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51.
Summary A model membrane system was used to investigate the ability of specific membrane constituents to modulate the precipitation of calcium phosphate. Intraliposomal precipitation was induced in phosphate-encapsulated liposomes composed of 7:2:1 molar mixtures of phosphatidylcholine (PC), dicetyl phosphate (DCP), and cholesterol (Chol) by ionophore-supported (X-537A) Ca2+ uptake. Extraliposomal precipitation occurred when these reactions were initiated in metastable external solutions. In this case, the endogenously formed crystals penetrated through the enclosing lipid bilayers and seeded the external solution phase. Transmission electron microscopy (TEM) was used to monitor the effect of acidic phospholipids [phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG)] on the precipitation reactions when these molecular species were incorporated into the liposome membranes. Compared with the precipitation reactions in 7PC:2DCP:1Chol liposomes containing no acidic phospholipids, calcium phosphate formation in the presence of monoester phosphate (PA) and amino-(PS) phospholipids was inhibited. Analyses of the lipid-mineral interactions in PA-containing (10 mol%) liposomes revealed close physical contact between the small crystals of apatite and the inner lipid bilayers; there was only minimal extraliposomal precipitation. A few small crystals adhered to the external surfaces of the liposomes. In PS-containing liposomes, lipid-mineral interactions were dependent upon the DCP content of the lipid membrane. Discrete clusters of crystals formed within the interior aqueous compartment when intraliposomal precipitation was initiated in 7PC:2DCP:1Chol liposomes doped with up to 10 mol% PS. There was no evidence for specific associations between these crystals and the enclosing lipid bilayers. In contrast, the liposomes clustered around extraliposomally formed crystals, with the lipid membranes adhering tightly to the exposed crystal surfaces. These crystallipid interactions were reversed when the DCP component was omitted from the liposome membrane (7PC:1PS:1Chol liposomes). These results suggest that PS may be localized preferentially on the outer membrane surface in the presence of DCP but concentrated on the inner aspect in its absence. No such interactions were observed in PI or PG-containing liposomes. The liposome-mediated precipitation events were not affected in these preparations. The data suggest that the inhibition of calcium phosphate formation resulted from specific interactions between the nascent crystals and lipid species present in the liposome membrane. The molecular conformation of the head group, the molecular geometry of the phospholipids in the membrane, and the relative affinity of the incorporated species for Ca2+ were key determinats of these interactions. 相似文献
52.
目的通过以脂质体为载体介导端粒酶反义寡核苷酸(antisense oligodeoxynucleotide,asODN)转染人膀胱癌EJ细胞,促进反义寡核苷酸对膀胱癌EJ细胞的生长抑制。方法利用脂质体为载体将针对端粒酶RNA模板区的asODN转染膀胱癌EJ细胞;荧光显微镜观察细胞转染率;PCR-ELISA法测定端粒酶活性;MTT法检测反义寡核苷酸对膀胱癌细胞的抑制。结果脂质体介导的asODN在膀胱癌EJ细胞中的转染率1/2h、4h、8h分别为15%、56%、80%,并且细胞的端粒酶活性和细胞生长明显被抑制,与对照组比较,具有显著性差异(p(0.05)。结论脂质体介导的端粒酶asODN能够有效抑制膀胱癌EJ细胞端粒酶活性和生长,可应用于实验性肿瘤基因治疗研究和端粒酶与膀胱癌关系的进一步研究。 相似文献
53.
背景:外源性肿瘤坏死因子(TNF)-α联合化疗药物对肿瘤的疗效较单独应用更佳,为肿瘤治疗提供了新的方向。目的:对裸鼠人肝癌移植瘤模型行脂质体介导的TNF-α基因瘤内转染,研究肝癌移植瘤的生长抑制情况及其机制。方法:经脂质体介导,以真核表达质粒pSVK3-TNF-α分别转染人肝癌细胞株SMMC-7721和裸鼠皮下SMMC-7721细胞移植瘤。测定SMMC-7721细胞的TNF-α浓度,甲基噻唑基四唑(MTT)法测定细胞杀伤率,流式细胞仪和原位末端标记(TUNEL)法检测细胞周期和凋亡情况。结果:TNF-α转基因治疗裸鼠人肝癌移植瘤结束第5d,移植瘤体积为(75.28±35.35)mm^3,显著低于对照组的(326.45±103.64)mm^3(P〈0.05)。TNF-α基因体外转染SMMC-7721细胞24、48、72h后,基因转染组每106个细胞的TNF-α表达量分别为(1680±187)pg、(1702±205)pg和(1650±164)pg,细胞杀伤率分别为(37.1±2.4)%、(79.4±4.3)%和(84.2±4.6)%。基因转染72h后,SMMC-7721细胞增殖指数为(30.5±3.2)%,显著低于对照组的(46.1±3.9)%(P〈0.05);凋亡指数为(10.0±2.1)%,显著高于对照组的(2.7±0.4)%(P〈0.01)。结论:脂质体介导的TNF-α基因转染裸鼠人肝癌移植瘤可明显抑制肿瘤生长,其机制可能为影响肿瘤细胞生长周期以及诱导肿瘤细胞凋亡。 相似文献
54.
