies the use of targeted contrast agents may allow for the improved identification of these disease states in the case of ct, high density materials eg metals, crystalline polymers and high atomic weights are ideal candidates indeed, early studies using iodinated nanoparticles have been used for the color chart for levothyroxine imaging of lymph nodes in spite of its utility, ct resolution is limited to mm nmr, a higher resolution imaging technology, has been classically limited to the use of pulmonary imaging yet, current advancement in imaging algorithms and contrast targeting may improve nmr imaging of diseases such as acute pulmonary embolism and chronic infiltrative disease gene delivery initial success with gene delivery to the pulmonary tissue was obtained using adenoviral carriers indeed, heat color chart for levothyroxine shock protein hsp, nitric oxide synthase nos, and interleukin have all been adenovirally transfected into pulmonary endothelial cells, for the attenuation of ischemiareperfusion injury however, systemic adenoviral transfection is greatly limited due to an associated cytokine release and immune response in this context, enhancement of local transfection by retargeting viral gene delivery is a highly promising strategy, to pulmonary endothelium eg using ace antibody coupled to viral particles nonviral gene delivery poses an interesting color chart for levothyroxine set of material requirements, allowing for the effective delivery of dna into a target cell and the subsequent trafficking of the dna into the nucleus these carriers must be able to load high levels of dna into a single particle, and be able to target endothelial cells with the subsequent internalization and endosomal escape mechanism to allow for the dna to reach the nucleus most of these processes have focused on charge coupling color chart for levothyroxine to condense dna into a nanoscale aggregate the most common of these have been the use of cationic polyplexes, for example, polycationic electrolytes such as polyethylenimine pei and polyllysine pll have been used to condense the negatively charged dna pei of small chain length has been shown to reverse charge at endosomal ph and release d pulmonary vascular delivery of dna was possible with cationic surface charge alone, yet lung specificity can be color chart for levothyroxine greatly improved upon application of immuno targeting toward endothelial markers such as thrombomodulin, pecam or ace while highly cationic vectors also display a significant inflammatory response, this immune reaction can be greatly attenuated without a reduction in degree of transfection by lowering the overall carrier charge delivery of therapeutic enzymes examples of enzymatic therapies amenable pulmonary targeting using nanocarriers, include delivery of i lysosomal enzymes enzyme replacement therapy, ert, for the treatment of color chart for levothyroxine nonneuronal lysosomal storage diseases that affect pulmonary endothelium eg niemannpick disease, ii antithrombotic enzymes eg plasminogen activators for the dissolution of blood clots formed or lodged in the pulmonary vessels, and iii antioxidant enzymes, for the containment of vascular oxidative stress in the lungs, which is a highly morbid pathological condition targeting can be achieved by the chemical coupling of enzymes with affinity carriers, producing nanoscale protein conjugates for example, catalase conjugated with antibodies color chart for levothyroxine to endothelial antigens ace, pecam or icam, accumulates in the lungs of laboratory animals after iv injection and protects against oxidative injury in the models of human diseases such as lung transplantation ischemiareperfusion injury and acute edematous vascular oxidant stress on the other hand, targeting of plasminogen activators to endothelial cell adhesion molecules boosts antithrombotic capacity of the pulmonary vasculature targeting enzymes clearly illustrates the importance of proper subcellular addressing of drugs, namely, color chart for levothyroxine luminal surface for fibrinolytics, nondegrading intracellular compartments for antioxidants, and lysosomes for ert loading into nanocarriers might optimize some of the enzyme therapies for example, antioxidant catalase loaded into hpermeable, proteaseresistant polymer nanocarriers might retain its protective activity even within lysosomes yet, loading into highly amphiphilic carriers ie micelle form, vesicle form may cause undue folding and inactivation of enzyme optimally, the carrier material would stabilize protein in an anhydrous state to avoid color chart for levothyroxine inactivation this can theoretically be achieved via the hydrophobic sequestering of solid protein into a polymer core