avidin ?�avidin � liposome inj feet no saline ho saline massage passagemassage massage fig scintigraphic images of rabbit feet and legs acquired hrs after administration of mtcbiotin liposomes subcutaneously in the feet of a rabbit demonstrating the effect of repeated massage and saline infusion on lymph node accumulation following injection of radiolabeled biotin liposomes and avidin was compared with the effect of massage on filtered mtcsc particles the massage and repeat saline infusions more than doubled the liposome accumulation in the popliteal node of the rabbits vs massage and saline infusion did not greatly increase the lymph node comandi apri ed esplora windows vista accumulation of filtered mtcsc particles vs it appears that the extra saline and massage simply pushed most of the mtcsc through the lymph node this was unlike what happened with the biotinliposomes, where the avidin continued to trap or aggregate the biotinliposomes in the lymph node the percent of the injected dose retained at hrs in the popliteal node was only minimally increased vs it appears that the extra saline and massage simply pushed most of the mtcsc through the lymph node this was very different from the biotinliposomes, where the avidin continued to trap or aggregate the biotinliposomes in the lymph node nanoparticles for lymph node antiinfectious agent delivery only a few studies have examined the delivery of nanoparticles to lymph nodes for the treatment of infectious disease in one study, liposome encapsulated amikacin was injected subcutaneously, intramuscularly, and intravenously drug levels in the lymph nodes were studied at various time points following injection drug level area under the curve aucs in regional lymph nodes exceeded plasma aucs by fold, after subcutaneous and intramuscular injection of liposomal amikacin the authors of the study conclude that liposomes encapsulating amikacin have much potential for drug delivery, and even suggest comandi apri ed esplora windows vista that these liposomes could potentially be used for local delivery in perioperative prophylaxis, pneumonias and intralesional therapy as well as sustained systemic delivery of encapsulated drugs this effectiveness of liposome encapsulated amikacin following subcutaneous injection differs significantly from a previous study, in which nm liposome encapsulated amikacin was administered intravenously the intravenously administered amikacin encapsulated liposomes were effective against m avium intracel lulare located in the liver and spleen, but they had no effect on the organisms that were located in the lymph nodes it is unlikely that these intravenously injected liposomes accumulated in the lymph nodes to any comandi apri ed esplora windows vista degree the use of nanoparticles to increase the drug delivery to hiv infected lymph nodes appears promising when injected intravenously, the antihiv drug, indinavir, was found to achieve drugs levels in lymph node mononuclear cells that were only of mononuclear cells in the blood lipid suspensions of the antiviral hiv drug, indinavir, form particles that are nm in size when these particles were injected subcutaneously in hiv infected macaques, very high drug levels were achieved in the lymph nodes and viral rna loads in these nodes were greatly reduced this lowering of hiv viral rna levels could not be achieved comandi apri ed esplora windows vista when the same drug was injected intravenously dufresne et al have investigated liposomes coated with antihladr fab fragments for specifically targeting liposomes to follicular dendritic cells and macrophages within the lymph nodes of mice, with the goal of increasing the delivery of antiviral drugs to these cells infected with hiv the uptake of antihladr fab coated liposomes within lymph nodes was to fold higher when compared with conventional liposomes however, of more importance is the potential specific delivery of the antihladr fab liposomes to antigen presenting cells within the lymph node more recently, researchers from this same group have comandi apri ed esplora windows vista investigated the targeting of lymph nodes with indinavir, a protease inhibitor, encapsulated into immunoliposomes coated with the same antihladr fab antibody fragment mice were injected subcutaneously below the neck with either free indinavir or liposome encapsulated indinavir animals were sacrificed at various times following injection and tissues collected and analyzed for indinavir drug levels drug levels were compared in lymph nodes from the mice receiving the subcutaneously injected free drug and subcutaneously injected liposome encapsulated drug drug levels in the brachial and cervical lymph nodes were and times greater with the liposome encapsulated drug, than the free drug liposomes comandi apri ed esplora windows vista for intraperitoneal lymph node drug delivery intraperitoneal drug delivery is currently considered a viable approach for the treatment of ovarian cancer studies in which free drugs are administered into the peritoneum have shown survival benefits in ovarian cancer patients although most intraperitoneally delivered unencapsulated free drugs are rapidly cleared from the peritoneal fluid without entering the lymphatic system, direct intraperitoneal administration of drugs can achieve much higher peak concentrations in the peritoneal fluid, compared with the same drug administered intravenously fold higher for cisplatin and carboplatin, to as high as fold for taxol although these drug levels quickly equilibrate comandi apri ed esplora windows vista with plasma after termination of the peritoneal infusion, transiently elevated peritoneal drug levels provide a significant therapeutic advantage these have led many investigators to be enthusiastic about this approach for ovarian cancer treatment unfortunately, rapid clearance of these free drugs from the peritoneum diminishes the advantages derived from the intraperitoneal infusion procedure one way of improving peritoneal drug delivery could be through the use of nanoparticle drug carriers nanoparticles have significant promise as carriers for intraperitoneal drug delivery many disease processes spread by dissemination through the peritoneum for instance, dissemination of cancer cells throughout the peritoneum is a very comandi apri ed esplora windows vista common manifestation of ovarian and gastric cancer when the cancer cells spread throughout the peritoneum, they are frequently trapped in lymph nodes that receive peritoneal fluid drainage the normal pathway of drug clearance from the peritoneum is either through direct absorption across the peritoneal membrane or by drainage into the lymphatic system