猕猴桃根多糖脂质体对伊半乳糖胺所致小鼠实验性急性肝损伤的药效作用

目的：研究猕猴桃根多糖（APPS）脂质体对D-半乳糖胺所致小鼠急性肝损伤的保护作用。方法：采用D-半乳糖胺所致小鼠急性肝损伤模型,以联苯双酯为对照药,以小鼠血清中ALT、AST等为指标,评价APPS脂质体的抗急性肝损伤作用。结果：APPS脂质体口服液高剂量（200mg／kg）对D-半乳糖胺所致小鼠急性肝损伤药效作用结果显著（P〈0．05或P％0．01）。低剂量（50mg／kg）对各肝损伤模型的治疗则无显著性意义（P〉0．05）。结论：APPS脂质体口服液对小鼠急性肝损伤有较好的保护作用。     

不同磷脂组成莪术油包合物脂质体的抗肿瘤作用比较

目的:考察不同磷脂组成莪术油包合物脂质体的抗肿瘤药效。方法:采用乙醇注入法制备了莪术油包合物脂质体。KM小鼠接种H22瘤株造成移植性荷瘤小鼠模型,比较莪术油不同制剂[包括莪术油溶液,莪术油包合物(ZTO-HPCD)、莪术油包合物SPC脂质体(ZTO-HPCD-SL)及莪术油包合物复合磷脂脂质体(ZTO-HPCD-SHL)]给药后荷瘤小鼠的抑瘤效果,比较给药后各组荷瘤小鼠的体质量和免疫器官(脾和胸腺)指数。并且还考察了对腹水癌模型小鼠生命延长率的影响。结果:磷脂组成对莪术油包合物脂质体的抗肿瘤效果具有显著影响。相同剂量下的莪术油溶液、ZTO-HPCD、ZTO-HPCD-SL、ZTO-HPCD-SHL的抑瘤率分别为17.90%、17.49%、39.77%、59.42%,与莪术油溶液相比,莪术油包合物脂质体制剂给药后未发现对免疫器官存在明显的抑制作用,具有一定的生命延长作用。结论:采用包合物脂质体与复合磷脂脂质体技术可以显著提高莪术油的抗肝癌效果。     

鲑鱼降钙素柔性脂质体大鼠鼻腔给药的降血钙效应

本文采用薄膜分散-超声挤压过膜法制备鲑鱼降钙素柔性脂质体，对其形态学及粒径进行了考察。以大鼠为实验动物，鼻腔给药，采用OCPC比色法测定大鼠血清钙离子浓度，计算降血钙百分率F%和降血钙效应D%，与鲑鱼降钙素普通脂质体、鲑鱼降钙素水溶液比较，以此评价鲑鱼降钙素柔性脂质体经大鼠鼻腔给药后的降血钙效应和附加剂对降钙素柔性脂质体的降血钙效应的影响。另外还对柔性脂质体的纤毛毒性进行考察。结果表明鲑鱼降钙素水溶液仅轻微降低血钙浓度，鲑鱼降钙素普通脂质体能提高降血钙效果，鲑鱼降钙素柔性脂质体呈现了最强的降血钙效果，其降血钙效果与脂质体中附加的表面活性剂的用量和种类相关，用去氧胆酸钠修饰的脂质体的降血钙效果最好，并且附加的表面活性剂用量越高，降血钙效果越强。柔性脂质体可以显著地降低去氧胆酸钠的纤毛毒性。结果显示，柔性纳米脂质体能显著提高降钙素经鼻腔给药的降血钙效果，柔性脂质体是蛋白多肽类药物鼻腔给药的一种有效的载体。     

