Hepatic Uptake and Tissue Distribution of Liposomes: Influence of Vesicle Size

Abstract

The size-dependent disposition of liposomes in rats was studied. Liposomes consisting of phosphatidylcholine, cholesterol, dicetylphospate and alphatocopherol in a molar ratio of 4:4:1:1, containing a trace of [¹⁴C]-labeled cholesterol as a marker of the lipid phase, were prepared and sized by extruding through polycarbonate membrane. [³H]-inulin was used as a marker of the aqueous phase. In situ liver perfusion in rats showed that hepatic extraction of liposomes was significant for multilamellar vesicles (MLVs) larger than 0.4 μm (0.40, 0.82 and 1.31 μm) and small unilamellar vesicles (SUV), but negligible for 0.25 μm MLV. Pharmacokinetic analysis after intravenous (i.v.) injection showed that the area under the plasma elimination curve (AUC) was significantly higher, but the volume of distribution (Vd) and the elimination rate constant (ke) were significantly lower for the 0.25 μm than for the 1.31 μm liposomes. Comparing the distribution of 1.36 and 0.25 μm MLVs after i.v. injection, the 1.31 μm MLV showed a significantly higher concentration in liver and spleen, but lower concentration in plasma and kidney, than the 0.26 μm in terms of dose percent. These results suggest that size is one of the important factors affecting the fate of liposmes in vivo. There must be a minimun size for effective uptake of liposomes by the reticuloendothelial system. If below the minimum effective uptake size, the MLV should remain in higher concentration in circulation.     

Influence of Particle Size on the Distributions of Liposomes to Atherosclerotic Lesions in Mice

ABSTRACT

In order to confirm the efficacy of liposomes as a drug carrier for atherosclerotic therapy, the influence of particle size on the distribution of liposomes to atherosclerotic lesions in mice was investigated. In brief, liposomes of three different particle sizes (500, 200, and 70 nm) were prepared, and the uptake of liposomes by the macrophages and foam cells in vitro and the biodistributions of liposomes administered intravenously to atherogenic mice in vivo were examined. The uptake by the macrophages and foam cells increased with the increase in particle size. Although the elimination rate from the blood circulation and the hepatic and splenic distribution increased with the increase in particle size in atherogenic mice, the aortic distribution was independent of the particle size. The aortic distribution of 200 nm liposomes was the highest in comparison with the other sizes. Surprisingly, the aortic distribution of liposomes in vivo did not correspond with the uptake by macrophages and foam cells in vitro. These results suggest that there is an optimal size for the distribution of liposomes to atherosclerotic lesions.     

乙草胺微囊悬浮剂的粒度及其分布

采用原位聚合脲醛树脂法制备乙草胺微囊悬浮剂,利用激光粒度仪、光学显微镜、扫描电子显微镜等研究剪切速率、芯材黏度及固化阶段搅拌速率等对乙草胺微囊悬浮剂粒度分布的影响。结果表明:乳化过程中,控制剪切速率不变,通过添加质量分数为6.25%的甲苯可以有效减小乳液的粒度;在固化阶段,选择600 r/min的搅拌速率能够减少微囊之间的粘连与破囊现象。     

水泥粒径分布对水泥石强度的影响

以水泥石水化物填充度最高为原则,综合考虑水泥水化度、水泥固相体积增量和水泥浆体初始堆积密度两个方面的匹配关系,通过理论推导和试验验证建立了多粒径(连续粒径分布)单组分水泥石强度与水泥粒径分布之间关系的计算方法,在此基础上就水泥粒径分布对水泥石强度的影响进行探讨。结果表明:计算值与试验值比较吻合,用本文中提供的方法可以根据水泥的粒径分布和各水灰比计算其不同龄期的填充度和抗压强度。     

悬浮法成型UPR微粒的粒径及其分布

以不饱和聚酯(UPR)为原料,采用悬浮法制备粒径在120～250 μm的UPR微粒.考察了搅拌速度,油水比、分散剂及电解质对聚合物颗粒平均粒径及粒径分布的影响.     

