Tissue Distribution Of Liposomes Research Articles

Abstract 1961: Evaluated mechanism of dual targeting using liposomal doxorubicin-modified novel PEG by imaging analysis

Abstract [Purpose] Liposome is one of the useful drug carriers and it may be applying to a lot of diseases from now on. One of the most reasons which liposomes were using as medicine was improvement of circulation time in bloodstream by modifying polyethyleneglycol (PEG)-lipid. We synthesized novel PEG-lipid with two different PEG lengths of 2000 and 500 (different double arms-PEG; DDA-PEG) for developing more superior passive targeting liposome. In our previous study, doxorubicin (DOX) containing liposome which was modified DDA-PEG (DDA-PEG modified liposomal DOX; DDA-LDOX) had dual effect for primary and hepatic metastasis cancer. In this study, we observed tissue distribution at primary tumor using the near infrared fluorescence and analyzed hepatic metastasis by histological observation for explain this dual effect. Moreover, this effect for pulmonary metastasis was also evaluated. [Methods] Liposome (DSPC/cholesterol/DSPG-Na/DDA-PEG = 100:100:60:7.5 μmol) was prepared according to the method of Bangham. For observing tissue distribution of liposome at primary tumor model, liposome was contained indocyanine green (ICG) as fluorescence probe. This liposome was injected in tail vein and sequentially observed using fluorescent imaging device (Clairvivo OPT, SHIMADZU). In histological observation at hepatic metastasis murine model, M5076 ovarian sarcoma cells were inoculated in tail vein of mice. These mice were injected liposome at a dose of 2.5 mg/kg (i.v.) as DOX on 6, 9 and 12 d after tumor inoculation. At 14 d, this liver was removed and examined by microscope after HE stain. At assessment of pulmonary metastasis, B16F10 melanoma cells were implanted in tail vein and treated similarly to liver metastasis.[Results and discussion] In fluorescent imaging of primary tumor, DDA-PEG modified liposome assembled into tumor at 48 h after injection. This analysis supported our previous finding that DDA-LDOX significantly decreased tumor size. Furthermore, it was proved that DDA-PEG modified liposome or encapsulated drug remained in tumor site for a long time. In histological examination for hepatic metastasis, the tumor area in the liver was 5% by DDA-LDOX injection (normal group: 90%). More lymphocytes around tumor thrombus were positive for CD45. It was suggested that macrophage or lymphocytes, especially T cell, were concerned in this therapy. Pulmonary metastasis was depressed by DDA-LDOX compared with control or DOX containing PEG unmodified liposome group. In DDA-LDOX group, DOX concentration in lung was 2.6 times higher than that in PEG unmodified liposome group. It is known that metastasis is the most severe factor in cancer chemotherapy. Antitumor agent containing DDA-PEG modified liposome may have not only superior effect for primary tumor but also hepatic or pulmonary metastasis. Hence, it was suggested that DDA-PEG modified liposome was useful drug carrier for passive targeting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1961. doi:1538-7445.AM2012-1961

Opsono-recognition of liposomes by tissue macrophages

On exposure to blood, liposomes of different morphology and lipid composition attract different arrays of proteins. The mode of interaction of blood proteins with liposomes vary in quantity and conformation. These differences may explain different observed patterns in blood clearance and tissue distribution of liposomes. In this paper, an attempt is made to assess the role of serum and its components in regulating liposome recognition by isolated phagocytes of rat liver and spleen.

Effect of Macrophage Elimination Using Liposome-Encapsulated Dichloromethylene Diphosphonate on Tissue Distribution of Liposomes

AbstractEffect of macrophage elimination using liposomal dichloromethylene diphosphonate (C12MDP)1 on tissue distribution of different types of liposomes was examined in mice. Intravenously administration into mice with CI2MDP encapsulated in liposomes composed of phosphatidylcholine, cholesterol and phosphatidylserine exhibits a temporary blockade of liver and spleen function for liposome uptake. At a low dose of 90 (ig/mouse, the liposome uptake by the liver was significantly decreased. Such decrease was accompanied by an increase in liposome accumulation in either spleen or blood depending on liposome composition and size. Direct correlation between the administration dose of liposomal CI2MDP and the liposome circulation time in blood was also obtained even for liposomes with an average diameter of more than 500 nm. These results indicate that temporary elimination of macrophages of the liver and spleen using liposomal CI2MDP may prove to be useful to enhance the drug delivery efficiency of liposomes.