The incidence of systemic fungal infections that has risen dramatically over the past three decades has propelled a continuous need for more potent antifungal drugs. The purpose of this research was to evaluate the chemotherapeutic activity of a new heptaene polyene macrolide antibiotic (SJA-95) and liposomal incorporated SJA-95 (lip. SJA-95) in a mouse model of aspergillosis and cryptococcosis respectively. Lip. SJA-95 was prepared in our laboratory by the proliposome method involving incorporation of the antifungal into the proliposome mixture and its subsequent conversion into a liposomal dispersion by a simple dilution step. Treatment with free SJA-95 and lip. SJA-95, both in aspergillosis and cryptococcosis, progressively prolonged the survival time and decreased the fungal loads in vital organs respectively. A higher LD50 value of lip. SJA as compared to that of free SJA-95 was indicative of reduced toxicity of lip. SJA-95. Our findings suggest lip. SJA-95 treatment results in prolonged survival time, effective microbiological clearance and reduced toxicity that might help to establish its usefulness as a chemotherapeutic agent in systemic fungal infections with fewer adverse reactions. 相似文献
55.
RP-HPLC法测定黄芩苷脂质体的体外释放度 总被引:1,自引:0,他引:1
目的:建立以反相高效液相色谱法测定黄芩苷脂质体的体外释放度的方法。方法:色谱柱为岛津C18(150mm×4.6mm,5μm),流动相为甲醇-水-磷酸(47∶53∶0.2),流速为1.0mL.min-1,检测波长为280nm,柱温为25℃,进样量为10μL。结果:黄芩苷检测浓度在1.01~80.80μg.mL-1范围内与峰面积积分值呈良好线性关系(r=0.9998);平均加样回收率为100.05%,RSD=0.93%。结论:本方法灵敏、简便、准确,可用于黄芩苷脂质体的体外释放研究。 相似文献
56.
Jason C. Steel Heather M.A. Cavanagh Mark A. Burton Mones S. Abu-Asab Maria Tsokos John C. Morris Wouter H.J. Kalle 《European journal of pharmaceutical sciences》2007,30(5):398-405
We aimed to increase the efficiency of adenoviral vectors by limiting adenoviral spread from the target site and reducing unwanted host immune responses to the vector. We complexed adenoviral vectors with DDAB–DOPE liposomes to form adenovirus–liposomal (AL) complexes. AL complexes were delivered by intratumoral injection in an immunocompetent subcutaneous rat tumor model and the immunogenicity of the AL complexes and the expression efficiency in the tumor and other organs was examined. Animals treated with the AL complexes had significantly lower levels of β-galactosidase expression in systemic tissues compared to animals treated with the naked adenovirus (NA) (P < 0.05). The tumor to non-tumor ratio of β-galactosidase marker expression was significantly higher for the AL complex treated animals. NA induced significantly higher titers of adenoviral-specific antibodies compared to the AL complexes (P < 0.05). The AL complexes provided protection (immunoshielding) to the adenovirus from neutralizing antibody. Forty-seven percent more β-galactosidase expression was detected following intratumoral injection with AL complexes compared to the NA in animals pre-immunized with adenovirus.
Conclusions
Complexing of adenovirus with liposomes provides a simple method to enhance tumor localization of the vector, decrease the immunogenicity of adenovirus, and provide protection of the virus from pre-existing neutralizing antibodies. 相似文献
57.