制备条件对ZrO_2超细粒子尺寸及分布的影响

本文采用胶体－超临界流体干燥法制备纳米级ＺｒＯ２超细粉料，用透射电镜（ＴＥＭ）、比表面积（ＢＥＴ）和粒度分析法对颗粒尺寸进行观察和测定，并详细考察了制备条件对产品粒子粒度及其分布的影响     

Tissue Tolerance of Diclofenac Sodium Encapsulated in Liposomes After Intramuscular Administration

ABSTRACT

In this work the effect of the encapsulation of diclofenac sodium within liposomes on the reduction of the myotoxicity after intramuscular administration in rats was studied. Diclofenac sodium was encapsulated in small unilamellar liposomes obtained from phosphatidylcholine, cholesterol, and α-tocopherol (40:10:0.04 mM), and administered by intramuscular injection in the quadriceps femoral muscle of male Wistar rats. After a single dose of 0.2 mg diclofenac formulations the local tissue damage was assessed by plasma creatine kinase (CPK) activity and histological analysis. It was demonstrated that formulations containing free diclofenac produced a higher increase in CPK activity, while those encapsulated in liposomes exhibited CPK activity similar to the control groups. Histopathological analysis of local muscle tissue performed on the third and seventh days following the injection showed intense cellular damage when free drug solution was used, while encapsulation in liposome protected the tissue against the local tissue inflammation.     

Pharmacokinetics and Tissue Uptake of Doxorubicin Associated With Erythroctte-nembrane:erithroctte-Ghosts vs Erythrocyte-Vesicles

This study examined the usefuless of erythrocyte-membrane as a biodegradable carrier for intravenous injection of doxorubicin (DOX). Two different preparations of erythrocyte-membrane were used, erythrocyte-ghosts and erythrocyte-vesicles. Ghosts were prepared from red blood cells by hemolysis and repetitive washing until complete removal of hemoglobin. Erythrocyte-vesicles were prepared by ultrasonication of the ghosts suspension by a sonic dismembrator. The membrane products were then incubated with DOX before the injection. In CD rats, the disposition of DOX solution (DOX in normal saline) and erythrocyte-vesicles-DOX followed a two-compartment open model, whereas the ghosts-DOX exhibited a three-compartment characteristics. The area under the curve of the amount in the heart vs time for ghosts-DOX was approximately the same as for the solution. However, the amount of DOX in the heart after erythrocyte-vesicles-DOX injection was below the sensitivity of the detection. The fraction of DOX excreted unchanged in the urine was 0.54 for ghosts-DOX, 0.22 for DOX solution and 0.06 for erythrocyte-vesicles-DOX. The uptake of the drug by the spleen was increased after the administration of erythrocyte-vesicles-DOX. The observed and the calculated data address the usefulness of these delivery systems for DOX.     

Pharmacokinetics and Tissue Uptake of Doxorubicin Associated With Erythroctte-nembrane:erithroctte-Ghosts vs Erythrocyte-Vesicles

Abstract

This study examined the usefuless of erythrocyte-membrane as a biodegradable carrier for intravenous injection of doxorubicin (DOX). Two different preparations of erythrocyte-membrane were used, erythrocyte-ghosts and erythrocyte-vesicles. Ghosts were prepared from red blood cells by hemolysis and repetitive washing until complete removal of hemoglobin. Erythrocyte-vesicles were prepared by ultrasonication of the ghosts suspension by a sonic dismembrator. The membrane products were then incubated with DOX before the injection. In CD rats, the disposition of DOX solution (DOX in normal saline) and erythrocyte-vesicles-DOX followed a two-compartment open model, whereas the ghosts-DOX exhibited a three-compartment characteristics. The area under the curve of the amount in the heart vs time for ghosts-DOX was approximately the same as for the solution. However, the amount of DOX in the heart after erythrocyte-vesicles-DOX injection was below the sensitivity of the detection. The fraction of DOX excreted unchanged in the urine was 0.54 for ghosts-DOX, 0.22 for DOX solution and 0.06 for erythrocyte-vesicles-DOX. The uptake of the drug by the spleen was increased after the administration of erythrocyte-vesicles-DOX. The observed and the calculated data address the usefulness of these delivery systems for DOX.     