Tissue distribution of liposomes prepared from synthetic amphiphiles after intraperitoneal injection into mice

The tissue distribution of 99mTc-labeled vesicles prepared from synthetic amphiphiles containing an amino acid residue (synthetic liposomes) after intraperitoneal (i.p.) injection in Ehrlich solid tumor-bearing mice was investigated. Synthetic liposomes were labeled with 99mTc using stearylamine-diethylenetriaminepentaacetic acid as a chelator. The accumulation of the synthetic liposomes in liver decreased and that in pancreas significantly increased in comparison with those after intravenous injection. Gamma camera images after i.p. injection also indicated high uptake of the synthetic liposomes in pancreas. The radioactivity of the synthetic liposomes in vitro was taken up most highly in pancreas among some excised organs.

Tissue distribution and cellular distribution of liposomes encapsulating muramyltripeptide phosphatidyl ethanolamide. Tissue and cellular distribution of LE-MTPPE.

In previous studies it was shown that administration of liposome-encapsulated MTPPE (LE-MTPPE) led to resistance against Klebsiella pneumoniae infection. To get more insight in the cell types that are involved in this by LE-MTPPE induced antibacterial resistance, the tissue distribution of liposomes encapsulating MTPPE and the distribution over the cells in the main target organs were investigated. After intravenous injection of the liposomes in mice a substantial amount was recovered from liver and spleen and a smaller amount from the lung. In the liver 83% of the liposomes was taken up by the macrophages. In the spleen also most liposomes were taken up by macrophages of the red and white pulp as well as by dendrocytes. The liver and spleen were also the organs in which, after intravenous inoculation, K. pneumoniae was trapped. It was observed that cells containing LE-MTPPE often had not taken up bacteria. Most bacteria, about 73%, were found in cells not containing liposomes. The capacity of the liposome-containing cells to take up bacteria did not change with time. This suggests that the by LE-MTPPE immunostimulating effect is due to the production of cytokines by the cells that take up LE-MTPPE. These cytokines might stimulate other cells to the killing of bacteria.

Effects of glycophorin and ganglioside GM 3 on the blood circulation and tissue distribution of liposomes in rats

The effects of glycophorin (GP) and ganglioside GM 3 (GM 3) on the blood circulation and tissue distribution of liposomes were investigated in rats. Liposomes composed of dipalmitoylphosphatidylcholine (DPPC)/cholesterol (Chol) or sphingomyelin (SM)/Chol, which contained additionally GP and/or GM 3, were prepared and the blood concentration and tissue (liver, kidney, lung and spleen) distribution after intravenous administration were compared with the control liposomes which contained neither GP nor GM 3. The blood concentration of DPPC liposomes containing GP and GM 3 (GP-GM 3-Lip[DPPC]) was significantly higher than those of the other DPPC liposomes for up to 6 h after administration, and about 3.3-fold higher than that of control liposomes (Con-Lip[DPPC]) at 6 h. The liver uptake of GP-GM 3-Lip[DPPC] at 6 h was significantly reduced compared with that of Con-Lip[DPPC], while the spleen uptake was increased significantly. Similarly, in the case of SM liposomes, the liposomes containing GP and GM 3 (GP-GM 3-Lip[SM]) prolonged the blood circulation time of liposomes and reduced their uptake by the liver, and the blood concentration was about 3.7-fold higher than that of control liposomes (Con-Lip[SM]) at 6 h. It was found that GP and GM 3 were useful and valuable for prolonging the blood circulation time of liposomes and reducing the uptake of liposomes by the liver.