P. Kaufmann-Kolle J. Drevs M. R. Berger J. Kötting N. Marschner C. Unger H. Eibl 《Cancer chemotherapy and pharmacology》1994,34(5):393-398
Hexadecylphosphocholine (HePC) shows remarkable antineoplastic efficacy in Sprague-Dawley rats bearing methylnitrosourea-induced mammary carcinoma. Unfortunately, this is accompanied by detrimental side effects that include gastrointestinal damage, body weight loss, and thrombophlebitis after i.v. injection, which has precluded the use of the HePC in humans, where nausea and vomiting can occur at noneffective dose levels. We have developed small unilamellar vesicles (SUVs) composed of HePC, cholesterol, and 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, which can be given p. o. and i.v. In contrast to the free drug, the toxicity of liposomal HePC is shown to be greatly reduced, and there is no risk of thrombophlebitis. Single administration of equimolar HePC doses results in differing pharmacokinetic values for free HePC (p. o.) and HePC-SUVs (p. o., i.v.).Abbreviations
AUC
area under the curve
-
BWC
body weight change
-
Clast
fast measured concentration
-
C
max
peak concentration
-
Cl
tot
total body clearance
-
Chol
cholesterol
-
DMBA
dimethylbenz(a)anthracene
-
HVD
half-value duration
-
HePC
hexadecylphosphocholine
-
HPLC
high-performance liquid chromatography
-
HPTLC
high-performance thin-layer chromatography
-
k
elimination constant
-
MNU
methylnitrosourea
-
PPG3PG
1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol
-
5-D
Sprague-Dawley
-
SUV
small unilamellar vesicle
-
t
a
distribution half-life
-
t
B
terminal elimination half-life
-
t
1/2
half-life
-
t
max
peak time
-
T/C
quotient of median tumor volumes of treated and control groups
-
V
d
relative volume of distribution 相似文献
58.
Shane A. Longman Pieter R. Cullis Lewis Choi Gary de Jong Marcel B. Bally 《Cancer chemotherapy and pharmacology》1995,36(2):91-101
A two-step targeting approach was used to deliver doxorubicin-loaded liposomes to a murine tumour cell (P388 leukaemia) grown in culture and, more importantly, in vivo. Targeting was mediated through the use of an antibody specific for the Thy 1.2 antigen that is highly expressed on P388 cells. Briefly, the approach consists of prelabeling target cells with biotinylated anti-Thy 1.2 antibody prior to administration of drug-loaded liposomes that have streptavidin covalently attached to their surface. Results from in vitro studies demonstrate that a 30-fold increase in cell-associated lipid and a 20-fold increase in cell-associated doxorubicin can be achieved over control liposomes using this two-step procedure. Flow-cytometry and fluorescent-microscopy data were used to confirm that P388 cells can be stably labeled with the biotinylated anti-Thy 1.2 antibody in vivo. Subsequently, liposome-targeting studies were initiated in vivo, where target cell binding was assessed following i.p. or i.v. injection of doxorubicinloaded liposomes into animals bearing P388 tumours prelabeled with biotinylated antibody. A streptavidin-mediated 3.7-fold increase in cell-associated lipid and drug was achieved when the liposomes were given i.p. When doxorubicin-loaded streptavidin liposomes were injected i.v., P388 cells located in the peritoneal cavity were specifically labeled, although the efficiency of this targeting reaction was low. Less than a 2-fold increase in cell-associated lipid was achieved through the use of target-specific (streptavidin-coated) liposomes. These studies demonstrate that the presence of a well-labeled target cell population within the peritoneal cavity will not promote accumulation of an i.v. injected, targeted liposomal drug. Furthermore, the importance of separating target-cell-specific binding from non-specific uptake by tumour-associated macrophages is discussed. 相似文献
59.
应用薄膜法制备小单层脂质体,阿霉素包封率为38.43%±3.46%,平均每个单抗携带阿霉素分子9.6个,每个单抗携带脂质体阿霉素分子336个。应用ADM、ADM脂质体、McAb-ADM-脂质体各4mg/4ml,分别给三组家兔腹腔注射。结果发现腹腔组织中,AUC(μg·hr/g)0~24在脂质体ADM组为311.933,ADM组为111.86(P<0.01)。心肌组织中AUC(μg·hr/g)0~24在ADM组为75.33,脂质全ADM组为11.29(P<0.01)。说明脂体ADM腹腔注射后能在腹腔组织中形成较高浓度,心肌组织内浓度较低,有利于提高化疗效果,降低心肌毒性。 相似文献
60.
脂质体介导的肝细胞生长因子基因在脐静脉内皮细胞中的表达与鉴定 总被引:1,自引:0,他引:1
目的构建含肝细胞生长因子(HGF)基因真核表达载体pEGFP-N1-HGF,观察HGF基因在人脐静脉内皮细胞中的表达。方法由重组质粒pRc/CMV-HGF中扩增出HGF基因,将其克隆到含增强型绿色荧光蛋白的真核表达载体pEGFP-N1中,应用脂质体将重组质粒pEGFP-N1-HGF转染到人脐静脉细胞株ECV304中,G418筛选获得稳定表达克隆,采用荧光显微镜观察、反转录聚合酶链反应(RT-PCR)、免疫细胞化学方法鉴定。结果经G418筛选后可形成抗性细胞克隆;荧光显微镜下观察到有绿色荧光;RT-PCR能扩增出HGFmRNA预期的699bp片段;免疫细胞化学证实转染HGF基因的细胞有HGF蛋白的表达。结论重组质粒pEGFP-N1-HGF能够在细胞株ECV304转录、表达。 相似文献