支链淀粉修饰双嘧达莫脂质体的制备及其在小鼠体内的组织分布

目的研究支链淀粉修饰双嘧达莫(DIP)脂质体的制备方法并考察其在小鼠体内的组织分布。方法 采用薄膜-分散法制备普通DIP脂质体；合成两亲性的棕榈酰化支链淀粉并用其修饰DIP脂质体；比较修饰前后包封率、zeta电位、平均粒径和径距的变化；采用反相高效液相法测定小鼠组织中的DIP浓度。结果修饰后DIP脂质体的包封率降低，zeta电位增加，平均粒径和径距无明显变化；普通脂质体可以增强DIP在肺部、肝脏和脾脏的分布，而较之普通脂质体，支链淀粉修饰的脂质体可以进一步增加肺部DIP水平，同时减少DIP在肝脏和脾脏的分布，并延长在肺部的滞留时间。结论与普通脂质体和注射液比较，支链淀粉修饰的脂质体可以改变DIP在小鼠体内的组织分布，具有显著的肺靶向性。     

肺靶向阿奇霉素脂质体的制备及其在小鼠体内的分布

目的研究肺靶向阿奇霉素阳离子脂质体的制备方法并考察其在小鼠体内的分布。方法利用旋转薄膜-冻融法制备肺靶向阿奇霉素脂质体。用高效液相色谱法测定给药后小鼠体内各组织中的药物浓度。结果制得的脂质体平均粒径为6.582 μm，表面电荷为+19.5 mV，包封率大于75%，稳定性好。药物体外释药符合Higuchi方程。小鼠尾静脉给药后，阳离子脂质体主要被肺摄取，在肺部的滞留时间明显延长，AUC值约为阿奇霉素溶液的8.4倍。结论采用薄膜-冻融法，添加十八胺可制得具有较高包封率及稳定性的阿奇霉素阳离子脂质体，在小鼠肺部的分布优于注射液，能达到肺靶向目的。     

静脉注射德氮吡格在小鼠的组织分布及排泄研究

<正>德氮吡格(Tetrazanbigen,TNBG)是重庆医科大学药学院余瑜教授首创合成的氮杂甾烷类化合物[1]。前期研究表明,TNBG主要干扰肿瘤细胞的脂代谢过程、干扰肝癌细胞株QGY-7701蛋白表达,从而发挥抗肿瘤的作用[2-3]。本课题组已经申请了TNBG专利保护,并已经成功建立了德氮吡格在血浆及肝脏组织中的含量测定方法[4],目前缺少该物质的组织分布研究资料。为全面了解TNBG在动物体内的动态变化规律和特点,进一步考察TNBG的体内药代动力学特     

超氧化物歧化酶脂质体在大鼠体内的药代动力学和组织分布

目的考察3种超氧化物歧化酶(SOD)脂质体静脉给药后在大鼠体内的药代动力学和组织分布。方法 用反相蒸发法制备SOD脂质体，采用黄嘌呤氧化酶法检测SOD活力，静脉注射给药后，测定大鼠血中SOD含量变化和不同组织中SOD含量变化。结果在血浆中，SOD水溶液、SOD普通脂质体、用DSPE-PEG2000修饰的SOD脂质体、用Tween 80修饰的SOD脂质体的半衰期分别为0.25，0.34，0.66和0.41 h；AUC分别为12.48，24.66，41.16和33.02 μg·h·mL^-1。与普通脂质体比较，经过DSPE-PEG和Tween 80修饰后的脂质体，使肝、脾中SOD的含量有不同程度的降低，脑中含量有所提高。结论3种SOD脂质体均可不同程度地延长SOD的血浆半衰期，并以用DSPE-PEG2000修饰的SOD脂质体效果最好。与普通脂质体相比，用Tween 80修饰的SOD脂质体可以提高进入脑中的SOD量，用DSPE-PEG2000修饰的SOD脂质体可以减少肝脾对SOD的摄取。     

紫杉醇隐形脂质体的制备及在小鼠体内的组织分布

目的　研究紫杉醇隐形脂质体的制备方法并考察其在小鼠体内的组织分布。方法　采用共沉淀和微流态化两步法制备紫杉醇隐形脂质体,用两亲性聚乙二醇-二硬脂酰磷脂酰乙醇胺(PEG-DSPE)修饰脂质体膜。以RP-HPLC法测定小鼠组织内紫杉醇药物浓度。结果　隐形脂质体粒径≤100 nm,药物包封率≥98%。均以5 mg.kg^-1经iv脂质体紫杉醇和游离紫杉醇,24 h后紫杉醇隐形脂质体在血液中驻留35%以上,在肝脾组织中摄取不足10%。而膜材中不含PEG-DSPE的紫杉醇传统脂质体在血液中驻留10%,被单核吞噬细胞系统(mononuclear phagocyte system, MPS)捕获了50%以上。证明紫杉醇隐形脂质体延长了在血循环中的时间并减少了MPS的吞噬。血液AUC隐形脂质体约为传统脂质体的2.0倍。结论　采用共沉淀和微流态化法可制得包封率高、粒径小的脂质体,用PEG-DSPE修饰磷脂膜可以增加隐形脂质体的AUC,并延长其在血循环中的时间。     