small molecule drugs liposomes have already seen fda approval for the delivery of small molecule delivery doxorubicin, an amphiphilic anticancer agent, has a great therapeutic potential, yet it is complicated by questionable low solubility, high toxicity and poor circulation by loading in aggregates in the liposome core, it has been able to target tumors via the color chart for levothyroxine previously mentioned epr effect with greater doses than previously possible as illustrated by this example, the key advantage is the ability to enhance serum solubility of the small molecule drugs and achieve longer release profiles in pulmonary settings, this has been used for the enhancement of free radical scavengers, enzyme inhibitors, and in anticancer treatments types of nanocarriers nanocarriers utilizing natural biomaterials or structures eg liposomes consisting of natural phospholipids found in cellular plasma color chart for levothyroxine membranes were the first to be explored for drug delivery since then, designs have included solid nanoparticles, double emulsion nanoparticles, polymeric micelles, polymersomes and wormlike micelles synthetic materials, especially polymeric materials, offer great freedom in that they can be designed to enhance circulation, reduce immunogenicity, provide environmentally responsive elements and possess biologically derived properties, also known as biomimetic properties, such as adhesion response elements and receptor ligands all these carriers are amenable for color chart for levothyroxine pulmonary delivery for a detailed review of the formation mechanisms and technical aspects of nanocarrier formulation, please refer to the reviews at refs mechanisms of drug loading the main mechanisms for loading drugs into nanoparticles include surface absorption, aqueous inclusion, solidphase immobilization, and complexation aggregates fig surface absorption occurs via either hydrophobic interactions between the particle surface and hydrophobic interactions eg tryptophan, tyrosine, phenylalanine for proteins or electric charge interactions this method is color chart for levothyroxine not effective for coating stealth nanocarriers, due to the nature of stealth mechanism, but can be used for the coupling of targeting moieties see below and therapeutic agents to nonstealth nanocarriers in the context of pulmonary vascular targeting via iv route, stealth characteristics are not critically important due to the option of first pass delivery surface absorption aqueous inclusion sol idphase immobilization fig methods of nanocarriers loading with therapeutic agents in the nanoscale color chart for levothyroxine range, surface absorption offers the greatest drugparticle loading, and most likely accounts for a fraction of loading in all reported nanocarriers, including those loaded by the alternative approaches however, isolation of a cargo en route to target is most effective with inclusion mechanisms of loading currently, aqueous inclusion methods are most extensively explored for the loading of hydrophilic agents into polymer nanocarriers therapeutic effect may be achieved via either release of cargoes or color chart for levothyroxine diffusion of their substrates via polymer solidphase immobilization is mostly used for loading of hydrophobic solutes, yet some proteins may also be amendable to this mechanism complexation relies upon the interaction of drug and polymer for particle formation, which permits formation of sizecontroled loaded vehicles however, homogeneity of nanocarriers and drug release from these carriers are difficult to control carrier materials eg polymers arc shown in a light grey color, drug loads are shown color chart for levothyroxine as dark spheres mechanism indeed, latex polystyrene beads used as model prototype non stealth nanocarriers nm diameter coated with surfaceabsorbed antiicam, but not control igg, showed very high pulmonary uptake after iv injection in mice surface absorption does not protect a cargo from inactivation en route or in aggressive intracellular compartments eg lysosomes, nor does it limit systemic side effects of circulating drugs however, it may prolong circulation time, alter tissue targeting, and color chart for levothyroxine subsequently alter subcellular addressing of the drugs it is the easiest method for nanocarrier loading with large mw drugs eg therapeutic proteins latex beads surfacc coated with antiicam and a therapeutic enzyme catalase provide a useful tool to the study of binding, internalization and degradation pathways for nanocarriers targeted to endothelial cells, the main cellular target in the pulmonary vasculature com pie xat ion liposomes can be loaded by aqueous core inclusion and color chart for levothyroxine