through absorption by the stomata in the diaphragm these diaphragmatic stomata are fairly large and can absorbed red blood cells from the peritoneal fluid intraperitoneally administered therapeutic nanoparticles not only increase and prolong the drug delivery in the peritoneum, but they can also increase delivery of therapeutic agents comandi apri ed esplora windows vista to the lymph nodes that filter lymph fluid drainage from the peritoneum these lymph nodes frequently contain cancer cells intraperitoneal liposome encapsulated drugs intraperitoneal administration of a liposome encapsulated drug not only increases the retention of the drug in the peritoneum, it also increases the delivery of the drug to lymph nodes that drain from the peritoneum this is because liposome encapsulated drugs are mostly cleared through the lymphatic vessels, with at least a portion of the administered drug being deposited in the lymph nodes, where it degrades and is slowly released from the liposome and lymph node macrophages comandi apri ed esplora windows vista in high concentrations other studies demonstrate an improved toxicity profile for instance, encapsulation of paclitaxel in a liposome has been shown to have decreased toxicity following intraperitoneal administration, while retaining equal efficacy for the treatment of intraperitoneal p leukemia in humans, the dose limiting toxicity from intraperitoneal administration of paclitaxel was severe abdominal pain, which was thought to be due to direct toxicity from either the paclitaxel or the ethanolpolyethoxylated castor oil delivery vehicle intraperitoneal delivery has also shown promise for nanoparticle gene transfection with novel cationic lipid containing liposomes these cationic liposome contained luciferase and betagalactosidase genes that comandi apri ed esplora windows vista served as reporter genes intraperitoneal gene delivery for peritoneal disseminated ovarian cancer in nude mice was achieved using a stable chloramphenicol acetyl transferase cat expressing ovarian cancer cell line ovcacat, which permitted quantification of the exact tumor burden of organs intraperitoneal gene delivery to these disseminated ovarian cancer cells was excellent, with gene transfection appearing to be specific to intraperitoneal ovarian cancer cells the choldna lipoplex appears to offer potential advantages over other commercial transfection reagents because of its higher level of gene expression in vitro and in vivo its reduced susceptibility to serum inhibition and its highly selective comandi apri ed esplora windows vista transfection into tumor cells these results suggest that the choldna lipoplex is a promising tool in gene therapy for patients with peritoneal disseminated ovarian cancer an important potential application of the intraperitoneal delivery of liposomes and other nanoparticles that carry anti cancer agents is in the prophylaxis of peritoneal carcinomatosis as of patients with malignant gastrointestinal or gynecological diseases experience peritoneal carcinomatosis shortly after local curative resection, there is a great interest in delivering intraperitoneal chemotherapy during the perioperative period one study found that the intraperitoneal administration of the chemotherapeutic agents, cisplatin and mitomycin, prevented perioperative peritoneal carcinomatosis in comandi apri ed esplora windows vista a rat model the rats receiving cisplatin did, however, experience severe, local toxicity with bleeding into the peritoneum and toxic necrotic reactions of the colon liposomes encapsulating anticancer agents could potentially be used for this type of perioperative chemotherapy the potential for the treatment of micrometastasis in lymph nodes with this liposomes is also great metastasis to mediastinal and other lymph nodes receiving lymph drainage from the peritoneal fluid are not uncommon findings in ovarian cancer at autopsy one important consideration that might influence the effectiveness of intraperitoneal lymph node drug delivery is the possibility that the lymphatics could be comandi apri ed esplora windows vista completely obstructed with tumor, and therefore not accessible for lymph drainage generally, the ascites that develops in patients with intraperitoneal cancer are thought to be due to the obstruction of the lymphatics by the metastatic cancer in a recent study, only of women diagnosed with early stage ovarian cancer presented with ascites biodistribution studies with liposome imaging could be performed to determine the effectiveness of lymph node targeting in situations of suspected lymph node obstruction effect of liposome size on intraperitoneal clearance it must be noted that simply making liposomes larger does not increase retention in the peritoneum or comandi apri ed esplora windows vista lymph nodes that receive drainage from the peritoneum hirono and hunt have performed an extensive study on the effect of liposome size on their subsequent distribution, after intraperitoneal administration of liposomes of different sizes in their studies, of the intraperitoneal dose of liposomes of varying sizes encapsulating carbon c labeledsucrose cleared from the peritoneum by hr in all liposomes studied these liposomes ranged in size from nm to nm the greatest amount of csucrose appeared in the urine after administration of the largest liposomes the authors speculated that the large nm and nm liposomes were unstable in the peritoneum, comandi apri ed esplora windows vista so that they rapidly released their encapsulated csucrose it is also unlikely that simply increasing the size of the liposomes, in and of itself, would be sufficient to result in increased peritoneal and lymph node retention, because particles as large as erythrocytes have been demonstrated to readily drain from the peritoneum, by passing through the diaphragmatic stomata and returning to the blood stream in one study of chromium labeled red blood cells injected into the peritoneal cavity of sheep, of the red cells returned to the blood circulation by hrs after administration avidinbiotinliposome system for intraperitoneal and lymph node comandi apri ed esplora windows vista drug delivery few of the above previously described studies with intraperitoneally administered liposome nanoparticles have focused on the fact that liposome nanoparticles clear from the peritoneum by passing through the lymphatic vessels the liposomes pass through and are only partially trapped to lesser or greater degrees in the lymph nodes that drain from the peritoneum these lymph nodes frequently contain cancer metastasis our group has applied the previously described avidinbiotinliposome system to intraperitoneal drug