cancer chemother pharmacol brigger i, morizet j, laudani l, aubert g, appel m, velasco v, terrierlacombe mj, desmaele d, dangelo j, couvreur p and vassal g negative preclinical results with stealth� nanosphereencapsulated doxorubicin in an orthotropic murine brain tumor model j control rel walz cm, ringe � and sabel ba nanoparticles in brain tumor therapy controlled release society th annual meeting proc glasgow gelperina se, khalansky as, skidan in, smirnova zs, bobruskin al, severin se, turowski b, zanella fe and kreuter j toxicological studies of doxorubicin bound to polysorbate coated polybutyl cyanoacrylate nanoparticles in healthy rats and rats with intracranial glioblastoma toxicol lett diehl kh, hull r, morton d, pfister r, rabemampianina y, smith d, vidal jm and van de vorstenbosch � a good practice guide to the strattera heart problems administration of substances and removal of blood, including routes and volumes} appl toxicol kreuter j, shamenko v d, petro v v, ramge p, cychu tek k, kochbrand t � and alya u td in r apolipoproteinmediated transport of nanoparticlebound drugs across the bloodbrain barrier } drug targ kreuter j, ramge p, petrov v, hamm s, gelperina se, engelhardt b, alyautdin r, von briesen h and begley dj direct evidence that polysorbate coated polybutyl cyanoacrylate nanoparticles deliver drugs to the cns via specific mechanisms requiring prior binding of drugs to the nanoparticles pharm res olivier jc, fenart l, chauvet r, pariat c, cecchelli r and couet w indirect evidence that drug brain targeting using polysorbate coated polybutylcyanoacrylate nanoparticles is related to toxicity pharm res san w, xie c, wand h and strattera heart problems hu y specific role of polysorbate coating on the targeting of nanoparticles to the brain biomater borchard g, audus kl, shi f and kreuter j uptake of surfactantcoated polymethyl methacrylatenanoparticles by bovine brain microvessel endothelial cell monolayers int j pharm ramge p, unger re, oltrogge jb, zenker d, begley d, kreuter j and von briesen h polysorbate coating enhances uptake of polybutylcyanoacrylate pbca nanoparticles by human, bovine and murine primary brain capillary endothelial cells eur j neurosci luck m plasmaproteinadsorption als moglicher schliisselfaktor fur eine kontrol lierte arzneistoffapplikation mit partikularen tragern phd thesis, freie universitat berlin, pp gessner a, olbrich c, schroder w, kayser � and muller rh the role of plasma proteins in brain targeting species dependent protein adsorption patterns on brain specific lipid drug conjugate ldc nanoparticles int} strattera heart problems pharm gutman rl, peacock g and lu dr targeted drug delivery for brain cancer treatment i control rel this page is intentionally left blank nanoparticles for targeting lymphatics william phillips introduction nanoparticles have received increasing attention as lymph node drug delivery agents the desire to develop of new methods of lymph node drug delivery stems from the recent awareness of the importance of lymph nodes in cancer prognosis, their importance for vaccine immune stimulation and the realization that the lymph nodes harbor human immunodeficiency virus hiv as well as other infectious diseases new methods of delivering drugs and antigens to lymph nodes are currently under investigation the lymphatic system consists of a network of lymphatic vessels and lymph nodes that serve as a secondary vascular system to return fluid that strattera heart problems has leaked from the blood vessels in the extremities and other organs back to the vasculature the lymphatic system also moves substantial volumes of fluid from the peritoneal cavity and pleural cavity back into the blood circulation in addition to this critical role in the regulation of tissue fluid balance, the lymphatic system also plays an important role in intestinal absorption of fats and in the maintenance of an effective immune defense lymphatic vessels serve as a major transport route for the dissemination of antigens, microorganisms and tumor cells as well as interstitial molecules that have gained entry to the interstitial space these lymphatic vessels are also traversed by immune cells such as dendritic cells, macrophages and as their name reveals, lymphocytes as a part of the lymphatic system that strattera heart problems recycles fluid from the interstitial spaces and the bodys cavity back to the arteriovenous vascular system, the lymph nodes are ideally positioned to serve as surveillance organs to monitor microbial invasion and to defend the body against these invading microorganisms the importance of the lymphatic system for the development of an effective immune response has led one author to describe the lymphatic vessels and lymph nodes as the bodys information superhighway the lymphatic vessels lymphatic vessels are composed of thin, endothelial cell lined lymphatic capillaries located in spaces between cells and tissues these lymphatic vessels are distributed throughout the body with the exception of cartilage, optic cornea and lens, and the central nervous system lymph fluid originating from the interstitial spaces between tissue cells and from within the bodys cavities strattera heart problems moves into lymphatic capillaries through lymph nodes and back into the blood circulation the overlapping nature of the lymphatic endothelial cells and loose attachment of intercellular junctions allows for the absorption of interstitial fluid into the lymphatic capillaries this mechanism also explains how macromolecules, infectious organisms and subcutaneously injected nanoparticles gain entrance into the lymphatic circulation these lymphatic capillaries carry lymph fluid into collecting lymphatic vessels and channels which slowly flow in the afferent lymphatic vessels into the lymph node after passing through the lymph node, the lymph fluid then exits the lymph node through the efferent lymphatic vessels the lymph fluid flows slower and under much lower pressure than blood in the artery and veins its flow rate can be greatly accelerated by body movement the efferent vessels combine strattera heart problems to form lymphatic vessels that branch either to the next set of lymph nodes or to larger lymphatic trunks as illustrated in fig in this way, lymph fluid of different organs and the bodys extremities in addition to body cavities is collected by large lymphatic trunks which feed into one of the two lymphatic ducts the thoracic duct and right lymphatic duct from these ducts, the lymph fluid then returns to the blood stream through veins in the neck region ie internal jugular and subclavian veins the lymphatic system also returns fluid from the bodys cavities back to the blood stream this includes fluid from the pleural space surrounding the lungs, the peritoneal space surrounding the intestines, the articular cavity of the joints, and the central spinal fluid surrounding the strattera heart problems brain the rate of movement of fluid from these body cavities varies between different cavities however, the volume of fluid moving through the lymphatic vessels coming from the bodys cavities is substantial studies in conscious sheep with tracers have found that clearance of fluid from the peritoneal cavity averaged mlhr per kg of body weight, which was more than twice as high as when the sheep were anesthetized this rate of diaphragm thoracic duct pleural cavity peritoneal cavity mediastinal lymph n fig the lymphatic system includes lymphatic vessels draining from the extremities and head and neck region as well as the fluid moving from the cavities of the body it is estimated that lymph nodes that filter drainage from the lymph vessels are in the average human body fluid movement strattera heart problems in a kg human would be more than ml per hr or nearly liters per day lymph nodes the lymphatic system is also interspersed with lymph nodes placed at intervals along this lymphatic vessel network as shown in fig lymph nodes are encapsulated dense masses of lymphoreticular tissue situated along the pathway of drainage of the lymph there are estimated to be lymph nodes in the human fig this diagram illustrate the structure of the lymph node efferent lymphatic vessels delivery lymph fluid to the lymph node and afferent lymphatic vessels take the lymphatic fluid from the lymph node each lymph node is supplied by an artery and a vein lymphatic fluid is filtered through the sinuses of the lymph nodes that are lined with macrophages to phagocytized foreign particulate strattera heart problems agents lymph nodes also contain cortical, paracortical and medullary regions which contain different immune system cells body the outer capsule of the lymph node is composed of dense collagenous fibers and smooth muscle fibers the interior of the lymph nodes is organized into different functional zones populated by different sorts of lymphocytes, as well as accessory and stromal cells, these lymph node zones as shown in fig are the cortex, which includes the lymphoid follicles with their germinal centers this is the bcell area of the lymph node which is associated with humoral immune mechanisms the paracortex, which is the densely cellular area that extends between the lymphoid follicles this is the tcell area which is the main site of cellular immunity the sinuses, a complex system of channels where strattera heart problems macrophages belonging to the mononuclear phagocytic system mps reside the medulla, rich in sinuses where the main site of plasma cell proliferation and production of antibodies the medullary cords are located the three main functions of the lymph nodes are the formation of lymphocytes known as lymphopoiesis, lymph filtration, and antigen processing, in terms of lymph fluid filtration, the lymph nodes provide two main types of filtration a simple mechanical type through the reticular meshwork which traverses the sinuses and a phagocytic filtration by macrophages and reticular cells, which is aided by the slow passage of the lymph fluid through the channels of the sinuses one of the major functions of the lymph nodes is to help defend the body against diseases by filtering bacteria and viruses from the lymph strattera heart problems fluid, and to support the activities of the lymphocytes, which furnish resistance to specific diseasecausing agents however, in abnormal conditions, as in the case of cancer and some infections, it is well known that lymph nodes can act as holding reservoirs from where tumor cells, bacteria or viruses can spread to other organs and regions of the body, for example, in the case of cancer, disseminating tumor cells can take root in lymph nodes and form residual metastatic tumors that are difficult to detect and treat in anthrax