卡莫司汀脂质体的制备及其在小鼠体内的分布

采用旋转蒸发法制备卡莫司汀(1)脂质体,以HPLC法测定小鼠单剂量(62.5 mg/kg)尾静脉注射1脂质体混悬液或溶液后血浆和各组织(脑、心、肺、脾和肾)中的药物浓度.结果表明,1脂质体组的血浆、脑、心、肺、脾和肾中的AUC分别为1溶液组的1.77、1.84、1.25、1.56、2.81和1.22倍.表明1制成脂质体后在小鼠体内的稳定性提高.     

β-榄香烯脂质体的制备及其在大鼠体内的组织分布

目的:研制β-榄香烯脂质体并考察其在大鼠体内的组织分布。方法:采用薄膜分散法制备β-榄香烯脂质体,考察其形态、粒径、Zeta电位、药物含量及包封率。并以榄香烯注射液为对照,大鼠尾静脉注射给药,考察β-榄香烯脂质体在血浆及心、肝、脾、肺、肾的分布特征。结果:制备的β-榄香烯脂质体均匀圆整,粒径为(158±s 37)nm,Zeta电位为(-67±4)mV,药物含量为(5.76±0.21)g·L~(-1),包封率为(45.08±0.15)%(n=3)。大鼠尾静脉注射β-榄香烯脂质体和榄香烯注射液后,2种制剂在心、肝、脾、肾中的AUC_(0-t)均有显著差异,其中β-榄香烯脂质体在肝、脾、肾组织中分布相对较多,在心脏中分布较少。结论:薄膜分散法制备β-榄香烯脂质体方法可行,β-榄香烯脂质体在大鼠体内的分布特性有不同程度的改变,可提高疗效,降低心脏毒性。     

Pharmacokinetics and tissue distribution of liposomal etoposide in rats

Precipitation of etoposide and adverse events associated with the co-solvents in intravenous solutions can be avoided by using liposomal etoposide (LE). The pharmacokinetics and distribution of the commercial formulation (ETPI) and LE were compared in rats. The pharmacokinetic profiles were biphasic and similar in the initial phase (C_max, Vd, and t_1/2α). However, LE showed a 60% increase in AUC with a 35% decrease in clearance (p?<?0.05). This decreased clearance resulted in a 70% increase in the MRT of etoposide. The uptake of etoposide from LE was higher in macrophage-phagocytic endowed tissues indicating that LE is superior to ETPI for targeted delivery of etoposide.     

基因重组人肿瘤坏死因子α衍生物在小鼠组织中的分布(英文)

目的:研究基因重组人肿瘤坏死因子衍生物α(rhTNFαDa)的组织分布及其机制。方法:用Iodogen法制备~(125)I-rhTNFαDa,测定在小鼠全身组织的分布;用离体心肺灌流研究~(125)I-rhTNFαDa在肺组织的分布机制。结果:除甲状腺组织外,~(125)I-rhTNFαDa的组织浓度-时间曲线下面积在肺组织中最高,为血清的12.2倍;离体心肺灌流显示~(125)I-rhTNFαDa在肺中的浓度高于灌流液3.7-7.4倍,而心脏组织低于灌流液.~(125)I-rhTNFαDa在肺中分布具有时间依赖性,剂量依赖性,可竞争性,和高亲和性特征,K_d为47.6 pmol·L~(-1),B_(max)为348 fmol·g~(-1)(肺组织),结论:~(125)I-rhTNFαDa在肺组织中有特异性的高分布,此过程可能有受体介导。     

Preparation and the in-vivo evaluation of paclitaxel liposomes for lung targeting delivery in dogs

