• Journal of Pharmaceutical Investigation
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• v.40 no.spc
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• pp.75-82
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• 2010

Specific diseases like cancer and acquired immune deficiency syndrome (AIDS) occur at various organs including lymphatics and spread through lymphatic system. Thus, if therapeutic agents for such diseases are more distributed or targeted to lymphatic system, we can obtain several advantages like reduction of systemic side effect and increase of efficacy. For these reasons, much interest has been focused on the nature of lymphatics and a lot of studies for lymphatic delivery of drugs have been carried out. Because lymphatics consist of single layer endothelium and have high permeability compared with blood capillaries, especially, the studies using nano-sized carriers have been performed. Polymeric nano-particle, liposome, and lipid-based vehicle have been adopted for lymphatic delivery as carriers. According to the administration route and the kind of carrier, the extent of lymphatic delivery efficiency of nano-sized carriers has been changed and influenced by several factors such as size, charge, hydrophobicity and surface feature of carrier. In this review, we summarized the key factors which affect lymphatic uptake and the major features of carriers for achieving the lymphatic delivery. Lymphatic delivery of drug using nano-sized carriers has many fold improved ability of lymphatic delivery compared with that of conventional dosage forms, but it has not shown whole lymph selectivity yet. Even though nano-sized carriers still have the potential and worth to study as lymphatic drug delivery technology as before, full understanding of delivery mechanism and influencing factors, and setting of pharmacokinetic model are required for more ideal lymphatic delivery of drug.

• Journal of Pharmaceutical Investigation
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• v.25 no.1
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• pp.55-62
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• 1995

W/O and O/W emulsions of tegafur (50 mg/5 ml/kg) were orally administered to rats to compare with their mesenteric lymphatic delivery effects. And also in order to demonstrate the lymph targeting associated to the oral route, it was deemed necessary to investigate the fate of solution after oral administration as a control. Lymph and plasma samples were periodically taken from each subject of mesenteric lymphatic duct cannulated rats. Then, lymph and plasma levels of tegafur and its active metabolite, 5-FU, were simultaneously observed. Also pharmacokinetic parameters were compared with each others. On the other hand, most previous studies of lymphatic transport have not addressed the question of whether an increase in mesenteric or thoracic lymph transport by the manipulation of a suspected variable was due to a selective delivery to the intestinal lymphatics or an overall increase availability. Therefore, based on a physiologically based pharmacokinetic model which represents the characteristics of lymphatic systems, we are also going to determine the contributions of mesenteric lymph transport versus thoracic lymph transport of tegafur reported in reference(13). In comparison with tegafur solution, AUC and mean residence time of plasma tegafur were significantly increased in W/O emulsion but significantly decreased in O/W emulsion. Lymph flow rates were similar in both solution and W/O emulsion but half in O/W emulsion. AUC of tegafur in mesenteric lymph and in plasma for W/O emulsion were 3.7 times and 2.9 times more than those for O/W emulsion, respectively. And AUC of 5-FU in thoracic lymph for W/O emulsion was 3.7 times more than that for O/W emulsion. These results suggested that lymphatic delivery or tegafur by W/O emulsion was more effective than that by on emulsion due to its differences or formation ability of chylomicrons.

• Journal of Pharmaceutical Investigation
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• v.23 no.3
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• pp.19-30
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• 1993

The influence of emulsion type of tegafur, an oral anticancer agent, on lymphatic transport was studied in rats. The water-in-oil-type of emulsion and the oil-in-water-type emulsion of tegafur each in 50 mg, calculated in terms of tegafur, were prepared by adding tegafur aqueous solution to sesame oil containing hydrogenated castor oil following ultrasonic treatment, and then the prepared emulsions and aqueous solution as a comparative formulation were administered orally to rats (50 mg/5 ml/kg). The concentration levels of tegafur in plasma of femoral artery and lymph from thoracic duct cannula were measured simultaneously along a time course after administration and the pharmacokinetic parameters were investigated. At the same time, we examined the above described factors of 5-FU which is known as an active metabolite of tegafur. In comparison with tegafur solution, AUC and mean residence time of plasma tegafur were significantly increased in w/o-emulsion but significantly decreased in o/w-emulsion. Lymph flow rates were similar in both solution and w/o-emulsion but half in o/w-emulsion. Ratios between area under the lymph and plasma concentration time curves were always less than 1 reflecting the passive lymphatic delivery after oral administration of the prepared tegafur emulsions, but those to the 5-FU in the case of w/o-emulsion were more than 1. These results suggested that lymphatic delivery of tegafur by w/o-emulsion was more effective than that by o/w-emulsion due to its differences of formation ability of chylomicrons.