infection, endospores from bacillus anthracis that gain entrance into the body are phagocytozed by macrophages and carried to regional lymph nodes, where the endospores germinate within the macrophages and become vegetative bacteria the vegetative bacteria are then released from the lymph nodes, strattera heart problems multiply in the lymphatic system and invade the blood stream causing massive septicemia adequate therapy of lymph nodes affected by disease runs a considerable risk of side effects for example, current methods of treating or preventing metastasis in lymph nodes are characterized by serious drawbacks including radical surgical excision of lymph nodes is a burdensome procedure, and the risk of postoperative lymph node cancer recurrence is often high external radiation therapy can damage sensitive organs unnecessarily, while delivering a small percentage of radiation to the targeted lymph nodes and intravenous chemotherapy to patients with advanced disease is associated with significant toxicity, even though adequate therapeutic concentrations in the targeted lymph nodes are rarely achieved for these reasons, nanoparticle targeted drug carriers offer a potential solution to the challenge of adequate strattera heart problems lymph node therapy potential for nanoparticles for drug delivery to lymphatics nanoparticles are ideal structures fluoxetine and lipozene for delivering therapeutic agents to the lymph nodes their ideal features are based on their size, which prevents their direct absorption into the blood, the large amount of drugs and other therapeutic agents that nanoparticles can carry, and their ability to be retained in the lymph nodes in comparison, small molecules will be directly absorbed into the blood at the site of injection and will not move into the lymphatics although larger molecules such as dextran and albumin will move into the lymphatics, they rapidly pass through the draining lymph nodes and are not well retained in individual lymph nodes although nanoparticles are too large to be directly absorbed into the blood stream, they strattera heart problems are small enough to enter the lymph vessels and lymph nodes, following either subcutaneous injection, intradermal injection, intramuscular injection or injection directly into organs or tumors and injection into the bodys cavities following subcutaneous injection or injection directly into the tissue of a body organ, it appears that a certain portion of nanoparticles are taken up locally and retained for a prolonged time, while another portion of the nanoparticles are cleared from this local site and move into the lymphatic vessels, where they can be trapped in lymph nodes or else move completely through the lymphatic system and return to the blood at the thoracic duct nanoparticles that are injected directly into the bodys cavities appear to have much less local retention at the site of injection, as they disperse strattera heart problems freely throughout the whole cavity and then drain almost completely into lymphatic vessels, where they can be trapped in lymph nodes or return to the blood circulation these intracavitary sites whose fluid is cleared through the lymphatics include the pleural space surrounding the lungs, the peritoneal space surrounding the intestines, the articular cavity of the joints, and the central spinal fluid surrounding the brain if the particular particle that is injected into the intracavitary space is only minimally retained in all of the draining lymph nodes, then the ultimate fate of the nanoparticles injected into a cavity can appear very similar to the same distribution that it would have had, following intravenous administration this similar distribution has been demonstrated with radiolabeled nanoparticles that are injected into the peritoneal space by strattera heart problems hrs following intraperitoneal administration, these nanoparticles have a high liver and spleen uptake and minimal retention in the peritoneum, as if they had been injected intravenously this is the normal distribution of neutral and anionic liposomes unless there is special modification of the liposomes to increase their uptake in the lymph nodes considering the importance of the lymphatics in relationship to many disease processes, the number of studies investigating drug delivery or targeting of other therapeutic agents to the lymphatics has been relatively modest the recent development of an increasing number of different types of nanoparticles that can facilitate the lymphatic transport of therapeutic agents provides many new approaches to lymphatic drug delivery and the basic investigation of lymphatic transport importance of lymph nodes for disease spread and potential applications strattera heart problems of lymph node drug delivery cancer the majority of solid cancers spread primarily by lymph node dissemination the status of the lymph node in regard to cancer metastasis is a major determinant of the patients prognosis this includes very small metastasis detected by histopathologic analysis of removed lymph nodes, as well as by magnetic resonance imaging mri imaging using magnetic nanoparticle mri contrast agents accurate lymph node staging is the most important factor that determines the appropriate care of the patient therapeutic interventions that treat metastatic cancer in lymph nodes with either surgery or local radiation therapy have been shown to improve patient survival hiv primary infection with human immunodeficiency virus hiv is characterized by an early viremia, followed by a specific hiv immune response and a dramatic decline of strattera heart problems virus in the plasma long after the hiv virus can be found in the blood, hiv can be found in high levels in mononuclear cells located in lymph nodes viral replication in these lymph nodes has been reported to be fold higher than in the peripheral blood mononuclear cells drug delivery to these lymph node mononuclear cells is difficult with standard oral or intravenous drug administration although highly active antiretroviral therapy haart reduces plasma viral loads in hiv infected patients by , active virus can still be isolated from lymph nodes even after months of haart therapy filaria lymph nodes are an important part of the life cycle of several parasite organisms, including filaria adult worms are found in the lymphatic vessels and lymph nodes of infected patients these adult filaria strattera heart problems are responsible for the obstruction of lymphatic drainage that causes swelling of extremities that are distal to the infected lymph node the condition associated with very swollen limbs often found in patients with filarial disease has been termed elephantiasis ultrasound imaging can be used to visualize the adult worms by detecting the classic filaria dance sign which is associated with the adult worms this ultrasound imaging has demonstrated that the worms reside in nests located in the lymph nodes and lymphatic vessels the preferred site for adults worms in males is the intrascrotal juxtatesticular lymphatic vessels adult worms are also commonly found in the inguinal nodes and they have even been reported to be found in the mediastinal lymph nodes it is very difficult to eradicate the adult worms located strattera heart problems in the lymphatic system, although microfilaria that are released into the blood stream from adult worms are very responsive to antifilarial medications this difficulty in treatment may be due to the localization of adult worms within nests in the lymphatic system, where drug penetration is very poor frequently, eradication of adult worms is not possible and it commonly takes a very extended course of medical therapy to have any effect on the adult worms nanoparticle drug delivery has potential for drug delivery in filarial disease, particularly before the lymphatics have become totally obstructed many asymptomatic patients have been shown to carry adult worms in their lymph nodes thus, early diagnosis may be crucial for the treatment of filaria before adult worms are well established in the lymphatic vessels and nodes strattera heart problems anthrax new methods of treating anthrax have become of urgent interest, following the recent outbreak of terrorist caused infections and deaths in the united states as a result of terrorism following inhalation of the anthrax spores and their deposition in the lungs, the bacteria spread to the mediastinal lymph nodes where their local invasion and associated toxin production is the cause of death patients are frequently found to have a widened mediastinum due to the expansion of mediastinal lymph nodes with anthrax computed tomography of the chest has been performed on recent patients infected with inhalational anthrax mediastinal lymphadenopathy was present in of the patients in a recent case report of one patient, the anthrax bacillus was shown to be rapidly sterilized within the blood stream after initiation of antibiotic strattera heart problems therapy however, viable anthrax was still present in postmortem mediastinal lymph node specimens this case demonstrates the difficulty that drugs have in penetrating the mediastinal lymph nodes a potential use of nanoparticles could be for delivery of antianthrax drugs to the mediastinal lymph nodes for therapy or prevention of anthrax extension to the lymph nodes tuberculosis the tuberculosis infection is caused by mycobacteria which invade and grow chiefly in phagocytic cells tuberculosis is frequently found to spread from the lungs to lymph nodes, so that lymph node tuberculosis is the most comm on form of extrapulmonary tuberculosis in one study, of the tuberculosis lymph node involvement was located in the intrathoracic lymph nodes, while of the cervical lymph nodes were involved with tuberculosis and in the axillary lymph nodes the strattera heart problems development of methods to target drugs to these lymph nodes could greatly improve the therapy of tuberculosis and potentially decrease the amount of time that drug therapy is required currently, patients with tuberculosis are required to take medication for months one possible reason for this lengthy treatment is the difficulty in deliverying drugs into these tubercular lesions this requirement of lengthy drug treatment could also be responsible for the development of resistance to antituberculosis drugs, as the organisms are exposed to relatively low levels of drugs over a very prolonged time the development of resistance to antituberculosis therapy is a growing health problem and the number of tuberculosis cases has been increasing worldwide multidrugresistant tuberculosis presents an increasing threat to global tuberculosis control nanoparticles could be used to specifically