delivery the intraperitoneal biotinliposomeavidin delivery method previously described in this paper has potential as a delivery system for the local treatment of intraperitoneal and intralymphatic comandi apri ed esplora windows vista disease processes, by increasing the retention of drugs in the peritoneum and in the lymph nodes that receive lymphatic drainage from the peritoneum the interaction of biotinliposomes with avidin apparently results in the aggregation of the liposomes in the peritoneum this aggregation greatly alters the distribution of liposomes and appears to result in a prolonged retention of liposomes in the peritoneum, as well as an increased accumulation and retention of liposomes in lymph nodes receiving drainage from the peritoneum rats that received intraperitoneal injection of biotinliposomes and avidin had only a minimal percentage of the injected dose of liposomes that comandi apri ed esplora windows vista reach the systemic circulation by hrs and a low id was found in the spleen, blood and liver at hrs id in contrast, control animals, administered only the biotinliposomes without the avidin, had id in the spleen, id in the blood, and id in the liver, for a total of id in these organs at hrs lymph nodes in the abdomen and in the mediastinum in rats receiving avidin had also greatly increased uptake of the biotinliposomes delivery of liposome encapsulated drugs using this method should provide sustained local release of drug within the peritoneum and the lymph nodes comandi apri ed esplora windows vista draining the peritoneum, as the liposomes degrade or become phagocytized by macrophages this delivery system could also attenuate systemic drug toxicities by greatly reducing the rate at which a drug returns to the systemic circulation by either preventing rapid direct absorption through the peritoneal membrane, or by moderately preventing rapid passage through the lymphatic vessels and lymph nodes back to the blood intraperitoneal administration using the avidinbiotinliposome system has potential as a carrier system for the delivery of anti cancer agents in the peritoneum, as well as liposome encapsulated radiotherapeutic betaemitters for the treatment of peritoneally disseminated ovarian and comandi apri ed esplora windows vista upper gastrointestinal cancers mediastinal lymph node drug delivery with avidinbiotin system by intrapleural injection mediastinal nodes are involved as centers of incubation and dissemination in several diseases including lung cancer, tuberculosis, and anthrax treatment and control of these diseases is hard to accomplish because of the limited access of drugs to mediastinal nodes, using common pathways of drug delivery also, the anatomical location of mediastinal nodes represents a difficult target for external beam irradiation, due to its close proximity to major vessels and the heart the use of the avidinbiotinliposome method has been investigated as a carrier system for comandi apri ed esplora windows vista drug delivery to mediastinal nodes, using intrapleural injection as the pathway of delivery drug delivery, using the avidinbiotinliposome system, injected intrapleurally could solve some of these limitations and offer several advantages for the treatment of these diseases only minimal investigation has been performed using intrapleural administration as a pathway for drug delivery to mediastinal nodes perezsoler et al have investigated the intrapleural route of administration of liposome encapsulated drugs for the treatment of malignant pleural effusion in human patients our group has performed studies to investigate the use of the avidinbiotin liposome system for targeting the mediastinal node following comandi apri ed esplora windows vista intrapleural administration in rats studies were performed by injecting biotinliposomes into the pleural space following by an injection of avidin hrs previously by hrs after injection, good retention idmediastinal nodes idg of liposomes was achieved in the mediastinal nodes with the avidinbiotinliposome system the scintigraphic image that visually demonstrates the mediastinal node uptake is shown in the image in the left panel of fig an actual photograph of the blue stained mediastinal nodes obtained during necropsy is shown in fig the images demonstrate the high uptake of liposomes in the mediastinal nodes in the absence of avidin, liposomes were minimally comandi apri ed esplora windows vista retained in the nodes idorgan idg this approach was the reverse of the sequence used in prior subcutaneous and intraperitoneal studies, in which avidin was injected after the biotinliposomes the specific targeting of a liposomeencapsulated drug to mediastinal lymph nodes could result in a prolonged targeted sustained depotlike delivery of high drug concentrations to these nodes, while the liposomes are slowly degraded and metabolized by phagocytic cells located within these nodes future experiments using intrapleural injection of the avidinbiotinliposome system to target drugs to mediastinal nodes should be pursued avidin biotin for diaphragm and mediastinal lymph node targeting avidin comandi apri ed esplora windows vista pleural biotinliposomespleural avidin pleural biotinliposomes peritoneal fig using the avidinbiotin liposome system in a rat model, high levels of liposomes were trapped in the mediastinal node when the avidin was injected in the pleural space and followed hrs later by injection of the radiolabeled biotinliposomes as demonstrated on the image on the left hand side the avidin alone was injected in the pleural space and radiolabeled biotin liposomes were injected in the peritoneal space scintigraphic images were performed at hrs high levels of liposomes accumulated in the diaphragm as well as the mediastinal nodes the diaphragm is the linear comandi apri ed esplora windows vista structure with intense uptake at the bottom of the chest region n using the avidinbiotin liposome system, it was serendipitously discovered that when biotinliposomes were injected into the peritoneal cavity and avidin was simultaneously injected into the pleural cavity, the liposomes aggregated strongly in the diaphragm as well as in the mediastinal nodes this accumulation in the diaphragm occurred when the avidin draining from the pleural space into the diaphragmatic lymphatics encountered the biotinliposomes draining from the peritoneal space, causing the liposomes to aggregate within the diaphragm the scintigraphic image of this diaphragm and mediastinal node accumulation is shown in the image of the right panel in fig the scintigraphic image shows the intense activity of linear uptake in the region of the diaphragm, as well as