• Biotechnology and Bioprocess Engineering:BBE
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• v.10 no.6
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• pp.516-521
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• 2005

Drug delivery to the lymphatic system may be important in terms of the treatment with lymphatic involvement, such as tumor metastases and immunization. Especially, drug transport via the intestinal lymphatics after oral administration has been attracted lots of interests. The purpose of this study was to prepare cyclosporin A (CSA)-loaded liposomes, with different characteristics, and evaluate their mucoadhesivity. Three liposome preparations were formulated: cationic stearylamine liposomes (SA-Lip), anionic phosphatidylserine liposomes (PS-Lip), Polymer (chitosan)-coated liposomes (CS-Lip), and characterized. The liposome preparations were found to be spherical in shape, with PS-Lip being the smallest. The liposome preparations exhibited entrapment efficiencies in the order: PS-Lip $(52.5{\pm}2.9%)$ > SA-Lip $(48.8{\pm}3.3%)$ > CS-Lip $(41.7{\pm}4.2%)$. Finally, mucoadhesive tests were carried out using rat intestine, with SA-Lip (67%) showing the best adhesive rate of the three preparations (PS-Lip: 56%, CS-Lip: 61%). These results suggest that a positive charge on the surface of drug carriers may be an important factor for the intestinal drug delivery.

• Journal of Microbiology and Biotechnology
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• v.18 no.9
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• pp.1599-1605
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• 2008

Biodistribution and lymphoscintigraphy of cyclosporine A (CyA) and technetium-99m ($^{99m}Tc$) were studied using ${^99m}Tc$-labeled dextran acetate (DxA) including CyA. DxA particles were prepared from dextran with acetic anhydride, and CyA was loaded into them. Lymphatic delivery of ${^99m}Tc$-labeled DxA particles containing CyA was evaluated after subcutaneous injection into the foot pad of rats and compared with those of ${^99m}Tc$-labeled human serum albumin (HSA). The labeling efficiency of CyA-loaded ${^99m}Tc$-DxA particles was about 95% at 30 min. The labeling efficiency maintained stably above 80% for 12 h. The percent injected dose (%ID) of CyA-loaded ${^99m}Tc$-DxA was similar to that of ${^99m}Tc$-HSA at the inguinal lymph node after 40 min. The CyA-loaded ${^99m}Tc$-DxA could be as well distributed as ${^99m}Tc$-HSA through the lymph node. The DxA particles could steadily distribute the CyA as well as the ${^99m}Tc$ radiolabeling through the lymph node.

• Journal of Pharmaceutical Investigation
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• v.38 no.3
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• pp.191-197
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• 2008

The purpose of the present study was to examine the pharmacokinetics and lymphatic delivery of the oligopeptide, a model peptide of X antigen epitope peptides, after the intramuscular administration of the peptide-bearing liposomes in rats. $^{14}C$-labelled peptide was used as a tracer to analyze the peptide levels in plasma, bile, urine, tissue homogenates, and lymph nodes (superior cervical nodes, brachial nodes and superior mesenteric nodes). Model peptide rapidly disappeared from the plasma by 30 min (${\alpha}$ phase) after i.v. administration, which was followed by the late disappearance. The apparent plasma half-lives ($t_{1/2({\alpha}),app}$) of the peptide at the ${\alpha}$ phase when administered at a dose of 0.2-1.0 mg/kg were about 5 min. The maximum plasma concentration ($C_{max}$) was $1.52\;{\mu}g/mL$, after the i.m. administration of the peptide at a dose of 1.0 mg/kg. The bioavailability, which was calculated from the time zero to last quantitative time, of the i.m. administered peptide was over 60%. Of the various tissues tested, the peptide was mainly distributed in the kidney after the i.m. administration. The peptide levels in the kidney 3 hr after the i.m. administration were higher than those of maximum plasma concentration ($C_{max}$). The cumulative amounts of the peptide found in the urine 72 hr after the administration of 1.0 mg/kg were 2-folder higher than those in the bile, suggesting that the peptide is mostly excreted in the urine. Moreover, the concentrations of the peptide in the lymph nodes were as high as that of the plasma and the tissues. In conclusion, the peptide concentration in the lymph nodes was maintained by 24 hr after the i.m. administration of the peptide-bearing liposomes.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.40 no.2
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• pp.195-201
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• 2014