蛞蝓冻干粉对急性支气管炎的治疗作用

目的研究蛞蝓冻干粉对急性支气管炎的治疗作用。方法用二氧化硫(SO2)刺激法建立小鼠急性支气管炎模型,观察蛞蝓冻干粉的镇咳作用;采用气管段酚红法观察蛞蝓冻干粉的祛痰作用;采用兔离体气管纤毛粘液流运动法观察蛞蝓冻干粉对家兔气管纤毛运动的影响。结果蛞蝓冻干粉能明显延长急性支气管炎模型小鼠的咳嗽潜伏期,减少咳嗽次数(P<0.05);使急性支气管炎小鼠的酚红排出量明显增加(P<0.05),蛞蝓冻干粉300mg/kg给药,与氯化铵具同样效果。中、高剂量的蛞蝓冻干粉能明显促进兔离体气管纤毛运动的活跃程度,加快纤毛粘液运送速度(P<0.05)。结论蛞蝓冻干粉对急性支气管炎有较强的镇咳和祛痰作用。     

1,3-二苯-1,3-丙二酮对可卡因致小鼠肝毒性及神经毒性的保护作用

目的:探讨1,3-二苯-1,3-丙二酮(DPPD)对可卡因致小鼠急性肝损伤及神经毒性的保护作用。方法:可卡因急性肝损伤模型采用♂C57BL/6N小鼠,DPPD(200,400,800 mg·kg–1/d,ig)预给药4 d,末次给药30 min后,sc可卡因70 mg·kg-1造模,24 h后处死,测定血清ALT,AST,LDH的活性及肝脏MDA含量,观察肝脏病理变化。DPPD抗可卡因神经毒性实验采用♂ICR小鼠,DPPD预给药3 d(给药剂量同前),末次给药30 min后,sc可卡因20mg·kg-1造模,记录小鼠0-180 min的活动次数。结果:可卡因70 mg·kg-1致部分小鼠死亡(5/7),存活小鼠血清ALT,AST,LDH活性及肝脏MDA含量显著升高,肝脏病理损伤明显,而DPPD预给药组无死亡,血清ALT,AST,LDH活性及肝脏MDA含量显著降低,肝脏损伤明显改善,呈剂量-效应关系;DPPD抗可卡因神经毒性研究发现,DPPD预给药组小鼠自主活动量较模型组显著降低。结论:DPPD对可卡因致小鼠急性肝毒性及神经毒性有拮抗作用。     

抗焦胶囊抗焦虑作用的实验研究

目的观察抗焦胶囊的抗焦虑作用。方法采用戊四唑诱发小鼠惊厥模型,观察抗焦胶囊对小鼠惊厥及死亡潜伏期的影响;采用小鼠期待性焦虑实验,观察抗焦胶囊对焦虑小鼠体温的影响;采用戊巴比妥钠的小鼠睡眠模型,观察抗焦胶囊对小鼠入睡的影响。结果抗焦胶囊2.0g、1.0g、0.5g生药/kg组给药30min可显著延长惊厥潜伏期,2.0g生药/kg组给药60、90、120min能显著延长死亡潜伏期;抗焦胶囊2.0g生药/kg组对焦虑小鼠体温升高有明显抑制作用;抗焦胶囊2.0g生药/kg组能显著增加注射阈剂量戊巴比妥钠小鼠的入睡比率。结论抗焦胶囊对焦虑症有一定缓解作用。     

尼莫地平前体脂质体的制备和大鼠药动学的研究

目的：研究增加尼莫地平在脑中分布的方法。方法：采用薄膜载体沉积法制备尼莫地平前体脂质体，考察其性质，并在大鼠体内进行药动学研究。结果：用该法所得前体脂质体包封率可达95％以上，稳定性好；药动学指标优于尼莫地平注射剂。结论：尼莫地平制成前体脂质体可显著提高药物在脑中的分布。     

苗药窝嘎抗炎镇痛作用的实验研究

目的研究苗药窝嘎的抗炎、镇痛作用。方法采用小鼠耳廓肿胀法、急性关节炎模型、热板法和扭体法观察苗药窝嘎的药理作用。结果窝嘎对急性关节炎和小鼠耳廓肿胀法有抑制作用,有明显的镇痛作用。结论苗药窝嘎具有显著抗炎、镇痛作用。     