水泥粒度分布对水泥性能影响的研究进展

从两个方面总结了水泥粒度分布对水泥性能影响的研究进展,一方面总结了反映水泥颗粒群整体情况的特征参数比表面积S、特征粒径x′和均匀性指数n对水泥性能的影响;另一方面总结了不同粒径区间水泥颗粒的性能。介绍了描述水泥粒度分布的RRB方程和Fuller曲线,综述了理论上粒度分布对水泥性能的影响情况,认为水泥的粒度分布是与其性能有明确定量关系的细度参数,是水泥粉磨细度控制的最终目标。     

Simultaneous Quantification of Tumor Uptake for Targeted and Nontargeted Liposomes and Their Encapsulated Contents by ICPMS

Liposomes are intensively being developed for biomedical applications including drug and gene delivery. However, targeted liposomal delivery in cancer treatment is a very complicated multistep process. Unfavorable liposome biodistribution upon intravenous administration and membrane destabilization in blood circulation could result in only a very small fraction of cargo reaching the tumors. It would therefore be desirable to develop new quantitative strategies to track liposomal delivery systems to improve the therapeutic index and decrease systemic toxicity. Here, we developed a simple and nonradiative method to quantify the tumor uptake of targeted and nontargeted control liposomes as well as their encapsulated contents simultaneously. Specifically, four different chelated lanthanide metals were encapsulated or surface-conjugated onto tumor-targeted and nontargeted liposomes, respectively. The two liposome formulations were then injected into tumor-bearing mice simultaneously, and their tumor delivery was determined quantitatively via inductively coupled plasma mass spectroscopy (ICPMS), allowing for direct comparisons. Tumor uptake of the liposomes themselves and their encapsulated contents was consistent with targeted and nontargeted liposome formulations that were injected individually.     

激光粒度仪测定煤粉粒度及分布的方法研究

采用激光粒度分析仪对具有粘附特性的3种煤粉的粒度及其粒度分布的测试方法进行了研究,以获得最佳测试效果;分别研究样品浓度、吸收率和折射率、表面活性剂、进样器泵转速以及超声时间等因素对煤粉粒度测量结果的影响。结果表明:表面活性剂和进样器泵转速对煤粉的测定结果影响较大,泵转速为1 800~2 600 r/min,加入约3 mL无水乙醇作表面活性剂时测量结果重复性好,数据比较准确。     

矿渣粉比表面积及粒度分布对水泥强度的影响

采用勃氏透气仪和激光粒度分析仪,对矿渣粉试样进行比表面积和颗粒群粒度分布的测试,研究矿渣粉比表面积及粒度分布对水泥强度的影响。结果表明:矿渣粉总体颗粒越细,则比表面积越大,特征粒径越小,颗粒群分布越宽;细颗粒含量(小于5μm)越多的矿渣粉,其比表面积越大,水泥砂浆的早期强度就越高。     

Autohated Deterhination of Dissolution Rate: Effect of Particle Size Distribution

The effect of particle size distribution on the dissolution of salicylic acid in an automated dissolution apparatus has been studied. Tablets were prepared by individually weighing 200 mg of the drug particles having a narrow size distribution, compressing the tablets using a hydraulic press and employing identical compression force for the same time period for each tablet. The results showed that the range values obtained were not significantly different from those obtained when the particle size was not controlled. However, the range values obtained from the dissolution of drug particles recovered from the tablet formulation were found to be similar to the range values obtained from the dissolution of the tablet formulation, indicating that compression during tabletting was responsible for observed differences.     