uptake in the mediastinal nodes a photographic picture of the diaphragm is shown in fig the blue dye containing biotinliposomes accumulate in the linear lymphatic vessels coursing through the diaphragm this study confirms the fact that in the rat, the pleural lymphatic drainage pathway and the peritoneal lymphatic drainage pathway share the same lymphatic vessels in the diaphragm it is not known if there could be some useful applications for diaphragmatic comandi apri ed esplora windows vista drug delivery, but one potential application is for the treatment of mesothelioma methelioma is a cancer of the diaphragm that generally has a very poor prognosis this prognosis has not changed with any attempted therapies including surgery, chemotherapy and radiation fig � photographic picture of the diaphragm of a rat hrs following injection of the biotin liposomes containing blue dye in the peritoneum and injection of avidin in the peritoneum corresponding to the right hand image on fig the blue dye containing biotin liposomes accumulate in the linear lymphatic vessels coursing through the diaphragm fig a photographic picture of the comandi apri ed esplora windows vista biotinliposome containing blue dye accumulating in the two mediastinal lymph nodes hrs following injection of avidin in the pleural space followed by biotinliposomes administration in the pleural space as corresponding to the left hand image of fig the heart is between and forceps and the mediastinal nodes are just in front of the thymus the intense blue staining of the mediastinal lymph nodes can clearly be seen at hr post administration of the liposomes nanoparticles for cancer therapy intralymphatic drug delivery to lymph nodes one of the first studies to investigate the possible use of drugs delivered intralym phatically comandi apri ed esplora windows vista was performed by hirnle this study investigated the anti cancer drug bleomycin, which was suspended in an oil suspension known as oil bleo this oil bleo was injected directly into catheterized lymphatic vessels in dogs the movement of this agent through the lymph nodes and lymphatic vessels was fairly rapid with peak drug concentrations reached in the blood min after the intralymphatic administration of oil bleo the drug entering the blood was considered to be a spillover from the lymphatic system spillover occurred because the drug moved completely through the lymphatic vessels and rejoined the circulation at the thoracic comandi apri ed esplora windows vista duct administering the drug this way required a very tedious catheterization process of the small lymphatic vessels of the extremities although drug concentrations were very high in the lymphatic vessels for a fairly short time, the retention of the oil emulsion in the lymphatics was minimal following this work with anticancer bleomycin oil emulsions, hirnle turned to liposomes as an ideal carrier for intralymphatically delivered drugs a study in rabbits used liposomeencapsulated bleomycin in which the liposomes were injected directly into the lymphatic vessels of the hindlegs of rabbits lymph nodes were removed and measured for bleomycin content at comandi apri ed esplora windows vista various times following administration three days following intralymphatic administration, the drug concentration in the popliteal lymph nodes was xgramgram of node drug deposition and apparent release was sustained over a very long period because concentrations of bleomycin in the lymph nodes of xggram were measured in the popliteal nodes at one month following injection further studies were performed by hirnle with blue dye containing liposomes composed of phosphatidylcholine and cholesterol the liposomes had a homogeneous size of approximately nm in diameter the total amount of blue dye injected was mg when the rabbits were sacrificed days later, the retroperitoneal comandi apri ed esplora windows vista lymph nodes were visually blue and had a concentration of ig blue dyegram of lymph node unfortunately, when these liposomes were administered by direct intralymphatic injection in the hindleg of a rabbit, a large fraction of the intact liposomes were found to spill over into the circulation several conclusions were derived from this endolymphatic research with liposomes directly infused into the lymphatic vessels the amount of drug administered intralymphatically should not exceed that which would be administered intravenously, because of the large amount of liposomes that spill over from the lymphatics to the circulation the limiting factor in administering drugs comandi apri ed esplora windows vista lymphat ically is the amount of the therapeutic agent that moves completely through the lymphatic system and into the circulation through the thoracic duct the tolerated amount of spillover should be considered in regard to the toxicity of these liposomal agents to the rest of the body the volume used in humans should remain low, with no more than ml of liposomes being administered into the canulated lymphatic vessels of each leg it was also suggested that the drug will remain longer in the lymphatics, if the patient remains in bed for day after endolymphatic liposome administration most importantly, comandi apri ed esplora windows vista the lymph nodes will still be filled with measurable amounts of drug a month after injection hirnle also introduced the concept that the prolonged retention of anticancer drugs in the lymphatics might be effective for the prevention of lymphatic metastasis nanoparticles for treatment of metastatic lymph nodes of upper gl malignacies much work has been performed by investigators in japan to develop a novel drug delivery system for the treatment of lymph node metastasis from the cancers of the esophagus and stomach this interest by japanese researchers are likely to stem from the high incidence of upper gastrointestinal cancer comandi apri ed esplora windows vista in japan this work has also been stimulated by the fact that examinations of surgically resected specimens revealed that the cancer of the upper digestive tract metastasize to regional lymph nodes in of patients, even when cancer invasion is limited to the mucosa or submucosa this has led to the conclusion that even in patients with these superficial cancers, it is important to treat patients with gastric and esophageal cancer for potential lymph node metastasis as an attempt to increase drug delivery to lymph nodes that drain from these upper digestive system cancers, a new activated carbon nanoparticle formulation comandi apri ed esplora windows vista of the anti cancer drug methotrexate was developed for the treatment of lymph node metastasis in patients with