三磷酸腺苷脂质体鼻用凝胶制备及其抗缺氧作用

制备三磷酸腺苷(adenosine triphosphate, ATP)脂质体,评价其对缺氧性脑损伤的治疗作用。采用离子对薄膜分散法制备ATP脂质体,其最优处方:三磷酸腺苷二钠、十六烷基三甲基溴化铵、大豆磷脂、胆固醇的质量比为1∶1.98∶8∶3,此时ATP脂质体包封率为(81.50±0.82)%,载药量为(6.79±0.07)%。通过体外释放实验与流变学测定分别考察ATP脂质体与空白凝胶的理化性质;将ATP脂质体、ATP水溶液分别加入甲基纤维素凝胶中,以甲基纤维素凝胶为阴性对照,进行小鼠鼻腔给药。动物实验获得军事医学研究院伦理委员会批准。连续给药9天后,与空白凝胶或ATP水凝胶相比, ATP脂质体水凝胶显著提高了血中红细胞与血红蛋白数值(P<0.01);连续给药13天后,在常压密闭缺氧实验中,与ATP水凝胶或空白凝胶相比, ATP脂质体鼻用凝胶能显著提高小鼠标准缺氧耐受时间(P<0.05)。小鼠海马促凋亡基因p53免疫组化染色显示, ATP脂质体对脑组织有明显保护作用。结果表明, ATP脂质体鼻用凝胶预防给药能明显提高小鼠耐缺氧能力,是一种前景广阔的抗缺氧制剂。     

口服鲨鱼肝再生因子脂质体对小鼠急性肝损伤的保护作用

为研究口服鲨鱼肝再生因子脂质体对四氯化碳(CCl4)和硫代乙酰胺(TAA)对小鼠急性肝损伤的保护作用,采用CCl4和TAA致小鼠肝损伤,观察肝组织切片,测定生化指标,检测小鼠给药后血清谷丙转氨酶(ALT)、血清谷草转氨酶(AST)活力。结果口服鲨鱼肝再生因子脂质体能明显减轻CCl4和TAA所致小鼠急性肝损伤模型的肝组织损伤作用,降低ALT、AST活力。因此口服鲨鱼肝再生因子脂质体对急性肝损伤也有明显的保护作用。     

Development and pharmacokinetics of nimodipine-loaded liposomes

In order to improve the water solubility of nimodipine and prolong the time of the drug in the circulation, nimodipine-loaded liposomes with a small size and high entrapment efficiency were prepared by a method that was easy to scale up (the modified ethanol injection method). The nimodipine liposome dispersions were characterized with respect to particle size distribution, zeta potential and entrapment efficiency. Liposomal nimodipine and nimodipine solution were intravenously administered to mice as a single dose of 4 mg kg-1. The pharmacokinetic parameters of nimodipine changed significantly when encapsulated in liposomes. The clearance of nimodipine encapsulated in liposomes was reduced and the elimination half-life was prolonged. The ratios of the area under the curve values of nimodipine liposomes to nimodipine solution were 1.78 and 1.90 in plasma and cerebral tissue, respectively. The drug concentration in cerebral tissue and in plasma showed a good linear correlation, which showed that liposomes could efficiently deliver nimodipine into brain tissue. These findings suggest that intravenous administration of liposomal nimodipine produces higher and more stable plasma and cerebral drug concentrations compared with nimodipine solution. In conclusion, liposomal nimodipine is a promising alternative to the solution preparation.     

Hybrid liposomes as a drug carrier for the oral administration of insulin in diabetic rats

It is known that hybrid liposomes composed of dimyristoylphosphatidylcholine (DMPC) and micellar surfactant (Tween 20) are effective for encapsulating drugs and for the treatment of meningeal gliomatosis in vivo without toxicity. In this study, we attempted to use these hybrid liposomes as a drug carrier system for the oral administration of insulin using diabetic model rats. The noteworthy aspects were as follows: (a) The hybrid liposomes of 90 mol% DMPC/10 mol% Tween 20 were stable and uniform for more than 4 weeks. (b) The blood glucose level of diabetic model rats decreased after the oral administration of hybrid liposomes including insulin. These results suggest that the oral administration of hybrid liposomes including insulin should be effective for the treatment of diabetes.     