Particle Size Distribution of Limestone Fillers: Granulometry and Specific Surface Area Investigations

Mineral fillers can be defined as “inert materials included in a mix design for some useful purpose” (NF P18-508 Janvier 2012). They can be added to compounds in order to complete a large variety of final properties without increasing costs or to improve specific characteristics like hardness, brittleness, impact strength, compressive strength, softening point, fire resistance, surface texture, electrical conductivity, and so on. In Belgium, locally available limestone fillers are specifically very well adapted for the optimization of particle packing and flow behavior of cementitious pastes in concrete mixes. Limestone fillers may be easily characterized in terms of chemical and mineralogical properties. These properties are fundamental for the study of the behavior of concrete mixes in fresh state and for understanding interactions existing at the level of the interfacial transition zone between aggregates and cement paste. These properties are however insufficiently discriminant and particle size, as well as shape distribution, seem to have a potential influence on physical phenomena which happen during the setting process. The aim of this article is to compare five major techniques used to quantify the size and the shape of limestone fillers particles: laser diffraction scattering, wet sieving, and image analysis for particle size measurement; and BET adsorption and Blaine permeability methods for specific surface area.     

Size and Surface Charge Effect of 5-Aminolevulinic Acid-Containing Liposomes on Photodynamic Therapy for Cultivated Cancer Cells

5-Aminolevulinic acid (ALA)-containing liposomes having various average diameters and/or positive surface charges were prepared, and their photodynamic therapy (PDT) efficacy for murine thymic lymphoma cells, EL-4 cells, cultivated in vitro was investigated. The PDT efficacy for EL-4 cells and the accumulation of ALA-induced protoporphyrin IX (PpIX) in the cells increased with a decrease in the average diameter of liposomes. In particular, the ALA-containing liposomes smaller than 63.5 nm in diameter promoted the PDT efficacy in comparison with that of ALA alone. We also found no significant changes in PDT efficacy and PpIX accumulation with increasing positive surface charges of liposomes.     

The Influence of Five Selected Processing and Formulation Variables on the Particle Size, Particle Size Distribution, and Friability of Pellets Produced in a Rotary Processor

A factorial-designed study has been performed to investigate the effect of two formulation variables and three processing variables on size, size distribution, and friability of pellets made in a rotary processor by the wet granulation technique. The first are the microcrystalline cellulose content and the ratio of the amount of added water to the amount of microcrystalline cellulose in the powder mixture; the latter are the rotor speed, the spheronization time after water addition, and the water addition rate. Both formulation variables and the three processing variables have a major influence on pellet size and percentage loss in weight in the friability test. With the exception of the spheronization time, increasing an independent variable results in a wider size distribution. The wet granulation technique in the rotary processor has been judged to be a critical technique. However, if all variables are fully controlled, rather good reproducibility can be obtained     

粒径分布对循环床内颗粒速度分布的影响

利用激光相位多普勒粒子分析仪（PDPA），在截面尺寸为100mm×15mm的二维循环流化床实验装置上测量比较了平均粒径基本相同的3种不同粒径分布的玻璃珠颗粒在相同操作气速下的颗粒时均速度、脉动速度与数量密度的截面分布特性；初步考察了粒径分布对气固并流上行两相湍流流动行为的影响问题。     

Influence of One Quinolone on the Formation and the Physical Stability of Liposomes

Abstract

The influence of one quinolone on the formation and physical stability of phosphatidylcholine (PC) liposomes is described. Based on Photon Correlation Spectroscopy (PCS) measurements, namely mean diameter and polydispersity, the maximum proportion of quinolone which is compatible with liposome morphology and homogeneous population was established in 30% mole of drug in a PC matrix. This lead to a pharmaceutical formulation which includes the additive D-α-tocoferol as antioxidant, glycerol as a co-solvent and phosphatidylcholine-cholesterol (2:1, mole/mole) as the formal lipid matrix. Drug encapsualtions between 30–40% were found. The feasibility of the method to scale-up this liposome formulation is discussed in terms of PCS, efficiency of encapsulation and preliminary assays in vivo.