Uptake and tissue distribution of liposomes after intraperitoneal administration to rainbow trout, Oncorhynchus mykiss (Richardson): a preliminary report

Uptake and tissue distribution of liposomes after intraperitoneal administration to rainbow trout, <i>Oncorhynchus mykiss</i> (Richardson): a preliminary report

The effect of elimination of macrophages on the tissue distribution of liposomes containing [ 3H]methotrexate

In the present study the tissue distribution of [ 3H]methotrexate was studied after intravenous injection of [ 3H]methotrexate-containing liposomes in normal and macrophage-depleted mice. Elimination of macrophages was performed by treatment with dichloromethylene diphosphonate- (DMDP)-containing liposomes. After thorough elimination of the macrophages from spleen and liver, by two intravenous injections of DMDP liposomes 6 and 4 days before tissue distribution studies, we found dramatic changes in the localization pattern of [ 3H]methotrexate liposomes in the blood, due to a decreased uptake of [ 3H]methotrexate liposomes by the DMDP liposome-treated liver. Because of the absence of these macrophages that are able to clear the blood of liposomes, and because of the resulting higher blood level of liposomes, we found an enhanced uptake of [ 3H]methotrexate liposomes by the spleen. It may be concluded that, in the spleen, apart from uptake of liposomes by macrophages, at least one other mechanism is responsible for the clearance of liposomes from the circulation. When comparing cholesterol-rich with cholesterol-poor liposomes, we found basically the same results, although uptake of cholesterol-rich liposomes by macrophages was smaller than that of cholesterol-poor liposomes, as found in several other studies. We suggest that pretreatment with DMDP liposomes can help to maintain a high level of intravenous-injected liposome-entrapped material in the blood, which otherwise would be removed by macrophages.

The effect of reticuloendothelial blockade on the blood clearance and tissue distribution of liposomes

The blood clearance and tissue distribution of liposomes have been studied in mice subjected to reticuloendothelial blockade with dextran sulphate or carbon. The liposomes have been labelled in the lipid membranes with [ 3H]-cholesterol, [ 14C]phosphatidylcholine and/or 99mTc and the content with [ 14C]inulin. Reticuloendothelial blockade has been shown to slow the rate of clearance of neutral, positively and negatively charged liposomes and of both small unilamellar vesicles and large multimellar vesicles. In normal animals, the liver uptake accounted for only 20–55% of the total injected radioactivity, the amount varying with the charge and size of the liposomes. Following blockade, the liver uptake of charged and neutral multilamellar liposomes was depressed. This was also true for negatively charged small unilamellar vesicles. The degree of depression of hepatic uptake was between 25–50%, which contrasts with the 80–90% reduction in uptake of a wholly phagocytosed particle (sheep red cells). This difference suggests that mechanisms other than Kupffer cell phagocytosis are also responsible for the normal uptake of liposomes into the liver. In the case of neutral and positively charged small unilamellar vesicles, delayed clearance due to blockade was not associated with ‘depressed’ hepatic uptake. The site of action of blockading agents for these preparations is not clear. With all preparations of liposomes, blockade produced a slight and variable increase in uptake in the lung and spleen. The alteration of distribution of liposomes by reticuloendothelial blockade is therefore not great and the value of the technique in modifying the tissue distribution of substances within liposomes may be limited.

Hepatic uptake and degradation of unilamellar sphingomyelin/cholesterol liposomes: a kinetic study.

The kinetics of hepatic uptake and degradation of sphingomyelin/cholesterol (2:1, M/M) small unilamellar liposomes were investigated in a BALB/c mouse. The tissue distribution of liposomes was determined by scintillation spectrometry. The percentage of intact liposomes in tissues was estimated by the technique of gamma-ray perturbed angular correlation. A kinetic model was developed to analyze the above data. A remarkable agreement was noted between the experimental data and the corresponding theoretical values. Our results indicate that the sphingomyelin/cholesterol unilamellar liposomes had an unusually long half-life of 16.5 hr in the circulation after intravenous administration to mice. The hepatic degradation of the liposomes in vitro at 37 degrees C followed first-order kinetics, with a half-life of 3.5 +/- 0.2 (SEM) hr. Furthermore, the rate of the in vivo degradation of liposomes in the liver was found to be quite similar to that in vitro, with a half-life of 3.6 +/- 0.4 hr. The rate of release of the liposome-encapsulated agent, indium-111, in the liver was not constant, and reached a maximum at about 8 hr after the administration of liposomes. The approach developed in the present study is general and can be applied to the investigation of factors that may control the release of pharmacologically active agents in any tissue.

Plasma clearance and tissue distribution of liposomes containing different sterols.

Plasma clearance and tissue distribution of liposomes containing different sterols.