carry strattera heart problems high levels of drugs to lymph nodes containing tuberculosis nanoparticles encapsulating antituberculosis drugs have already been developed as potential intravenous therapeutic agents for the treatment of tuberculosis importance of lymph node antigen delivery for development of an immune response the importance of the lymph nodes in the development of an immune reaction induced by vaccines is gradually becoming recognized experimental evidence suggests that the induction of immune reactivity depends on antigen reaching and being available in lymphoid organs in a dose and timedependent manner this concept has been termed the geographical concept of immune reactivity the delivery of antigen to a lymph node in a manner that resembles an actual microbial invasion may be one of the most important functions of a vaccine adjuvant the adjuvants are considered effective, if strattera heart problems they either enhance or prolong expression of antigen components to reactive t cells in lymph nodes antigenpresenting cells are thought to be of critical importance in transporting antigen from the periphery to local organized lymphoid tissue however, delivery of antigen to the lymph node by any means may be more important several studies have investigated the immune response following direct injection of antigen into lymph nodes instead of injecting peptidebased vaccines subcutaneously or intradermally, researchers injected these agents directly into the lymph nodes this intralymphatic injection enhanced immunogenicity by as much as times when compared with subcutaneous and intradermal vaccination intralymphatic administration induced cd t cell responses with strong cytotoxic activity and interferon ifngamma production that conferred longterm protection against viral infections and tumors this greatly increased response based on strattera heart problems direct delivery to the lymph node has also been reported with naked dna vaccines naked dna vaccines are usually administered either intramuscularly or intradermally when naked dna was injected directly into a peripheral lymph node, immunogenicity was enhanced by to fold, inducing strong and biologically relevant cd cytotoxic t lymphocyte responses nanoparticles can be used to greatly increase the delivery of an antigen to the lymph node for instance, animal experiments have shown that immunization by the intramuscular or the subcutaneous route with liposomeentrapped plasmid dna encoding the hepatitis � surface antigen leads to much greater humoral igg subclasses and cell mediated splenic ifngamma immune responses than with naked dna in other experiments with a liposome encapsulated plasmid dna encoding a model antigen ovalbumin, a cytotoxic t lymphocyte ctl response strattera heart problems was also observed these results could be explained by the ability of liposomes to protect their dna content from local nucleases and direct it to antigen presenting cells apcs in the lymph nodes draining the injected site in spite of this awareness of the importance of antigen delivery to lymph nodes, there have been very few studies in which the biodistribution of an injected vaccine antigen has been determined, following either subcutaneous, intradermal or intramuscular administration studies of antigen encapsulated within nanoparticles could easily be carried out using scintigraphic tracers and imaging scintigraphic imaging can provide quantitative information of the total dose and percentage of the antigen that reaches the lymph node it appears that the purpose of a vaccine adjuvant is to simulate as closely as possible the strattera heart problems delivery of a virus, that enters the body subcutaneously or through a body cavity, to the lymph node one reason that nanoparticles appear to be useful for vaccine delivery is because their processing resembles that of viruses viruses can be considered as naturally occurring nanoparticles, against which the human immune system has evolved a defense mechanism in this regard, it is remarkable that there have been very few studies investigating the distribution of nanosized viruses, following their administration subcutaneously or intracavitary in methods in which the first encounter with the immune system is likely to be in the lymph node these studies could easily be performed in experimental small animal imaging models, by labeling the viruses with a scintigraphic imaging agent and injecting them subcutaneously or into a body cavity strattera heart problems their distribution in the body could be followed by performing serial imaging studies there have been, however, several studies of viral sized radiolabeled colloidal particles being injected subcutaneously, in which assumptions were made about the likely distribution of viral particles in one of these studies, subcutaneously injected, viralsized particles were found to initially arrive in the blood and later in the lymph accumulation in lymph and blood increases for a prolonged time following subcutaneous administration the results of this study suggested the possibility that strategies could be developed to limit the spread of infectious agents by early aggressive local antiviral treatment nanoparticles also have the potential to be delivered to lymph nodes by means other than subcutaneous injection particles as large as um in diameter have been found to be strattera heart problems translocated from the nasal mucosa to lymph nodes following intranasal administration hrs after intranasal administration of relatively large um diameter fluorescent microspheres, significant fluorescence was visualized in the posterior cervical lymph nodes and in the mediastinal lymph nodes factors influencing nanoparticle delivery to lymph nodes nanoparticle size many factors appear to influence the fraction of the nanoparticles that are retained at the initial site of subcutaneous injection nanoparticle size appears to be one of the most important factors affecting the clearance of nanoparticles from the subcutaneous site of injection the larger the size of the nanoparticles that are injected subcutaneously, the greater the fraction of the nanoparticles that will be retained locally and the lesser that will enter the lymphatic vessels and have a chance to target the lymph nodes strattera heart problems much work has been performed evaluating the effect of particle size of liposomal subcutaneously injected nanoparticles on lymph node targeting liposomes are nanoparticles composed of naturally occurring phospholipids that form spontaneously in an aqueous environment much recent research has investigated the potential of liposomes as carriers of drugs and other therapeutic agents to lymph nodes when small neutral liposomes are injected subcutaneously, more than of the liposomes will be cleared from the injection site by hrs with only of the injected dose remaining at the site of injection liposomes larger than nm will have remaining at the injection site the dose of lipid administered does not appear to have an effect on the percentage of liposomes retained in the lymph node lymph node uptake did not appear to become saturated strattera heart problems over a large of lipid dose administered ranging from nmol lipid to , nmol of lipid factors that enhance clearance of liposomes from a local site of subcutaneous injection also appear to decrease liposome uptake in the lymph node for instance, larger liposomes are not cleared from the subcutaneous site of injection as readily as smaller liposomes however, they are better retained in the lymph node even though larger liposomes are less well cleared from the injection site, their total retention in the lymph node is similar to other liposomes due to their improved lymph node retention this improved lymph node retention by liposomes that are poorly cleared from the injection site results in liposome retention doses that are approximately equal to liposomes that have improved clearance from the local subcutaneous strattera heart problems injection site nanoparticle surf a ce several studies have been carried out to determine the ideal nanoparticle surface characteristics for the delivery of drugs to the draining lymph nodes following subcutaneous injection moghimi et al have performed studies of nm polystyrene nanospheres which have been coated with poloxamers, the effect of a variety of different polyoxamers with varying lengths of ethylene oxide eo units has been studied if the nanospheres are coated with polyoxamers with a large number of eo units per chain, the nanospheres will clear rapidly from the site of injection, but they will also escape removal by macrophages in the lymph nodes, so that lymph node uptake will be minimal if nanospheres are not coated with any polyoxamer surface, they will remain largely retained at their site strattera heart problems of subcutaneous injection and only a small percentage of the injected dose will accumulate in the lymph node the polystyrene nanospheres with the most effective delivery and retention in the draining lymph nodes have a polyoxamer coating of eo units per chain and a coating thickness of less than nm nanospheres of this type have both rapid clearance from the subcutaneous site of injection, as well as significant retention in the draining lymph nodes by hrs, these ideal nanospheres have less than located in the rat footpad and approximately retained in the primary lymph node and retained in the secondary node based on findings with the model particles, moghimi suggested that it should be possible to develop liposomes or other nanoparticles with ideal properties for lymph node delivery a suggestion strattera heart problems was made to test liposomes composed of mol of mw polyethylene glycol lipids surface modification of liposomes with polyethylene glycol peg did not appear to have a very large effect of lymph node uptake ousseren et al found that the amount of liposomes that cleared from the injection site was slightly greater with the pegcoated liposomes however, this improved clearance did not result in improved lymph node retention, because the fraction of pegliposomes retained by the lymph node is decreased the slightly improved clearance of pegcoated liposomes from the subcutaneous site of injection was also found by our research group effect of massage on lymphatic clearance of subcutaneously injected liposomes the rate of clearance of nanoparticles from a subcutaneous injection site can be greatly accelerated with local manual massage without strattera heart problems any mechanical stimulation, subcutaneously injected mm liposomes are usually trapped in the interstitial subcutaneous space for a prolonged time however, min of manual massage over the subcutaneous injection