cancers of the upper digestive system methotrexate was mixed with nmsized activated carbon nanoparticles in a concentration of mg activated carbonml and polyvinylpyrrolidone this made a suspension of methotrexate loaded carbon particles with an average size of nm, as determined by photon correlation spectroscopy methotrexate was shown to be absorbed onto the activated carbon nanoparticles at a concentration of mgml mouse leukemia p cells were used as an experimental tumor because subcutaneously implanted p was known to metastasize to lymph nodes comandi apri ed esplora windows vista within days experiments were carried out on day when the cancer metastasis were known to be in the popliteal lymph nodes in mice which received an inoculation of p leukemia cells and drug treatment using the same procedures, the treatment effects on metastases to the regional lymph nodes were significantly greater in mice treated with the methotrexate loaded activated carbon particles than in those given methotrexate aqueous solution methotrexate concentrations in the popliteal lymph nodes were x molkg, with the carbon particles at hr versus x molkg with the free drug this level rapidly dropped to x molkg by hrs comandi apri ed esplora windows vista versus x molkg for the free drug by hrs, levels of methotrexate were undetectable in the lymph node blood levels of drug in the serum also increased rapidly, indicating that the association of the drug with the carbon nanoparticles was not very stable blood levels at min following injection were only slightly lower than those of subcutaneously injected free drug these levels peaked at min and were at very low concentration at hrs and were non detectable in the serum at hrs this rapid drop in drug blood levels would suggest that the carbon particles were not as effective comandi apri ed esplora windows vista at binding the methotrexate, compared with other liposomeencapsulated drugs, reported to be measured in lymph nodes in detectable quantities for month after subcutaneous injection no studies were reported describing the stability of this drug attachment to the carbon nanoparticles during incubation in serum such studies are essential for the evaluation of the stability of the nanocarrier even with this small effect of improved delivery to lymph nodes, survival in this animal model was increased from days in the nontreatment group to days in the carbon particle methotrexate group, days in the free methotrexate group injected subcutaneously and days in comandi apri ed esplora windows vista the free methotrexate group injected iv this same group has gone on to perform clinical trials in human patients, in which methotrexatecarbon nanoparticles were injected locally for the treatment of cancer of the upper digestive tract this treatment approach has also been applied in small pilot studies by other groups in japan, who have also reported survival benefit for the treatment of gastric cancer another group injected carbon nanoparticles with absorbed bleomycin for the treatment of esophageal cancer in this study, bleomycin nanoparticles were injected into the esophageal cancer days prior to surgery degenerative or inflammatory changes were microscopically comandi apri ed esplora windows vista observed in of lymph nodes, with metastatic foci indicating to these researchers that bleomycin carbon particles could be a useful tool in targeting chemotherapy for esophageal cancer this same activated carbon particle methodology has been applied to the treatment of other cancers in one study, breast cancer patients were injected intratu morally and peritumorally, with aclarubicin absorbed to activated carbon nanoparticles or in free solution following this injection, the patient had surgery and the tumor and peritumoral tissue were removed as well as regional lymph nodes drug levels in the lymph nodes were shown to be significantly higher with comandi apri ed esplora windows vista the carbon nanoparticle associated drug, compared with that of free drug xgg tissue versus xg g tissue in a recent study, local injection of mitomycin � bound to activated carbon mch combined with intraperitoneal hyperthermic hypoosmolar infusion iphhoi was intraoperatively administered to prevent lymph node recurrence and peritoneal recurrence of gastric cancer the and year survival rates for the mch iphhoi group were and , and those for the control group were and the mchi phhoi group reaped a significant survival benefit p � compared with the control group although this study was conducted in a small number of randomly selected comandi apri ed esplora windows vista patients with a short followup period, compared with the control group, the ��� iphhoi group had a beneficial effect in preventing lymph node recurrence and peritoneal recurrence, after curative gastrectomy for advanced gastric cancer lessons from endolymphatic radioisotope therapy much of the earlier work has been performed on the lymphatic delivery of the radiotherapeutic lipid emulsion, ilipiodol, which is a lipid emulsion of iodinated ethylic ester of poppyseed oil emits a therapeutic beta particle which is responsible for its therapeutic effects this early work provides useful lessons for the potential delivery of radiotherapeutic nanoparticles into the lymphatics for the comandi apri ed esplora windows vista treatment of cancer endolymphatic therapy consists of direct infusion of ilipiodol into the lymphatic vessels of the cancer affected extremity initially, endolymphatic isotope therapy had such promising early clinical results that the mrc medical research council in the uk set up a clinical trial in this clinical trial compared patients with lower extremity melanoma who received ilipiodol endolymphatic therapy to those who were treated with standard methods although there was no difference in the year survival rate between the groups, lymph node recurrence was significantly different with only a lymph node recurrence rate with the ilipiodol therapy, versus lymph comandi apri ed esplora windows vista node recurrence rate with standard therapy the conclusion from this study was that endolymphatic isotope therapy was justified in specialized centers where good results could be obtained following this initial investigation, many other studies of endolymphatic radiotherapy were performed studies of radiation dosimetry found that the average radiation dose absorbed by the lymphatic tissues with this therapy was rads unfortunately, this method was found to be limited by the hazard of radiation damage to the lungs approximately of these patients had detectable concentrations of radioactivity in the lung fields the average radiation dose to the lungs was rads