Objectives The aim of this study was to develop paclitaxel liposomes for a lung targeting delivery system. Methods The liposomes composed of Tween‐80/HSPC/cholesterol (0.03 : 3.84 : 3.84, mol/mol), containing paclitaxel and lipids (1 : 40, mol/mol), were prepared by a combination of solid dispersion and effervescent techniques, and then subjected to ultrasonication. The pharmacokinetics and biodistribution of liposomal and injectable formulation of paclitaxel in dogs were studied after intravenous administration. Key findings The mean diameter, polydispersity index, zeta‐potential and entrapment efficiency of the liposomes were 501.60 ± 15.43 nm, 0.28 ± 0.02, ?20.93 ± 0.06 mV and 95.17 ± 0.32%, respectively. The liposomal formulation kept stable for at least 3 months at 6 ± 2°C and didn't cause haemolysis. The liposome carrier decreased the area under the curve and terminal half‐life of paclitaxel compared with paclitaxel injection ranging from 0.352 ± 0.031 mg/l*h and 0.0671 ± 0.144 h to 0.748 ± 0.062 mg/l*h and 1.978 ± 0.518 h, respectively. The paclitaxel liposomes produced a drug concentration in the lung that was markedly higher than that in other organs or tissues and was about 15‐fold of that of paclitaxel injection at 2 h. Conclusions To sum up, these results demonstrated that the paclitaxel liposomes are an effective lung targeted carrier in the treatment of lung cancer.     

不同粒径辅酶Q_(10)乳剂和脂质体小鼠药物动力学和组织分布

目的研究不同粒径辅酶Q10乳剂和脂质体小鼠药物动力学和组织分布。方法以市售辅酶Q10注射液(S)为对照,考察其60 nm乳剂(E60)、120 nm乳剂(E120)、60 nm脂质体(L60)和120nm脂质体(L120)小鼠尾静脉给药后的药物动力学及组织分布特征;采用DAS2.1.1药物动力学软件,进行房室模型和统计矩两种模式拟合;以组织相对摄取率(re)为指标,评价载体的粒径和种类对组织靶向性的影响。结果不同粒径辅酶Q10乳剂和脂质体体内分布均符合双隔室模型;E60、E120、L60和L120的统计矩AUC分别是S组的1.17、1.50、5.99和8.65倍;re结果显示,E60组在心、脾和脑的含量分别是S组的2.64、2.74和1.95倍,E120组在心、脾和脑的含量分别是S组的4.89、3.77和2.38倍;L60组在脑中的含量是S组的1.56倍,L120组在脑和肺的含量分布是S组的2.28和1.85倍。结论载体粒径和种类对辅酶Q10体内分布的影响十分明显,市售注射液组、乳剂组和脂质体组的AUC依次增大,且同一载体中,120 nm组较60 nm组的AUC高;相对市售注射液,乳剂组对心、脾和脑有一定的靶向性,而脂质体组主要靶向于脑和肺,同一载体内,120 nm组在多数组织的富集量多于60 nm组。     

Pharmacokinetics and tissue distribution of larotaxel in rats: comparison of larotaxel solution with larotaxel-loaded folate receptor-targeting amphiphilic copolymer-modified liposomes

1.?The aim of this study was to compare the pharmacokinetics (PKs) and tissue distribution of larotaxel (LTX) solution with a newly developed formulation called LTX-loaded folate-poly (PEG-cyanoacrylate-co-cholesteryl cyanoacrylate) (FA-PEG-PCHL)-modified liposomes in rats.

2.?An ultra-performance liquid chromatography-tandem mass spectrometry method has been developed and validated for the determination of LTX in rat plasma and tissues to investigate the in?uence of FA-PEG-PCHL-modified lipid carrier on LTX PKs and tissue distribution.

3.?The PK study result showed significantly higher area under the concentration-time curve (97.2%, **p?p?p?p?p?p?p?p?4.?These results indicated that the FA-PEG-PCHL-modified liposome could be an effective parenteral carrier for the delivery of LTX in cancer treatment.     

Distinction Between the Depletion of Opsonins and the Saturation of Uptake in the Dose-Dependent Hepatic Uptake of Liposomes

Opsonins play a role in the hepatic uptake of particles such as bacteria, lipid emulsion, and liposomes. The objective of this study was to distinguish between opsonin depletion and uptake saturation in the dose-dependent hepatic uptake of liposomes. The uptake of opsonized and unopsonized liposomes was determined in the isolated perfused liver. Serum (2.9 mL) was required to opsonize 1 µmol liposomes fully, indicating that a rat (250 g with 10 mL of serum) can opsonize 3.5 µmol liposomes. Next the dose effect on hepatic uptake of opsonized and unopsonized liposomes was examined. Saturation of uptake was found only for the opsonized liposomes. On the other hand, the hepatic uptake clearance decreased dose dependently from 4.31 to 0.79 (mL/min), with increasing doses from 0.075 to 17 µmol/250 g, respectively, after i.v. administration. Thus, the decrease in the hepatic uptake clearance at the medium dose was due to the saturation of uptake alone, and at the high dose it was due to opsonin depletion as well. These results show that the saturation of liposomal uptake in the liver and the depletion of opsonins occurred at different liposome dosage levels.     

Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs

Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ^®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18–94 µg/mL.     