by hydrophobic association within the lipid bilayer liposomes provide a large internal aqueous cargo compartment separated from milieu by the bilayer membrane since the cargo remains in an aqueous environment, its molecular mobility and enzymatic activity are not compromised liposomes afford effective loading and delivery of small hydrophobic agents eg doxorubicin in doxil� in polymer nanocarriers, a polymer layer can provide even more protective barrier via either selfassembly mechanisms employed in synthesis of color chart for levothyroxine polymersomes, double emulsion formation mechanism, or in nanoscale hydrogel synthesis techniques solidphase immobilization is an alternative strategy in which crystallized or lyophilized protein and small mw drugs are loaded as a suspension within the solid core of an organic, hydrophobic nanoparticle high loadings of certain hydrophobic drugs have been reported for instance, irinotecan, an anticancer therapeutic, was capable of being loaded at wt into nm nanoparticles, composed of diblock pegpolylacticcoglycolic acid this method may color chart for levothyroxine provide an added benefit in the delivery of bioactive drugs the organic environment restricts mobility for some therapeutic protein resistant to unfolding, that may paradoxically yet simultaneously reduce activity and extend functional use moreover, since the protein is not in a soluble state, loading is not constrained by aqueous solubility limits and the entire particle core could support inclusion hence, this mechanism may provide highly effective loading the fourth mechanism for loading employs color chart for levothyroxine the complexation of a drug with the carrier material common approaches to complexation include interionic associating mechanisms, the biotinstreptavidin crosslinking system, or covalent bonding for instance, regular polymeric micelles of polyethylene glycolbpolyaspartic acid were formed in the presence of the positively charged lysozyme complexes can also take the form of polyplexes eg polyethylimide pei and dna, or in a single polymer chain coupling multiple proteins, this latter form has been popularized by the color chart for levothyroxine use of hydrophilic polymers such as polyn hydroxypropylmethacrylamide hpma, which uses amide linkages to covalently attach proteins and small molecules onto the polymer backbone this also includes the polymer prodrugs that utilize degradable bonds to limitcontrol the therapeutic release rate yet, even hydrophobic associations, disulfide linkages, streptavidinbiotin or antibodyantigen pairs can be used to form drugpolymer complexes by control ing the extent of modification of a therapeutic cargo and the affinity carrier by color chart for levothyroxine crosslinking agents and feed conditions, the complexation mechanism can result in nanosized aggregates with a relatively high degree of drug inclusion however, these conjugates polyplexes are characterized by significant heterogeneity, both in molecular composition and in size due to the nature of the conjugation mechanism, release from these systems is typically poor and mainly controled by degradation of the components thus, in the case of enzyme therapies see sec , conjugates of this type, function color chart for levothyroxine effectively, typically only if enzymes substrates are small and diffusible enough to be accessible within the aggregate core, such as ho in the case of catalase delivery drug release mechanisms nanocarriers can provide main mechanisms of release for its drug cargo fig the most commonly considered release profile is that of continuous release for a more detailed review, see dziubla and lowman under this regimen, the drug slowly diffuses out of carrier particles color chart for levothyroxine over time, allowing for sustained high local concentrations of the drug however, current nanocarrier formulations typically release of the total drug loaded within the first hrs this does not permit longterm therapy, but is rather suitable for therapies that require a burst release eg gene and cancer treatment ideally, the cargo remains isolated from the systemic circulation and tissues until the intended target cells are reached and the release is triggered this pattern color chart for levothyroxine allows for both the minimization of deleterious side effects, loss of activity, and � ib � � � ir aj � k a ro = e � � a s a e n � product substrate � time fig modes of drug release a controled release allows for a therapeutic level of drug to be maintained for the greatest amount of time b delayed burst release is ideal for gene and cancer therapy, color chart for levothyroxine where immediate, local high concentrations are desired c sequestered enzyme delivery allows