site can clear up to of the injected liposomes from the subcutaneous site into the blood via the lymphatic pathway investigators were able to use this effect to control the rate of drug delivery of the vasoconstrict ing hormone angiotensin ii encapsulated in a liposome they demonstrated that a physiological response to encapsulated drug average blood pressure increase can also be induced and modulated by massage macrophage phagocytosis it is generally accepted that nanoparticles are retained in the lymph node by macrophage phagocytosis several research findings using nanoparticle liposomes appear to support this contention for example, inclusion of phosphatidylserine ps in the strattera heart problems liposome lipid formulation moderately increased lymph node uptake ps is a strong signal for stimulating macrophage uptake because it is present on the outer surface of cells undergoing apoptosis instead of its usual location on the inner surface of the cell membrane the strong supporting evidence of the role of macrophages in lymph node uptake was provided by a study in which macrophages were temporarily depleted from lymph nodes, by prior administration of liposomes containing dichloromethy lene diphosphonate clodronate clodronate is toxic to macrophages and much previous work has been performed using clodronate to temporarily deplete macrophages in the liver, six days after injection of the clodronate liposomes, small and large sized liposomes were also injected subcutaneously there was a drastic reduction in the uptake of both large and small strattera heart problems liposomes in the lymph node this reduction in liposome uptake supports the hypothesis that macrophages play the most important role in nanoparticle uptake in lymph nodes fate of nanoparticles in lymph nodes only a few studies have looked at the fate of nanoparticles once they arrive at the lymph node, in one study, subcutaneously injected liposomes were found to have accumulated in the subcapsular sinus subsequently, these liposomes were dispersed throughout the lymph node either by permeation along the sinus or within cells involved in liposome uptake such as macrophages once they were in the macrophages, the liposomes were observed to be digested by lysosomes nanoparticle diagnostic imaging agents for determining cancer status of lymph nodes subcutaneous injection of iodinated nanoparticles for computed tomography imaging nanoparticles have been developed for strattera heart problems the delivery of image contrast agents to lymph nodes lessons learned in the development of these nanoparticles as lymph node contrast agents can be applied to lymph node drug delivery subcutaneously injected iodinated nanoparticles were found to target the lymphatics and have been investigated as computed tomography imaging ct contrast agents these nanoparticles were composed of ethyl ester of diatrizoioc acid, stabilized with tetronic with an average particle size of nm nanoparticle accumulation in the draining lymph node was found to consistently enhance the contrast by at least hounsfield units in rabbits a hounsfield unit is a description of relative attenuation of xrays in ct imaging in this system, water density attenuation is assigned and air density attenuation is � and compact bone attenuation is a contrast change of hounsfield strattera heart problems units is easily recognized visually on the image the contrast enhancement by the iodinated nanoparticles provided excellent detailed images of the intranodal lymph node architecture which would permit the diagnosis of cancer metastasis different size iodinated nanoparticles have been compared for lymph node targeting characteristics when a comparison was made between the lymph node contrast of smaller nm iodinated nanoparticles and larger nm particles, there was minimal difference in the total lymph node contrast eventually obtained with the iodinated nanoparticles however, the smaller nanoparticles were found to have somewhat faster kinetics for lymph node accumulation and they also clear more rapidly from the lymph node this iodinated contrast agent has been shown to aid in the discrimination of lymph nodes with cancer in this study, perilesional subcutaneous injections ml per strattera heart problems lesion of a wtvol iodinated nanoparticle suspension were made in pigs with cutaneous melanomas the average xray attenuation by the iodine and average iodine concentration in the lymph nodes with cancer was higher than in normal nodes the presence of cancer within the node did not block uptake of the iodinated nanoparticles, as total iodine uptake was higher in cancerous nodes with greater than cancer replacement p the lymph nodes with cancer were larger in size, but the uptake of the iodinated contrast agent in the lymph nodes was lower this suggests that the uptake in the region of the cancer was lower, but the normal areas became larger and compensated for the portion of the lymph node that contained cancer the architectural alterations in opacified cancerous nodes included strattera heart problems medullary lymph node filling defects, expansile cortical lesions, and disruption of corticomedullary junctions the authors of this study concluded that both quantitative and qualitative differences in iodinated nanoparticle enhancement are characteristics that are useful in distinguishing between normal and cancerous lymph nodes with ct imaging, following subcutaneous injection of iodinated nanoparticles in an interesting study, iodinated nanoparticles were administered into the thorax of dogs using bronchoscopy with this technique, a tube was inserted into the lung bronchi under visual guidance with the flexible scope the nanoparticles were injected in the bronchi of the right diaphragmatic lobe of the lung two days after this procedure, ct images were obtained that did not show any uptake in the tracheobronchial lymph nodes however, images that were obtained after week had excellent contrast enhancement strattera heart problems of the tracheobronchial lymph nodes this contrast enhancement remained fixed for weeks following administration the slow delivery and prolonged retention of nanoparticles in the tracheobronchial lymph nodes has interesting implications for drug delivery the uptake in the tracheobronchial lymph nodes appeared to be secondary to phagocytosis of nanoparticles by macrophages the lymph nodes were enlarged and the histologic specimens showed macrophage hyperplasia did the macrophages phagocytize the particles in the lungs and carry them to the lymph nodes or did the nanoparticles somehow get to the lymph nodes, where they became phagocytized subcutaneous and intraorgan injection of magnetic resonance mri contrast agents a limited amount of research has been performed, investigating subcutaneously injected gadolinium bound albumin, ms, for lymph node diagnosis in a study of normal as well as tumorbearing strattera heart problems hindlegs of rabbits, the subcutaneous administration of ms resulted in rapid delineation of popliteal, inguinal, iliac, and paraaortic lymph nodes tumor invasion into lymph nodes presented as magnetic resonance imaging mri signal voids in the areas infiltrated by tumor, whereas the surrounding residual lymphatic tissue showed enhancement identical to that of normal nodes in addition to providing a safe means of displaying the normal lymphatic system, d image reconstruction of the mri image was able to depict direct tumor invasion in lymph nodes direct injection of magnetic particles into the brain has also been shown to be a method for tracking local lymphatic drainage when small magnetic nanoparticles were injected into the brain of rats, up to of the particles were found to drain from the cns via perivascular, perineural strattera heart problems and primitive lymphatic drainage to the cervical lymph nodes central nervous system cns lymphatic drainage may occur via connections to the vasculature, but in animal models, up to occurs via perivascular, perineural and primitive lymphatic vessels to cervical lymph nodes the trafficking of the superparamagnetic iron particles from the cns in the rat could be visualized both by magnetic resonance imaging mri and histology these magnetic particles appear to provide a tool to rapidly assess drainage of virussized particles from the cns using mri intravenous injection of magnetic nanoparticles for mri imaging ultrasmall nanoparticles can target all of the bodys lymph nodes when injected intravenously these ultrasmall superparamagnetic iron oxide particles uspio, also known as ferumoxtran, and commercially as sinerem� in the netherlands laboratoire guerbet, aulnay sous bois, france, and strattera heart problems as combidex� in the us advanced magnetics, cambridge, ma, have been developed for improved lymph node metastasis detection these particles are composed of to nm iron oxide cores surrounded by a dextran coating after the dextran coating, these particles are nm in size these particles produce mri contrast by shortening the t weighted signal when injected intravenously, these small particles accumulate in the lymph node in a high enough concentration to cause significant mri contrast the percent injected dose that ends up in these lymph nodes has not been well studied in spite of lack of quantitation, the uptake in the lymph nodes is sufficient to result in effective lymph node contrast in all the lymph nodes of the body their halflife in circulation is approximately hrs these intravenously injected strattera heart problems nanoparticles were associated with a low incidence of adverse reactions the adverse events most frequently seen with uspio were dyspnea , chest pain , and rash these effects are most likely due to the known complement activation associated with intravenous administration of nanoparticles no serious adverse events were reported during the hr observation period there were no clinically significant effects on vital signs, physical examination, and laboratory results slow infusion of a relatively low dose avoids previously reported adverse reactions associated with uspio nodal accumulation of intravenously injected uspio is thought to occur, following movement of the uspio through permeable vascular endothelium in lymph node vessels of the postcapillary venules and the adjoining capillaries in one study, uspio were regularly observed at the periphery of the lymph nodes, but not in the strattera heart problems center of the lymph nodes isolated iron particles were observed extracellularly within lymph vessels in the first hr after injection and by hrs after injection, as small dots within macrophages numerous dense clusters appeared within the cells at later times ie and hrs after injection these results