Safety,Toxicokinetics and Tissue Distribution of Long-Term Intravenous Liposomal Amphotericin B (ambisome®): A 91-day Study in Rats

Purpose. Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated. Methods. Rats (174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg), dextrose, or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated. Results. Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] 51 mg/dl; creatinine unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma; kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues. Conclusions. Despite nonlinear accumulation, AmBisome revealed predictable hepatic and renal toxicities after 91 days, with no new or delayed effects after prolonged treatment at high doses that resulted in plasma levels >200 g/ml and tissue levels >3000 g/g.     

A study on liposomal encapsulation of a lipophilic prodrug of LHRH

This study aimed at evaluating whether derivatization of luteinizing hormone-releasing hormone (LHRH) peptide with an amphiphilic lipoamino acid moiety could allow, along with other technological and/or pharmacokinetic advantages, to improve its encapsulation in liposomes, potentially driving its further body distribution and cellular uptake. Experimental data confirmed that a lipophilic derivative of LHRH was efficiently incorporated in various liposomal systems, differing in lipid composition and surface charge, and obtained using different methods of production. Incubation of liposomes, loaded with a fluorescent derivative of the LHRH prodrug, with NCTC keratinocytes or Caco-2 cell cultures showed that the carriers can be rapidly internalized. Conversely, the internalization of the free prodrug occurred only at very high concentrations.     

Formulation and characterization of boanmycin-loaded liposomes prepared by pH gradient experimental design

This study reports the development of a novel liposomal formulation containing boanmycin (BAM) by the pH-gradient, spherical symmetric experimental design. DSC was used to elucidate the thermotropic transition of the soybean egg phosphatidylcholine (EPCS) bilayers. The DSC analysis showed that the incorporation of cholesterol into the EPCS bilayers caused a reduction in the cooperativity of the bilayer phase transition, leading to a dense and more stable structure. To further explore the possibility of the facilitated molecular interaction between BAM and lipids, the effective chemical shift anisotropy (Δδ) of EPCS was measured by ³¹P-NMR spectroscopy in the presence and absence of BAM at 25°C. The results revealed that the amino group of BAM interacted with the hydrophilic head group of EPCS by electrostatic attraction. Effects of the lipid concentration, pH of the outside buffer and incubation temperature on the encapsulation efficiency of the liposomes were investigated by the spherical symmetric design. Multiple nonlinear regression and second-order polynomial model were fitted to the data, and the resulting equations were used to produce the three dimensional response graphs. The actual response values were in good agreement with the predicted values calculated by the visual FoxPro software. To determine the plasma pharmacokinetics and tissue distribution characteristics of BAM, mice were i.v. injected with BAM-loaded liposomes and the commercial injection solution. The BAM-loaded liposomes exhibited significantly different t_1/2, CL and AUC in plasma and tissues. The MTT assay showed that the BAM-loaded liposomes effectively inhibited the cell proliferation by inducing apoptosis of HepG2 cells in a dose- and time-dependent manner. Compared to the control group, the BAM-loaded liposomes induced marked apoptotic morphologic alterations, including cell shrinkage and granular apoptotic bodies.     

Altered Tissue Distribution and Elimination of Amikacin Encapsulated in Unilamellar,Low-Clearance Liposomes (MiKasome®)

Purpose. Amikacin in small unilamellar liposomes (MiKasome^®) has prolonged plasma residence (half-life > 24hr) and sustained efficacy in Gram-negative infection models. Since low-clearance liposomes may be subject to a lower rate of phagocytic uptake, we hypothesized this formulation may enhance amikacin distribution to tissues outside the mononuclear phagocyte system. Methods. Rats received one intravenous dose (50 mg/kg) of conventional or liposomal amikacin. Amikacin was measured for ten days in plasma, twelve tissues, urine and bile. Results. Liposomal amikacin increased and prolonged drug exposure in all tissues. Tissue half-lives (63–465 hr) exceeded the plasma half-life (24.5 hr). Peak levels occurred within 4 hours in some tissues, but were delayed 1–3 days in spleen, liver, lungs and duodenum, demonstrating the importance of characterizing the entire tissue concentration vs. time profile for liposomal drugs. Predicted steady-state tissue concentrations for twice weekly dosing were >100 g/g. Less than half the liposomal amikacin was recovered in tissues and excreta, suggesting metabolism occurred. Amikacin was not detected in plasma ultrafiltrates. Tissue-plasma partition coefficients (0.2-0.8 in most tissues) estimated from tissue-plasma ratios at T_max were similar to those estimated from tissue AUCs. Conclusions. Low-clearance liposomal amikacin increased and prolonged drug residence in all tissues compared to conventional amikacin. The long tissue half-lives suggest liposomal amikacin is sequestered within tissues, and that an extended dosing interval is appropriate for chronic or prophylactic therapy with this formulation.