for a continuous activity of enzyme, even when the nanocarriers reside in compartments typically hostile to protein activity eg lysosomes in this scenario, carrier must be permeable for enzyme substrates orand products the minimization of the necessary effective dose finally, the nanocarrier may also be designed not to release the drug at all for most instances, this prevents pharmacological activity however, in color chart for levothyroxine the case of enzyme delivery where the substrate is diffusible eg hydrogen peroxide, no, oxygen, glucose, nad across the carrier wall, therapeutic activity may be achievable this is especially suitable if the final targeting destination is lysosomes, which is likely to degrade the enzyme, thereby resulting in a loss of activity nanocarriers for active targeting in order to achieve active targeting, affinity ligands are coupled to the surface of nanocarriers affinity and specificity color chart for levothyroxine of these ligands govern targeting yet, targeting of multivalent antibodycarrying nanoparticles differs from that of individual maternal antibodies in several important aspects firstly, high affinity of such complexes results in highly significant, in some instances, order of magnitude, enhancement of the pulmonary targeting of iv injected nanocarriers vs maternal antibodies, secondly, multivalent nanocarriers crosslink endothelial determinants, thus inducing highly effective endocytotic uptake, even though maternal antibodies are non internalizable surface absorption, protein conjugation chemistries or biotinstreptavidin crosslinking can be utilized for the coupling of targeting entities, mainly monoclonal antibodies and their fragments to nanocarriers yet, the most important consideration is that of antibody presentation onto the carrier surface for example, the antibodies attached covalently directly to the phospholipid head group of peg ylated liposomes, providing rather poor targeting due to the fact that extended peg chains masked antibodies this shortcoming can be solved by coupling the color chart for levothyroxine antibodies to the distal end of peg chains in fact, targeting of such stealth immunoliposomes exceeds that of standard liposomes, due to suppression of clearance mechanisms, and target group mobility and accessibility one of the most commonly employed conjugation strategies is that of maleimide sulfhydryl chemistry maleimide group is more hydrolytically stable than other protein conjugation means, such as the amine directed nhydroxysuccinate esters maleimide reacts with free thiol to create a nonreducible sulfide color chart for levothyroxine linkage since most proteins do not contain a free thiol group, competition between the drug eg therapeutic protein and the targeting moiety for available binding sites can be eliminated maleimide can be included onto the distal end of a peg group in a peg diblock copolymer, upon nanoparticle synthesis, the peg chain will extend out into the hydrophilic solution, ensuring the exposure of the maleimide group for subsequent conjugation this allows for the color chart for levothyroxine separation of drug loading and nanocarrier formation from the conjugation of the targeting group however, while maleimide hydrolysis is relatively slow at typical nanoparticle synthesis temperatures, it may still occur to a significant extent, thereby limiting the overall capacity for target group addition conclusion safety issues, limitations and perspectives results of in vitro and animal studies accumulated within the last decade strongly suggest that nanocarriers, especially those utilizing active targeting principles, will eventually color chart for levothyroxine provide a versatile and powerful technology platform for optimized drug delivery to the pulmonary vasculature extended surface of the pulmonary endothelium represents arguably the best target for drug delivery in the body, hence higher chances for sufficiently specific and effective drug delivery on the other hand, in contrast with drug delivery to tumors, in which local toxic side effects can be considered as secondary benefits, safety of drug delivery to pulmonary vasculature is color chart for levothyroxine of greater concern thus, acute and delayed effects of targeting and endothelial uptake of nanocarriers on health and functions of the lung must be tested extremely rigorously for example, pulmonary circulation is sensitive to subtle proinflammatory changes, often leading to edema and proliferation of subendothelial and interstitial components, pulmonary fibrosis and hypertension in this context, an important question is how will nanoscale structures residing in a given pulmonary compartment, ie vascular lumen, lysosomes, be tolerated?