suggest that the contrast agent moves rapidly across the capillary wall to the lymph and is then taken up by macrophages in an initial evaluation of safety and effectiveness of ultrasmall superparamagnetic iron oxide particles, adults with suspected lymph node metastasis were evaluated with mr imaging before and hrs after an intravenous dose of uspio nanoparticles the sensitivity for metastatic lymph node diagnosis was found to be with a specificity of another study evaluated uspio for sensitivity and specificity for differentiating metastatic from strattera heart problems benign lymph nodes the study was carried out in patients with lung cancer each patient was evaluated for the homogeneity of the lymph node image and change in the post contrast mr signal all the patients underwent resection of the lymph nodes and histopathologic correlation was performed uspio was found to have a sensitivity of and a specificity of studies have also shown that uspio are effective in diagnosing metastasis in mesorectal lymph nodes uniform and central lowsignalintensity patterns in lymph nodes are features of nonmalignant nodes reactive nodes frequently show central low signal with tweighted imaging recently, a semiautomated technique was developed to detect lymph nodes with cancer, following injection of uspio using computer assisted quantitative analysis, accurate discrimination between metastatic and normal lymph nodes was achieved with a strattera heart problems sensitivity of and a specificity of nanoparticle diagnostic agents for localizing the sentinel lymph node in the last decade, cancer surgeons have become very interested in methods to definitively localize the sentinel lymph node the sentinel lymph node is the first lymph node that receives lymphatic drainage from the site of a primary tumor the sentinel node is much more likely to contain metastatic tumor cells than other lymph nodes in the same region it is believed that the initial draining lymph node ie sentinel node of a tumor may reflect the status of the tumors spread to the remaining lymphatic bed localization of the sentinel lymph node and its close histological assessment, following its removal from the body was initially developed as prognostic indicator in patients with malignant melanoma strattera heart problems if no cancer cells are found in the sentinel node on pathologic examination, the prognosis for the patient is greatly improved after many detailed studies validating the effectiveness of this approach for patient prognosis and as a method to guide future therapy of melanoma patients, this technique has begun to be applied in other cancers, particularly breast cancer total lymphadenectomy procedures are being replaced by intraoperative lymphatic mapping and sentinel lymph node biopsy this particular lymph node is now being studied in greater detail, since it is able to accurately identify the sentinel node close pathological examination of the sentinel node with reverse transcriptasepolymerase chain reaction rtpcr has shown that the traditional procedures of hematoxylin and eosin h&e staining and immunohistochemistry underestimate the true incidence of cancer micrometasta sis use strattera heart problems of rtpcr has been shown to be a more powerful predictor of disease relapse than traditional h&e staining and immunohistochemical methods the advent of the use of sentinel node localization studies has stimulated a general interest in lymph node therapy, including both the surgical removal of specific lymph nodes as well as lymph node drug delivery radiolabeled nanoparticles for sentinel lymph node identification nanoparticles have played a crucial role in helping to identify and localize the sentinel lymph node this is because many types of nanoparticles have significant retention in the first lymph node that they encounter as much as of the nanoparticles that move from the injected site can be retained in the first lymph node encountered, the retention of nanoparticles in the first lymph node is due to strattera heart problems phagocytosis of the nanoparticles by macrophages the total amount of retention in the sentinel node is higher than retention in the subsequent draining lymph nodes, because less of the initial dose reaches these secondary nodes this characteristic led to the introduction of radioactive technetiummsulfur colloid particles mtcsc particles as a second method to localize the sentinel lymph node in addition to blue dye which was also being used by surgeons, the use of mtcsc in addition to blue dye was a significant improvement over blue dye alone the blue dye was not well retained in the sentinel lymph node and it moved so rapidly that the surgeons frequently had difficulty in distinguishing the sentinel node from secondary lymph nodes this problem was solved by the additional use of mtcsc which strattera heart problems provided a better mark of the sentinel node although the blue dye provides a desired visual guide for the surgeon, the mtcsc provided verification that the correct lymph node had been biopsied as the mtcsc could be imaged and also localized in the operating room prior to and during the surgery, it frequently led to a smaller operative incision and a decrease in the time required to find the sentinel node the use of radiolabeled nanocolloids, in addition to blue dye has been shown to be complementary techniques that are best used simultaneously studies to localize the sentinel lymph node in malignant melanoma and breast cancer are now considered the standard of care in patient management investigations are now being conducted to research the feasibility of using this same methodology strattera heart problems in many other types of cancer including colon, stomach, head and neck, prostate, rectal, lung, uterine, vulvar, and penile cancer mtccolloidal nanoparticles for sentinel node identification the most common colloidal particle used in the united states is technetiumm sulfur colloid mtcsc mtc is readily available, inexpensive and has ideal imaging and dosimetry characteristics its energy of kev is high enough for emitted photons to escape the body without absorption of overlying body tissues, but low enough to be readily collimated by lead and absorbed by sodium iodide scintillation crystal standard sc particles range in size from nm to nm and they are clinically approved for use as liver imaging agents in this application, the particles are injected intravenously, after which they are rapidly removed by macrophages of the liver, spleen strattera heart problems and bone marrow mtcsc makes a physiologic image of the liver and prior to the advent of ct scans, it was commonly used to assess the liver for tumors following the advent of ct scans, it has been used to assess the physiology of the liver due to the fact that diseases that damage the liver for any reason, such as alcoholic liver disease or infectious hepatitis, also decrease the uptake of nanoparticles by the macrophages the are located in the liver, and shift the liver uptake to the spleen and the bone marrow this effect provides a physiologic indicator of the health of the liver mtcsc has been the nanoparticle used for lymph node identification in the united states, because these particles were already widely available and approved strattera heart problems for clinical use as liver and spleen imaging agents in the united states, no agent has been specifically approved for lymph node detection these mtcsc particles range in size from nm to nm however, these particles are not ideal agents for the detection of the sentinel lymph node, due to the retention of the majority of the injected dose at the peritumoral site of the injection studies in animals have demonstrated that of the injected dose id is cleared from the site of injection within min after injection with this low clearance, of the injected dose accumulates in the sentinel lymph node at min the intensity of the mtc activity that is retained at the site of injection frequently makes it hard to locate the sentinel lymph node, either by strattera heart problems imaging or by the use of a handheld detector probe used in surgery as a result of this problem of retention at the injection site, mtcsc particles have been filtered through a nm filter, so that only particles smaller than nm would be administered these filtered mtcsc nanoparticles have greater movement from the injection site, although there is still a debate as to whether filtered mtcsc is better than standard mtcsc for sentinel node identification in europe, several other colloidal nanoparticles, mtcnanocolloid and mtc rhenium colloid, are available for use as sentinel node detection agents mtc rhenium colloid has an average particle size of less than nm and filtration is not required this mtcrhenium colloid has been shown to be highly effective for the identification of the sentinel lymph node strattera heart problems several other techniques have been investigated that use other nanoparticle based systems to enhance the ability of the surgeon to detect the sentinel node one investigated technique has utilized liposomes containing blue dye to localize the sentinel lymph node hirnle et al encapsulated patent blue dye within liposomes for potential use in localizing the sentinel lymph node during surgery when this technique was studied following injection of the blue liposomes into the lymphatic vessels, the lymph nodes were stained blue most notably, retroperitoneal lymph nodes in rabbits remained dark blue up to days after hindlimb endolymphatic instillation of liposomal patent blue dye this group has also investigated blue liposome for sentinel node detection in the pig the blue liposomes were found to provide greater intensity blue staining which lasted for strattera heart problems a longer duration than free unencapsulated blue dye this group later performed a study in humans, in which blue liposomes were injected directly into the lymphatic vessels of the foot of a patient prior to retroperitoneal staginglymphadenectomy the lymph nodes were well stained with blue dye and were readily visualized at the time of the surgery performed hrs following the intralymphatic injection of the blue liposomes plut et al have also developed a liposome formulation containing blue dye that can be radiolabeled with mtc the use of the liposome nanoparticle to provide a visual identification and the tracking of the liposomes through the lymphatic channels, along with the ability to trace the preparation using standard radiation detection instrumentation, provides the surgeon with an improved radiolabeled compound for lymphoscintigraphy and intraoperative strattera heart problems sentinel lymph node identification this method also demonstrates the