it comandi apri ed esplora windows vista is very evident that ilipiodol becomes trapped in the lungs after reentering the thoracic duct following therapy this spillover from the lymphatic system that accumulates in the lungs, led to the recommendation that patients receiving this ilipiodol endolymphatic therapy rest in bed for several days, so that the maximum amount of would remain in the lymphatic vessels and not be pushed through to the lungs it was this large lung radiation dose that eventually led to the discontinuation of these ilipiodol studies, even in the face of promising results for lymphatic therapy and the prevention of local lymphatic metastasis comandi apri ed esplora windows vista endolymphatic ilipiodol therapy has been used to treat patients with lymphoma traditional xray lymphography was performed during the administration of the therapeutic ilipiodol these studies found that endolymphatic therapy was not of value in cases where there was evidence of lymph nodes already involved with cancer at the time of the treatment however, in cases where the lymphography was apparently negative, the ilipiodol did produce a statistically significant reduced incidence of relapse in the inguinoretroperitoneal nodes this suggests that the ilipiodol therapy was effective in treating micrometastasis in the lymph nodes one interesting study carried out with ilipiodol examined the comandi apri ed esplora windows vista effect of prior external beam irradiation on lymph node uptake of endolymphatically infused iodinated ilipiodol in this study, ml of ilipiodol mg of iodine per ml was injected subcutaneously into normal adult beagle dogs targeted lymph node groups were evaluated with computed tomography ct lymph nodes were irradiated with gy in fractions of gy per day, beginning days after the ct examination contrast media administration and quantitative ct imaging were again performed months after irradiation contrast material uptake resulted in a fold increase in node volume before irradiation p prior to the external beam irradiation, mean attenuation of contrastenhanced comandi apri ed esplora windows vista nodes increased to hounsfield units from a precontrast enhancement value of hounsfield units after irradiation, opacified node volumes decreased to approximately of their preirradiation volumes p , but contrast material uptake in the lymph node only decreased by after irradiation this uptake in the lymph node was not significantly less than the preirradiation uptake qualitatively, no substantial difference was found between irradiated and nonirradiated nodes the external beam irradiation treatment decreased lymph node size, but the imaging characteristics of opacification were not otherwise appreciably altered months after irradiation a later study at months showed slightly smaller lymph nodes and a comandi apri ed esplora windows vista lesser uptake of the subcutaneously injected ilipiodol, however, the lymph nodes appeared to tolerate the gy dose without significant alteration in their function advantages of nanoparticles for lymphatic radiotherapy compared with the previously discussedlipiodol emulsion, nanoparticles have many potential advantages as carriers of therapeutic radionuclides for endolymphatic therapy these include the fact that nanoparticles do not accumulate in the lungs to any degree and the ability to control the release and the choice of the particular isotope that is attached or encapsulated in the nanoparticle the high lung uptake of ilipiodol is due to the lipophilic nature of its comandi apri ed esplora windows vista oil component causing it to be absorbed by the lungs, which is the first significant vascular capillary bed encountered after the ilipiodol rejoins the circulation it is well known that intravenously administered liposome nanoparticles or liposome nanoparticles, returning to the blood following drainage from the lymphatic system, do not accumulate in the lungs to any significant degree intraoperative radiotherapy for positive tumor margins and for treatment of lymph nodes one possible use of radiotherapeutic nanoparticles is to target residual tumor in the intraoperative situation in many cases, the surgeon is unable to remove all of the cancer during surgery, comandi apri ed esplora windows vista so that the margins of the resected tumor are positive this generally means that there is cancer remaining at the operative site which severely compromises patients survival this positive margin can frequently be determined during the operation radiotherapeutic nanoparticles that target residual tumor could be injected in the region of the positive tumor margin to sterilize the surgical margin of tumor cells since the radiotherapeutic nanoparticles will drain through the lymph nodes, they would also have the potential to treat micrometas tasis in those nodes nanoparticles could therefore provide an additional tool for the surgeon, particularly when the margins of comandi apri ed esplora windows vista the tumor are positive even when the margins of the tumor are negative, there is frequently a reoccurrence of cancer in the local region or in the nodes that drain from the local region cancer surgeons spend many hours per surgery uncovering and removing lymph nodes in the region of the tumor carefully, without damaging other critical vessels and nerves although these surgeries are very long, it is not always possible to find and remove all of the lymph nodes in the local region of the tumor removal of distant lymph nodes that also receive lymph drainage from the comandi apri ed esplora windows vista tumor is usually not possible the application of therapeutic nanoparticles intraoperatively could provide an additional tool to treat micrometastasis in lymph nodes, with the goal of decreasing local reoccurrences extensive clinical trials would have to be performed to determine the effectiveness of this approach, similar to those that have already been performed with ilipiodol effective treatment of lymph nodes draining from a tumor could decrease the need for tedious surgical removal of lymph nodes one possible method to ensure good lymph node targeting of nanoparticles in the intraoperative situation would be to use the avidinbiotin lymph node targeting system comandi apri ed esplora windows vista to ensure trapping of the particles in the lymph nodes that drain from the tumor this methodology would also limit the spillover of radiotherapeutic nanoparticles from the lymphatic vessels into the bloodstream potential of using radiolabeled nanoparticles for intratumoral radionuclide therapy the direct injection of therapeutic agents into solid tumors has been recently investigated