LC-MS法研究尼莫地平脂质体原位凝胶在家兔体内的药动学

目的研究尼莫地平脂质体原位凝胶在家兔体内的药动学。方法单剂量(尼莫地平0.5 mg·kg~(-1))于家兔后腿股四头肌肌内注射尼莫地平溶液剂、尼莫地平脂质体、泊洛沙姆188(P188)修饰的尼莫地平脂质体和尼莫地平脂质体原位凝胶,建立高效液相色谱-质谱(LC-MS)法测定血浆中尼莫地平的浓度。结果尼莫地平在0.8～800μg·L~(-1)范围内线性关系良好(r=0.999 2),提取回收率大于90%,日内、日问精密度RSD<15%。尼莫地平脂质体原位凝胶和脂质体的c_(max)分别为(88±s 18)和(224±64)μg·L~(-1);t_(max)分别为(2.0±0.7)和(0.29±0.14)h;AUC_(0-∞)分别为(402±15)和(273±28)μg·h·L~(-1)。尼莫地平脂质体原位凝胶的c_(max)、t_(max)、AUC_(0-∞)等药动学参数与尼莫地平脂质体和P188修饰的尼莫地平脂质体均有显著或极显著差异。结论尼莫地平脂质体原位凝胶经肌内注射后可延长药物在体内的驻留时间,具有一定的缓释作用并提高了尼莫地平的生物利用度。     

Chemotherapy with hybrid liposomes without any drug in vivo

Prolonged survival was seen in a carcinoma model in mice intraperitoneally inoculated with B-16 melanoma cells after the intraperitoneal treatment with hybrid liposomes composed of L-alpha-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylenedodecyl ether (C12(EO)n, n = 10 and 23 respectivery) which had a uniform and stable structure. No drug was administered. The therapeutic effects of the single-component liposomes composed of lipids with a variety of hydrophilic head groups and different hydrophobic alkyl chains were investigated. Markedly prolonged survival (248%) of mice was achieved after treatment with DMPC liposomes. However, DMPC liposomes have the disadvantage of an unstable structure, requiring daily sonication. On the other hand, no life-prolonging effects or toxicity occurred with the administration of the other single-component liposome employed in this study. Next, we successfully prepared stable, uniform liposomes composed of 90 mol% DMPC and 10 mol% C12(EO)n (n = 10 and 23, respectively), which have diameters of 70 nm and 100 nm, respectively. Interestingly, prolonged survival (173-186%) of mice was achieved after treatment with hybrid liposomes of 90 mol% DMPC/10 mol% C12(EO)n (n = 10 and 23). Finally, we conducted toxicity tests using normal rats to determine hybrid liposome stability. There were no abnormal findings in blood chemistry or relative organ weights at autopsy of normal rats after hybrid liposome administration. In addition, hybrid liposomes were metabolized in the liver after intravenous administration to normal mice. These results suggest that hybrid liposomes could be used as a new single chemotherapeutic agent in the treatment of carcinoma with no side effects.     

Glutathione PEGylated liposomes: pharmacokinetics and delivery of cargo across the blood–brain barrier in rats