versatility of nanoparticles to carry multiple diagnostic tracers on the same nanoparticle our group has developed special formulation of liposome encapsulated blue dye that can be radiolabeled for imaging and probe detection with this system, liposomes trap in the lymph nodes for a prolonged time and they have a high efficiency of retention in the lymph nodes this blue liposome formulation will be discussed in detail, in relation to lymph node drug delivery in sec optical in a very interesting and recently developed technique, fluorescent quantum dots have been investigated as agents to determine the location of the sentinel lymph node, these quantum dots are particles that are nm in diameter they have ideal properties as a nonquenching fluorescent light emitter, strattera heart problems following stimulation with near infrared light animal studies of these quantum dots have shown trapping in the sentinel node, following injection in normal animals they move rapidly to the sentinel node so that they can potentially be used during surgery in one study in pigs, the quantum dots were introduced into the lungs as a method of finding the sentinel lymph node draining from a lung cancer the lymph node draining from the lung was rapidly identified this rapid identification of the sentinel lymph node using a nonradioactive method was thought to provide a significant advantage for the method an important consideration in the future will be the possibility of toxicity from the heavy metal, cadmium, which is a major component of these quantum dots the recent synthesis of quantum strattera heart problems dots from other agents such as silver may eventually lead to quantum dots with improved biological toxicity profiles ultrasound nanobubbles another type of nanoparticle under investigation for the localization of the sentinel lymph node is the nanobubble nanobubbles consist of a bilayered shell of albumin and an inner layer of a biodegradable polymer known as polycaprolac tone this shell encapsulates the gas, nitrogen following subcutaneous injection, these nanobubbles are tracked using ultrasound imaging in a study comparing microbubbles to submicron nanobubbles performed in dogs, the nanobubbles were more effective in detecting the sentinel nodes, with or of the sentinel nodes being detected this nanobubble technology could serve as an alternative method for detecting the sentinel lymph node this approach is also unique in that the use of ultrasound to detect strattera heart problems the bubbles also causes the bubbles to break apart and form smaller bubbles it has been proposed that jets released from these nanobubbles following exposure to highfrequency ultrasound could be used to nanoinject drugs into cells as these nanobubbles can also carry drugs, they could be used to deliver high levels of drugs to lymph nodes which could be rapidly released following insonation concerns have been expressed that the energy released during insonation of these nanobubbles could produce harmful bioeffects due to thermal damage, and further investigation will be required to examine these issues in detail recently introduced medical imaging devices for monitoring lymph node delivery and therapeutic response for studies of nanoparticle localization of lymph nodes and the assessment of drug delivery to lymph nodes for the treatment of strattera heart problems cancer metastasis and other lymphatic disease processes, the development of clinical imaging systems to direct and verify therapy will continue to gain importance in this regard, the recent advent of clinically available single photon emission computed tomography spect computed xray tomography ct systems will be important these systems permit the simultaneous image acquisition of a d scintigraphic image with a d ct image, which allows the perfect superimposition of the two types of images with this new spectct camera, scintigraphic imaging of the location of the nanoparticle can be superimposed upon the high resolution ct images which clearly demonstrate the anatomy of the body these systems are already proving to be useful for the diagnosis of lymph node metastasis in prostate cancer using targeting radiolabeled antibodies the ability to perform strattera heart problems a ct image to verify the location of the activity visualized on the d spect scan will be important without anatomic verification by ct, it is difficult to determine whether the hot spot visualized on the image is a lymph node it is also difficult to accurately diagnosis the occurrence of a lymphatic metastasis by having an imaging machine that can simultaneously coregister a ct image, which accurately displays the image, with high resolution and superimposing the location of the delivered activity, it will be possible to accurately determine the distribution of lymph node directed nanoparticle therapy in a recent study, the performance of spectct was particularly useful in identifying lymph nodes adjacent to the primary lesion such nodes are easily overlooked by planar lymphoscintigraphy and intraoperative gamma probes, as strattera heart problems the high activity at the injection site can obscure their detection another study also found that spectct was highly effective for precise preoperative localization of the cervical sentinel node in early nonmetastatic oral squamous cell carcinoma the authors of this recent study concluded that they believe the use of spectct will become extremely useful, once a consensus has been reached on the exclusive excision of the cervical sentinel node in oral cancers, as is the case for melanoma or breast cancer positron emission computed tomography pet has recently entered clinical practice for the diagnosis of cancer cancer is detected using f fluorodeoxyglucose ffdg due to the greatly increased glucose metabolism of cancer cells this technique is very powerful at detecting cancer in lymph nodes containing metastasis it frequently demonstrates cancer strattera heart problems in the lymph nodes that are not detectable with routine ct imaging this technique could be very useful in monitoring lymph node response, secondary to nanoparticle delivered therapeutic agents monitoring nanoparticle drug delivery with pet could be particular useful in situations where the lymph node if not easily surgically accessible a recent report of a new use of ffdg pet scanning in patients with hiv appears to clearly demonstrate specific lymph nodes that are harboring hiv ffdg is a marker of glucose metabolism which is increased in inflammation as well as tumors in this study using pet imaging, the total quantified summed activity in lymph nodes was found to correlate with the level of viremia across a log range cervical and axillary lymph nodes were found to have significantly more strattera heart problems activity than inguinal and ileal nodes p the lymph nodes were thought to have increased ffdg uptake due to increased glucose metabolism in lymph nodes, with lymphocyte turnover secondary to viral infection in these infected lymph nodes this work suggests that the level of virus encountered in the lymph nodes is directly related to the blood levels of hiv virus these pet studies also clearly indicated that particular lymph nodes were involved, suggesting the possibility that these nodes could be specifically targeted with nanoparticles for drug delivery a second article investigating pet scanning in patients with hiv has even suggested that surgical intervention to remove the specific nodes should be considered an alternative strategy would be to use nanoparticles to target antiviral medications to specific lymph nodes, based on the strattera heart problems pet imaging data imaging with spect�� could be used to determine that the nanoparticle associated drugs were specifically delivered to the targeted lymph node, and repeat pet imaging could be used to monitor the effectiveness of the delivered therapy for the treatment of the lymph node analogues of these human imaging systems have been developed for small animal imaging research these commercially available imaging systems combine microspect and microct into the same unit for image superimposition a new commercially available imaging system has become available, combining microspect, microct and micropet into the same unit these small animal imaging systems will prove to be valuable in the investigation of nanoparticle lymph node delivery they should facilitate the translation of basic research to imaging studies in the clinical environment nanoparticle lymph strattera heart problems node drug delivery several authors have recommended that in the case of diseases with lymphatic involvement, it is desirable to develop treatment approaches to deliver diagnostic and therapeutic agents to lymph nodes that could help prevent diseases from spreading this situation has motivated interest in developing methods for specific drug delivery to lymph nodes and lymphatic vessels, with the hope of improving cancer and infection control and treatment whatever the carrier system chosen, the following basic requirements need to be met in order to develop an effective drug delivery system a the carrier system must concentrate selectively in the target organ or tissue b the carrier system must release the drug in such a way as to achieve its chemotherapeutic or pharmacological effect, over the required time frame c the strattera heart problems carrier system must be stable before administration and during its journey to the target, but able to release the drug when it is at the target and d the carrier must also be compatible with the body in terms of toxicity, biodegradation and immunogenicity nanoparticles of different types can meet the above criteria as effective carriers for drug delivery to lymph nodes targeting of lymph nodes for drug delivery has been attempted by the use of emulsions, nonlipid macromolecules, antibodies, and nanoparticles nanoparticles appear to hold the most promise for lymphatic drug delivery, in comparison with other types of carriers in the present review, we will focus on the variety of nanoparticle systems that have been used for lymph node drug delivery confusion in reporting lymph node delivery the research strattera heart problems literature reporting nanoparticle uptake in lymph nodes can be very confusing this is due to the tendency of many investigators to report the percent uptake in the lymph node as a percent of the injected dose per gram of tissue although reporting uptake as a percent of the injected dose per gram is sensible from a tissue treatment standpoint, it does not easily allow the readers to determine the percent of the total administered dose accumulated in the lymph node for instance, in animals such as mice