Body fluid has been studied for diverse fields like Ringer's solutions, artificial joint fluids, cell growth culture media because it plays a crucial role in controlling body temperature and acts as a solvent for diverse metabolite processes in the body and delivery media of mineral, energy source, hormone, signal and drug from and to cell via blood or lymphatic vessel by osmotic pressure or active uptake. Stratum corneum containing extracellular lipids and NMF (natural moisturizing factor) absorbs atmospheric water residing outside of cells and utilize it to hydrate inside of their own. This process is related to skin barrier function. In this study, we conducted the cell viability test with Cell Bio Fluid $Sync^{TM}$, which mimicks body fluids including amino acids, peptides, and monosaccharides to strengthen skin barrier, and the clinical skin improvement test with cosmetics containing Cell Bio Fluid $Sync^{TM}$. In the cell viability test, HaCaT cell was treated with PBS for 3 hours, followed by the treatment of a cell culture medium (DMEM) and isotonic solution (PBS) and Cell Bio Fluid $Sync^{TM}$ for 3 hours each. Then, MTT assay and image analysis were conducted. In the clinical skin improvement test, twenty-one healthy women participated. Participants applied cosmetics containing Cell Bio Fluid $Sync^{TM}$ on their face for a week and evaluated the skin hydration, skin roughness, brightness and evenness. All measurements were conducted after they washed off their face and took a rest under the constant temperature ($22{\pm}2^{\circ}C$) and constant humidity conditions ($50{\pm}5%$) for 20 minutes. All the data were analyzed by SPSS (version 21) software program. Results showed that Cell Bio Fluid $Sync^{TM}$ improved both the cell viability and in vivo skin conditions such as skin hydration, roughness, brightness and evenness.

• Journal of Chest Surgery
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• v.37 no.8
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• pp.691-701
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• 2004

Background: Tissue hypoxia is a characteristic of many human malignant neoplasms, and hypoxia inducible factor-1 (HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increased oxygen delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-1 a has been reported in many human malignancies, but in esophageal squamous cell carcinoma, the influence of HIF-1 a on tumor biology, including neovascularization, is not still defined. Material and Method: The influence of HIF-1 a expression on angiogenic factors, correlation between the tumor proliferation and HIF-1 a expression, interaction of HIF-1 a expression and p53, and correlation between HIF-1 a expression and clinicopathological prognostic parameters were investigated, using immunohistochemical stains for HIF-1 a, VEGF, CD34, p53, and Ki-67 on 77 cases of resected esophageal squamous cell carcinoma. Result: HIF-1 a expression in cancer cells was found in 33 of 77 esophageal squamous cell carcinoma cases. The 33 cases (42.9%) showed positive stain for HIF-1 a. High HIF-1 a expression was significantly associated with several pathological parameters, such as histologic grade (p=0.032), pathological TMN stage (p=0.002), the depth of tumor invasion (p=0.022), regional lymph node metastasis (p=0.002), distant metastasis (p=0.049), and lymphatic invasion (p=0.004). High HIF-1 a expression had significant VEGF immunoreactivity (p=0.008) and Ki-67 labeling index (p<0.001), but was not correlated with microvascular density within tumors (p=0.088). The high HIF-1 a expression was correlated with aberrant p53 accumulation with a marginal significance (p=0.056). The overall 5-year survival rate was 34.9%. The survival rate of patients with a high HIF-1 a expression was worse than that of patients with low-expression tumors (log-rank test, p=0.0001). High HIF-1 a expression was independent unfavorable factors although statistical significance is marginal in multivariate analysis. Conclusion: It is suggested that (1) high HIF-1 a expression in esophageal squamous cell carcinoma is associated with tumor hypoxia, or with genetic alteration in early carcinogenesis and progressive stages, (2) high HIF-1 a expression may be associated with intratumoral neovascularization through HIF-VEGF pathway, and (3) high HIF-1 a expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma and may playa role as biomarker for regional lymph node metastasis.