these studies using direct injection of nanoparticles into tumor have used many different therapeutic agents for instance, direct injection of nanoparticles into solid tumor have been investigated as a method of delivery ing genes into tumors this approach has also been applied in combination with comandi apri ed esplora windows vista external physical modalities magnetic nanoparticles have been directly injected into a solid tumor and exposed to alternating current as a new type of thermal ablation of solid tumors the particulate nature of nanoparticles appears to offer significant advantages for direct intratumoral administration nanoparticles appear to diffuse to some degree through the interstitial space of the tumor along primitive and chaotic lymph vessels within the tumor the degree of diffusion may depend on the characteristics of the particular nanoparticle injected nanoparticle intratumoral diffusion should result in improved solid cancer therapy due to a more homogeneous distribution throughout the tumor in comandi apri ed esplora windows vista spite of this potential for intratumoral diffusion, nanoparticles can still be well retained within the tumor when free unencapsulated drug is injected intratumorally, it appears to be absorbed directly into the blood supply of the tumor with less diffusion through the tumor, so that there is a less homogeneous dose throughout the tumor following the intratumoral injection of a free drug, as compared with intratumoral injection of nanoparticles in addition, depending on the nature of the free drug, free drug is likely to be cleared from the tumor rapidly by direct absorption into the tumor blood capillaries even with this comandi apri ed esplora windows vista improved local diffusion associated with nanoparticles compared with free drug, obtaining a homogeneous distribution throughout the solid tumor with intratumoral administration of nanoparticles still remains a challenge one approach is to use modifications of the injection method such as multiple sites of injections within the solid tumor this approach has recently been applied in the case of gene delivery with nanoparticles another possibility is the use of beta emitting therapeutic isotopes attached to nanoparticles the betaemissions penetrate millimeter distances away from the nanoparticle, enabling the betaemitting nanoparticles to deliver therapy to regions of the solid tumor that the nanoparticles comandi apri ed esplora windows vista cannot reach themselves many other approaches to solve the problem of homogenous distribution within a solid tumor nanoparticles may be part of, but not likely the complete solution, to obtaining a very homogeneous distribution within a solid tumor a significant advantage of nanoparticles for use in intratumoral injection is that they are more likely to move into the lymphatic vessels that drain from the solid tumor, where they have the chance to deliver anti cancer therapy to the sentinel lymph node and other lymphatics that drain from the tumor therefore, it is anticipated that this intratumoral injection would not comandi apri ed esplora windows vista only treat the tumor, but could also potentially treat lymph nodes that receive drainage from the tumor such as the sentinel node these lymph nodes could possibly contain metastasis liposome pharmacokinetics after intratumoral administration studies of liposome intratumoral pharmacokinetics have been stimulated by attempts to use liposomes as gene carriers clinical trials using cationic liposomes, carrying ea gene, were performed to treat squamous cell carcinoma, using an intratumoral injection technique for intratumoral administration pharmacokinetic studies have indicated that the size and surface charge of liposomes have a significant effect on their in vivo distribution increasing the liposome diameter and comandi apri ed esplora windows vista adding a positive surface charge to the liposomes slowed their clearance from the injection site, compared with smaller sized and neutral charged liposomes respectively at hrs after intratumoral injection, and of injected dose remained in the tumor with a � nm neutral liposome and a � nm cationic liposome respectively based on their observation of intratumorally administered cationic liposomes, nomura et al stated that there is a need to improve the control of the cationic liposome complexes to ensure a better distribution throughout the tumor biodistribution of inlabeled pegylated liposomes following intratumoral administration has also shown that liposomes have comandi apri ed esplora windows vista excellent potential as vehicles for intratumoral drug delivery rheniumlabeled liposomes for tumor therapy our group has developed a novel method of labeling liposomes with the radioisotope of rhenium this method uses n,nbismercaptoethyln,n diethylethylenediamine bmeda to postload either mtc, rhenium re or rhenium re into liposomes one of the significant advantages of rheniumlabeled nanoparticles that carry therapeutic beta particles is the short range field effect that they have, due to the fixed range of beta particle penetration ie mm for rhenium and mm for rhenium this length of penetration is adequate to treat a large number of cancer cells comandi apri ed esplora windows vista in the region of the nanoparticle, but not so far as to cause extensive damage to normal tissue the mm range of beta emission penetration with the rhenium isotopes compares favorably with, which only has mm average beta particle penetration combined with a high energy gamma photon the mm treatment field with rhenium is adequate for treating most lymph nodes, while limiting the dose to normal structures this field effect of the beta particle can compensate, to some degree, for a heterogeneous distribution of the nanoparticles within cancer containing lymph nodes the nanoparticle simply has to reach within a comandi apri ed esplora windows vista mm vicinity of the cancer cells for every beta emissions, both rhenium isotopes, rhenium and rhenium , emit a single gamma photon this is an ideal ratio of beta to gamma emissions a higher number of gamma emissions would deliver an excessive dose outside the local region of the tumor, as is the case for which has a ratio of beta particles to gamma photons the photon emission energy of both rhenium isotopes is in the range of the photon energy of mtc kev, so that the radiolabeled nanoparticles can be tracked through the body as they move through the comandi apri ed esplora windows vista lymphatic vessels many therapeutic radioisotopes are pure beta emitter, so that it is more difficult to track their distribution in the body rhenium has also many other advantages