with very small lymph nodes that weigh only a fraction of a gram, the accumulated doses can be as high as of the injected dose per gram, but considering that a mouse lymph node weighs only gram this is only of the total strattera heart problems dose that was administered id had this same fraction of the injected dose accumulated in a rat lymph node that weighs approximately gram, this dose would have been only of the injected dose per gram and in a human with a lymph node with a weight of gram, it would have been only id per gram it is very important to keep these species differences in mind when interpreting the previous literature and it would be best if all investigators would report their research not only in terms of dose per gram, but also in terms of the percentage of the total injected dose delivered to the lymph node from a pharmacologic standpoint, percent dose per gram may be considered correct, but it is highly unlikely that these percent dose strattera heart problems per gram results in mice would translate into humans based on our experience, it is much more likely that the percent that clears from the injected site will always be approximately the same in each species and the percent that accumulates in the lymph nodes, no matter what its weight in grams, will also be approximately the same for example, in one study, researchers reported that subcutaneously injected liposomes without a lymph node targeting mechanism had much higher concentration in the lymph nodes on the side of the subcutaneous injection, compared with the lymph nodes of the opposite side that did not receive the injection hrs after subcutaneous injection, of the idgram of tissue was found in the inguinal node on the side of the injection ipsilateral side versus only strattera heart problems idgram of tissue in the lymph node of the opposite side of the injection contralateral side at hrs again, this study was carried out in mice and the id per gram is somewhat deceptive due to the fact that mice have very small lymph nodes this probably represents no more than of the total injected dose accumulating in the lymph node that drained from the subcutaneous site the important point is unchanged there was more than a fold increased amount of liposomes deposited on the side of subcutaneous injection, compared with the lymph node on the other side that did not receive the subcutaneous injection it is important that readers of the lymph node drug delivery literature take lymph node weight into consideration for instance, if of the total subcutaneous strattera heart problems injected dose were to accumulate in the lymph node of a mouse with a lymph node that weighs just gram, the idgram would be divided by or of the injected dose per gram calculation of lymph node retention efficiency using scintigraphic imaging, our group has developed a method to calculate lymph node retention efficiency the calculation describes the fraction of the nanoparticles that are cleared from the initial subcutaneous site of injection that become trapped and retained in the lymph node this estimated lymph node retention calculation describes how efficiently the lymph node can retain a particular subcutaneously injected nanoparticle it also describes the portion of the dose that enters a lymph node and then leaves that primary lymph node and moves to the next lymph node the calculation requires strattera heart problems that the nanoparticle be labeled with a radiotracer and imaged scintigraphically it is determined by drawing a region of activity around the injection site and determining the total percentage of the baseline injected activity that has cleared the injection site at various times post injection this total cleared activity is then assumed to be the amount that enters the first lymph node the activity retained in the lymph node is divided by the total activity cleared from the injection site, so that a lymph node retention efficiency can be calculated with most unmodified liposome preparations, lymph nodes only retain approximately of the liposomes that enter the lymph node retention efficiency is higher with other particles, such as unfiltered mtcsc that have a lymph node retention efficiency, but these particles are strattera heart problems also associated with a very poor clearance from the initial injection site specific types nanoparticles for lymph node targeting plga nanoparticles polylactidecoglycolide plga nanoparticles have been investigated for lymph node drug delivery agents by modifying the surface of the plga nanoparticles with block copolymers, plga nanoparticles that deliver up to of a subcutaneously injected dose to regional lymph nodes have been developed lymphatic uptake was studied by labeling these plga nanoparticles with niinoxime lymphatic uptake of all coated plga nanoparticles was enhanced, compared with the uncoated plga nanoparticles this research suggests that the nanospheres are suitable for diagnostic and therapeutic lymph node delivery applications in clinical and experimental medicine in another study, the in vivo trafficking of plga particles, encapsulating a diphtheria antigen, was possible using a fluorescent marker following strattera heart problems subcutaneous administration for the immunization of mice, these fluorescent plga microspheres were observed in cells of lymphoid tissues such as mesenteric lymph nodes and spleen however, particle fluorescence in lymphoid tissues decreased rapidly, as they were degraded inside the cells, thereby enabling the presentation of the antigen to specific cells of the immune system this is one of the few studies in which a nanoparticle carrier for vaccine delivery was tracked in vivo micelles particles known as micelles can be formed from amphiphilic biocompatible polyoxyethylene peobased polymers these nanoparticles micelles are nm in diameter researchers have labeled micelles with amphiphilic indiumill inin and gadolinium chelates and used them as nanoparticulate contrast media for imaging lymph nodes, following subcutaneous injection into the rabbits paw corresponding images of local lymphatics were acquired strattera heart problems using a gamma camera and a magnetic resonance mr imager the entire lymphatic vessel chain from the paw to the thoracic duct could be visualized using in labeled micelles after injection site massage, of the injected dose cleared from the injection site into the lymphatics, min after massage was performed over the site of injection although approximately of the subcutaneously injected dose was in the popliteal lymph node at min, this amount decreased significantly after massage over the popliteal lymph node, with less than of micelles remaining in the lymph node when gadolinium containing micelles were administered, tweighted mr images of the primary lymph node had significant contrast enhancement within min following massage prior to this imaging research, torchilin had previously shown that micelles have much promise for the delivery strattera heart problems of poorly soluble drugs following intravenous delivery micelles also appear to be promising agents for lymphatic drug delivery, particularly if methods can be developed to increase their retention in lymph nodes liposomes the investigation of liposomes as carriers for lymph node drug delivery was first performed by segal et al following the intratesticular injection of liposomes encapsulating the anticancer drug actinomycin d, high concentrations of the drug were found in the local lymph nodes lymph node imaging using mtclabeled liposomes was first performed by osborne et alm liposome distributions were determined in rats following injection of the mtc liposomes in the rat hind footpads in these studies, to of the injected dose of neutral and cationic liposomes were found to localize in the draining lymph nodes negatively charged liposomes did strattera heart problems not show good accumulation in the lymph nodes soon after these studies were performed, the reliability of these previous studies for representing the actual distribution of liposomes was questioned and it was suggested that much of the activity localized in the lymph nodes was not associated with liposomes, due to instability of the mtc label this article recommended that new methods of labeling liposomes with mtc be developed followup studies demonstrated that the type of labeling used in the prior studies, in which mtc was labeled to the outer surface of liposomes following reduction of the mtc with stannous chloride, was not stable it was particularly unstable for labeling liposomes with a cationic and neutral surface charge, which possibly explained the low accumulation in lymph nodes found with anionic liposomes strattera heart problems these studies demonstrate the importance of label stability in the tracking of liposomes for quantitation of targeting to the lymph nodes since those early studies, more stable methods of labeling liposomes with , tc have been developed and applied to lymph node imaging a method developed by our group uses hexamethylpropyleneamine oxime hmpao, a clinically approved and commercially available chelator of mtc used for brain imaging in this method, mtcpertechnetate, which is readily available from a generator, is incubated for min with hmpao, which chelates the mtc into lipophilic mtc hmpao the mtchmpao is then added to previously manufactured liposomes that encapsulate glutathione it is generally believed that lipophilic hmpao carries the mtc across the lipid bilayer of liposome into the aqueous interior of the liposome where it interacts with strattera heart problems the encapsulated glutathione, resulting in its conversion to hydrophilic mtchmpao the hydrophilic mtchmpao is irreversibly trapped in the aqueous phase of the liposome because it is unable to cross the lipid membrane a similar mechanism has been proposed to explain the process whereby mtchmpao becomes trapped in brain cells for use as a brain imaging agent this liposome label is very stable with minimal dissociation of the mtc from the liposomes it has been used to study the distribution of intravenously administered liposomes using the above liposome labeling methodology, detailed studies were carried out to assess the effect of liposome size and surface modifications on movement from the subcutaneous site of injection, as well as the retention of the liposomes in the lymph node the fraction of liposomes that are strattera heart problems cleared from the subcutaneous injection site depends on the size and surface characteristics of a particular liposome formulation their large size of liposomes nm precludes their direct absorption into the blood stream in studying a wide range of liposome sizes from nm liposomes to nm