Abstract

Partly due to poor blood–brain barrier drug penetration the treatment options for many brain diseases are limited. To safely enhance drug delivery to the brain, glutathione PEGylated liposomes (G-Technology®) were developed. In this study, in rats, we compared the pharmacokinetics and organ distribution of GSH-PEG liposomes using an autoquenched fluorescent tracer after intraperitoneal administration and intravenous administration. Although the appearance of liposomes in the circulation was much slower after intraperitoneal administration, comparable maximum levels of long circulating liposomes were found between 4 and 24?h after injection. Furthermore, 24?h after injection a similar tissue distribution was found. To investigate the effect of GSH coating on brain delivery in vitro uptake studies in rat brain endothelial cells (RBE4) and an in vivo brain microdialysis study in rats were used. Significantly more fluorescent tracer was found in RBE4 cell homogenates incubated with GSH-PEG liposomes compared to non-targeted PEG liposomes (1.8-fold, p?<?0.001). In the microdialysis study 4-fold higher (p?<?0.001) brain levels of fluorescent tracer were found after intravenous injection of GSH-PEG liposomes compared with PEG control liposomes. The results support further investigation into the versatility of GSH-PEG liposomes for enhanced drug delivery to the brain within a tolerable therapeutic window.     

Brain delivery of proteins by the intranasal route of administration: A comparison of cationic liposomes versus aqueous solution formulations

The goal of this research was to evaluate the effectiveness of cationic liposomes for intranasal administration of proteins to the brain. Cationic liposomes were loaded with a model protein, ovalbumin (OVAL), and a 50 µg dose was administered intranasally to rats. In qualitative studies, liposomes were loaded with Alexa 488‐OVAL and delivery was assessed by fluorescence microscopy. By 6 and 24 h after administration, Alexa 488‐OVAL deposits were widely distributed throughout brain, with apparent cellular uptake in midbrain by 6 h after administration. In quantitative studies, liposomes were loaded with ¹¹¹In‐OVAL, and distribution to brain and peripheral tissues was monitored by gamma counting at 1, 4, 6, and 24 h after administration. The highest brain concentrations were achieved at the shortest time point, 1 h, for both liposomal and aqueous OVAL. However, the liposomes yielded higher ¹¹¹In‐OVAL concentrations in brain than ¹¹¹In‐OVAL in PBS. Moreover, a 2 µg/µL form of liposomal OVAL yielded a higher percentage of dose in brain, and a lower percentage in stomach and intestines, than twice the volume of a 1 µg/µL preparation. Cationic liposomes may provide a novel, noninvasive strategy for delivery of neuroactive proteins to the brain for treatment of central nervous system disorders. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1745–1761, 2010     

Pulmonary delivery of elcatonin using surface-modified liposomes to improve systemic absorption: Polyvinyl alcohol with a hydrophobic anchor and chitosan oligosaccharide as effective surface modifiers

The aim of this study was to investigate the feasibility of surface-modified liposomes for pulmonary delivery of a peptide. Chitosan oligosaccharide (oligoCS) and polyvinyl alcohol with a hydrophobic anchor (PVA-R) were used as surface modifiers. The effect of liposomal surface modification on the behavior of the liposomes on pulmonary administration and potential toxicity were evaluated in vitro and in vivo. In an association study with A549 cells, PVA-R modification reduced interaction with A549 cells, whereas oligoCS modification electrostatically enhanced cellular interaction. The therapeutic efficacy of elcatonin (eCT) after pulmonary administration to rats was significantly enhanced and prolonged for 48 h after separate administration with oligoCS- or PVA-R-modified liposomes. oligoCS-modified liposomes adhered to lung tissues and caused opening of tight junctions, which enhanced eCT absorption. On the other hand, PVA-R-modified liposomes induced long-term retention of eCT in the lung fluid, leading to sustained absorption. Consequently, surface modification of liposomes with oligoCS or PVA-R has potential for effective peptide drug delivery through pulmonary administration.     