over most heavy metal radiotherapeutic isotopes, such as yittrium, because it has almost no affinity for bone uptake it shares this characteristic with mtc, as both radioisotopes tend to be cleared through the kidney, while most heavy metal beta emitting radioisotopes have a high affinity for bone this high bone accumulation can deliver a high radiation dose to bone marrow cells which are very sensitive to radiation this occurs when the comandi apri ed esplora windows vista radioisotope becomes separated from its chelator, following metabolism in the body previous theoretical dosimetry studies have addressed the potential use of radiotherapeutic liposomes for the treatment of tumors via intravenous injection in addition to these intravenous investigations, our group has investigated the potential use of rheniumliposomes for intratumoral therapy there are some significant advantages of using the intratumoral delivery route for rheniumliposomes compared with intravenous injection, such as the much lower radiation dose delivered to liver, spleen, kidney and other normal tissues, and the potential of simultaneous targeting of metastatic lymph nodes that drain from the region of the comandi apri ed esplora windows vista tumor nl tcliposomes can be used to preevaluate the suitability of usingre re liposomes to treat a tumor this is because the same chemistry is used to label liposomes with the diagnostic isotope, mtc, as the therapeutic rhenium isotopes the likely dose distribution from the rheniumliposomes can be calculated by performing spectct images of the mtcliposome distribution, in order to determine the potential dose distribution of the rheniumliposomes we have performed studies with mtc to assess intratumoral administration of radiolabeled liposomes in these studies, prolonged tumor retention and very high tumortonormal tissue ratio of mtcactivity were observed manuscript submitted for comandi apri ed esplora windows vista publicationmtcliposomes were injected intratumorally into a head and neck tumor in a rat model, using the same methodology for labeling liposomes with radiotherapeutic rhenium mtcliposomes had good tumor retention with to of injected activity still remaining in the solid tumors at hrs after injection, while unencapsulated mtcbmeda cleared from tumors quickly, with only of injected activity remaining in tumors at hrs and at hrs nanoparticles for immune modulation a few very preliminary studies suggest that the delivery of therapeutic beta emitting radioisotopes to lymph nodes has the potential to modulate the immune system for therapeutic benefit of autoimmune disease comandi apri ed esplora windows vista and for the induction of tolerance in organ transplantation these preliminary studies suggest the possibility that betaemitters delivered to lymph nodes results in a decreased immune response in the organs and regions of the body that drain that lymph node this decreased immune response has been demonstrated in pilot studies of patients with rheumatoid arthritis, as well as in patients that have received transplanted kidneys in one study, a method was developed and tested for the treatment of patients with rheumatoid arthritis, using radiotherapeutic betaemitting gold colloid particles which were infused into the lower limb lymphatic vessels more than comandi apri ed esplora windows vista patients were treated a positive therapeutic effect was observed in of the treated patients this endolymphatic radiotherapy with gold colloid particles made it possible to give up cytostatic and glucocorticoid medications and to reduce the dosage of nonsteroid antiinflammatory drugs immune modulation by radioparticle accumulation in the lymph nodes could also explain some of the beneficial effects of radiation synovectomy in this procedure, radiolabeled particles that emit beta particles are injected into the joints of patients with rheumatoid arthritis a second study also provides evidence of tolerance induction by the pre transplant endolymphatic infusion of ilipiodol this procedure was comandi apri ed esplora windows vista performed as a pretransplant preparation for patients receiving a kidney transplant twenty six years later, the outcome in the patients that received the ilipiodol was compared with that of another group of patients that did not receive the lipiodol therapy, but were treated with a standard maintenance dose of azathio prine the incidence of rejection crises was greatly reduced in the group that received the ilipiodol therapy, compared with the standard treatment group versus , p = the authors of this study concluded that the pre transplant treatment with ilipiodol had an extended immunosuppressive effect and could be indicated for comandi apri ed esplora windows vista cadaveric renal allograft recipients, especially those showing high panel reactivity it was also relatively innocuous, as there was no compromising of either the thyroid gland or the gonad function and there was no increase in tumor incidence in these patients over the year period, local infusion of nanoparticles carrying therapeutic betaemitting radioisotopes that targeted the lymph nodes might have potential applications for the prevention of transplanted organ rejection, as well as the treatment of autoimmune disorders conclusions the delivery of nanoparticles to lymph nodes for therapeutic purposes is promising significant progress has been made in understanding the various processes involved comandi apri ed esplora windows vista in nanoparticle delivery and in the development of potential systems for targeting nanoparticles to lymph nodes lymph node delivery appears promising for improving cancer and infectious disease therapy, treatment of autoimmune disease and for improvement of vaccine systems acknowledgments the author is grateful to dr beth goins for her help and critical reading of the manuscript references hirnle p liposomes for drug targeting in the lymphatic system hybridoma wisner er et al sentinel node detection using contrastenhanced power doppler ultrasound lymphography invest radiol phillips wt, klipper r and goins � novel method of greatly enhanced delivery of liposomes to comandi apri ed esplora windows vista lymph nodes} pharmacol exp ther moghimi sm modulation of lymphatic distribution of subcutaneously injected poloxamer coated nanospheres the effect of the ethylene oxide chain configuration febs lett oussoren � and storm g liposomes to target the lymphatics by subcutaneous administration adv drug del rev duzgunes n et al enhanced inhibition of hiv replication in macrophages by antisense oligonucleotides, ribozymes and acyclic nucleoside 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