liposome, there was little difference in the ultimate accumulation of liposomes in the first or sentinel lymph node at hrs post administration this lymph node retention ranged from to of the total administered dose this retention in the lymph node is relatively low, considering that most subcutaneously injected liposome preparations more than of the injected liposomes are cleared from the injection site the lymph node retention for unmodified liposomes is low, compared with other colloidal particles such as mtcsc there were differences between the different strattera heart problems liposomes sizes and surface characteristics in regard to the percent of activity that cleared from the subcutaneous site of injection small liposomes and those coated with peg had the greatest clearance from the subcutaneous site of injection, with small nm liposomes having of the injected dose remaining at the injection site at hrs larger neutral and negatively charged liposomes had of the injected dose remaining at the initial site of subcutaneous injection however, this smaller amount of large liposomes that were cleared from the injection site was compensated for by better retention in the lymph node it appears that the properties of liposomes which enhance their clearance from the injection site, also decrease their retention in the lymph nodes the generally low overall lymph node retention of most standard liposome strattera heart problems formulations is likely to be due to their natural lipid composition, which probably allows a large percentage of liposomes that enter a lymph node to escape recognition and phagocytosis by macrophages that line the endothelium of the lymph node this relatively low retention of liposomes in lymph nodes has also been reported by ousseren et � one of the several liposome surface modifications that have resulted in modestly increased retention of subcutaneously injected liposomes in the lymph node is the use of positively charged lipids in the liposome liposomes containing positively charge lipids had approximately to times the lymph node localization up to of the injected dose, as liposomes containing neutral or negatively charged lipids of the injected dose coating liposomes with the antibody, igg, has been shown to increase strattera heart problems the lymph node localization of liposomes to of the injected dose at hr, but this level decreased to by hrs attaching mannose to the surface of a liposome has also been reported to modestly increase lymph node uptake by fold, compared with control liposomes none of these previously mentioned modifications has resulted in large increases in the percentage of liposomes deposited in the draining lymph nodes, while most of the lymphatically absorbed liposome dose passes through the lymph nodes this relatively low retention may be due to the fact that the natural lipid composition of liposomes allows them to escape recognition by the macrophages located in the lymph nodes in comparison with other particles, an abundant fraction of the subcutaneously injected dose of liposomes moves into the lymphatic system, so strattera heart problems that greater than clears from the site of injection by hrs even though this retention of liposomes is very low in comparison with the injected dose, its uptake can still be quite substantial in terms of drug delivery, when considered on a per gram of tissue basis for example, to of the injection dose in each lymph node represents a total per gram tissue uptake that is generally greater by fold than the liposome uptake that will eventually reach the liver and spleen following the same subcutaneous injection avidin biotinliposome lymph node targeting method the relatively low retention of liposomes in lymph nodes led our group to search for new ways to improve liposome retention in lymph nodes this research resulted in development of a new method of increasing liposome strattera heart problems retention in lymph nodes following subcutaneous injection this lymph node targeting method utilizes the high affinity ligands, biotin and avidin biotin is a naturally occurring cofactor and avidin is a protein derived from eggs avidin and biotin have an extremely high affinity for each other avidin has receptor sites for biotin associated with each molecule these receptor sites permit the binding of multiple biotin molecules which causes aggregation of liposomes that have biotin on their surface using this method, liposomes coated with biotin on their surface biotinliposomes are injected subcutaneously, followed by a nearby subcutaneous injection of avidin following their subcutaneous injection, the avidin and the biotinliposomes move into the lymphatic vessels it was orginally hypothesized that the biotinliposomes that are migrating through the lymphatic vessels meet with the avidin, strattera heart problems resulting in an aggregate that becomes trapped in the lymph nodes subsequent research suggests that an alternative possibility maybe more likely, this alternative hypothesis is that the positively charged avidin becomes bound to negatively charged endothelial cells in the lymph nodes and the biotinliposomes become bound by these avidin molecules attached to the endothelial surface it is possible that both processes are occurring, however, research with intracavitary avidinbiotinliposome systems suggests that the second possibility may be more likely this in vivo nanoassembly of biotinliposomeavidin aggregates mimics processes that occur naturally in the body such as the aggregation of platelets and the aggregation of infectious agents by antibodies the biotinliposomeavidin system has promising potential for therapeutic agent delivery to lymph nodes it can be applied not only to subcutaneous targeting of strattera heart problems lymph nodes, but also to intracavitary lymph node targeting although liposomes are the particular nanoparticle in which this methodology has been developed, it should also be possible to apply this methodology to the other types of nanoparticle carriers other high affinity ligands pairs as alternatives to avidin and biotin could also be used scintigraphic imaging of liposomes labeled with mtc, labeled in a stable fashion, has greatly aided the determination of the proper concentration of avidin and biotin and could be used to develop similar targeting methodology with other nanocarriers as an extension of the avidinbiotinliposome lymph node targeting system, we have developed a special liposome formulation that contains both encapsulated blue dye as a potential system for localizing the sentinel lymph node, visually as well as scintigraphically, andor with strattera heart problems a gamma probe potential advantages of this system over the current methods are that it can be performed any time from hr to day before the surgery is planned, because the lymph nodes are stained blue for a prolonged time and the sentinel lymph has the highest concentration of liposomes using this method, a separate blue dye injection just prior to surgery would not be necessary examination of blue lymph nodes by light microscopy reveals that the liposomes tend to be deposited only in the outer cortex of the lymph node, however, this is not always the case as lymph nodes can be completely stained, depending on the concentration and timing of the avidin and biotinliposome injection as part of these studies, we have found that lymph nodes remain blue strattera heart problems by visual observation in vivo, for more than a week following subcutaneous injection the prolonged retention and slow release observed with blue biotinliposomes demonstrates the potential of this system for the delivery and sustained release of drugs in the lymph nodes clinical studies would be required to determine whether the biotinliposome avidin system is effective in targeting the sentinel node in humans massage and the avidinbiotin liposome targeting method repeated massage and reinfusion of saline in a subcutaneous site of injection of the biotinliposomes and avidin can be used to further enhance lymph node accumulation, as well as the rapidity at which the liposomes leave the subcutaneous site in a study in our laboratory, the effect of this repeated massage on lymph node accumulation with the avidinbiotinliposomes technique was compared strattera heart problems with the same method with filtered mtcsc particles in this study, a gauge angiocatheter was placed subcutaneously in the dorsal foot of an anesthetized rabbit and ml mtc radiolabeled biotinliposomes or mtcsc were infused through the catheter into the subcutaneous tissue avidin mg in ml was injected into the rabbit hind foot, approximately cm proximal to the biotinliposome injection site, in the same manner as described in the initial biotinliposome study the injection site was massaged for min at serial min intervals, ml of saline was infused through the indwelling subcutaneous catheter and massage was performed for min, following each reinfusion of saline for the first hr during the second hr post injection, this ml saline infusion followed by massage was repeated at min intervals until min post injection images strattera heart problems were acquired at baseline and min and at hrs after acquiring images at hrs, the rabbits recovered from the anesthesia and were returned to the animal facility until they were imaged at hrs as shown in fig , the massage more than doubled the liposome accumulation in the popliteal node of the rabbits the intensity of mtc activity in the popliteal node is equal or greater than that of the activity at the injection site at hrs, an average of of the injected dose of liposomes were trapped in the popliteal node of the foot that received the serial massages and saline infusions versus in the popliteal node on the side that was not massaged at hrs, more than times the injected dose had cleared from the site of injection in strattera heart problems the foot on the side with the serial saline infusions and massage, compared with the control side versus , so that massage with serial saline infusions can greatly increase the rate and total movement from the injection site the liposome uptake in the popliteal node was generally fixed for an extended period at hrs, of the injected dose was still retained in the lymph node that received the repeated massage and saline infusions when this same methodology was compared in filtered mtcsc particles, the greatly increased accumulation in the lymph nodes was not observed although a greater amount of filtered mtcsc particles was cleared from the subcutaneous injection site in the foot with the serial saline infusions and massage, vs hours post subcutaneous injections in feet biotin liposomesulfur colloid �popliteal nodes�� avidin�?