Improving efficiency of adriamycin crossing blood brain barrier by combination of thermosensitive liposomes and hyperthermia

Adriamycin (ADM)-encapsulated thermosensitive liposomes (ts-lip-ADM) and common liposomes (lip-ADM) were developed and evaluated. The encapsulation efficiency of the two liposomes were above 99%, and the average sizes of liposomes were about 120 nm. Temperature-dependent drug release from loaded liposomes in vitro was investigated: more than 90% of loaded ADM was released from ts-lip-ADM within 30 min at 42°C, while less than 3% was released from lip-ADM at 42°C beyond 120 min. An in vitro model of blood brain barrier (BBB) was established and evaluated by permeability and transendothelial electrical resistance (TEER). The model was employed to study the permeability of liposomes in vitro. The permeability of ts-lip-ADM could be increased significantly after the temperature was raised to 42°C, which was about 10-16, 22-38, 38-45, 50-105 fold to that of ts-lip-ADM (37°C), lip-ADM (42°C), lip-ADM (37°C) and free ADM, respectively. C6 glioma-bearing mice model was developed and used to evaluate body distribution and anti-tumor efficacy in vivo. Mice were IV injected at a drug dose of 10 mg/kg. After administration the heads of mice were heated in water bath at 42°C for 30 min. The maximum brain concentration of ts-lip-ADM was 6.4, 3.7 fold compared with that of ADM solution and lip-ADM, respectively. The survival time of mice administered ts-lip-ADM (44 d) was remarkably longer than that of other three groups. This study indicates that ADM-encapsulated thermosensitive liposomes combined hyperthermia could enhance ADM delivery across BBB and prolong survival time of glioma-bearing mice.     

Surface Modification of Liposomes Using Polymer-Wheat Germ Agglutinin Conjugates to Improve the Absorption of Peptide Drugs by Pulmonary Administration

In this study, we investigated the feasibility of a system based on liposomal surface modification with a novel mucoadhesive polymer–lectin conjugate for the pulmonary delivery of therapeutic peptides and proteins. We covalently attached wheat germ agglutinin (WGA), a ligand that specifically interacts with alveolar epithelial cells, to carbopol (CP), a mucoadhesive polymer, using the carbodiimide method and then evaluated the efficacy and potential toxicity of CP–WGA surface-modified liposomes in vivo and in vitro. In association studies, CP–WGA modification enhanced the interaction with A549 lung epithelial cells compared with unmodified or CP-modified liposomes. This increased association was dependent on temperature and the surface concentration of free WGA. These results suggested synergy of WGA and CP, and retention of the biological cell binding activity of WGA, leading to improved liposome-cell interactions. Moreover, improvement of liposomal bioadhesion to lung epithelia significantly enhanced and prolonged the therapeutic efficacy of calcitonin, a model peptide drug, without any evidence of toxicity, following administration of calcitonin-loaded CP–WGA- modified liposomes. Hence, surface modification of liposomes with CP–WGA has potential for effective pulmonary administration of peptides.     

Reduced dose-limiting toxicity of intraperitoneal mitoxantrone chemotherapy using cardiolipin-based anionic liposomes

Intraperitoneal chemotherapy confers limited clinical benefit as a result of the dose-limiting toxicity of anticancer drugs. We aimed to develop optimized liposomes for mitoxantrone (MTO) administration that provide high encapsulation efficiency and increase the therapeutic index. Cationic MTO was loaded onto anionic liposomes by electrostatic surface complexation. The anticancer activity was evaluated in a peritoneal carcinomatosis model. The retention of MTO at the tumor site was monitored by molecular imaging. MTO loading efficiencies by electrostatic complexation were >95% for all anionic liposomes but <5% for neutral liposomes. Among anionic liposomes, cardiolipin liposomes (CLs) exhibited the strongest binding affinity for MTO, the highest anticancer activity, and the lowest toxicity. MTO delivered by CLs showed prolonged retention at tumor sites. Unlike free MTO showing significant cardiotoxicity, MTO administered in CLs provided negligible cardiotoxicity. CL-mediated delivery may increase the therapeutic index of MTO chemotherapy by prolonged retention and reduced cardiotoxicity.From the Clinical EditorThe authors report the development of optimized liposomes for intraperitoneal mitoxantrone delivery that provides high encapsulation efficiency and increases the therapeutic index. Cardiolipin liposomes exhibited the strongest binding affinity for mitoxantrone, along with the highest anti-cancer activity and lowest toxicity, including negligible cardiotoxicity.