RGD肽介导阿魏酸脂质体的大鼠体内抗氧化活性研究

目的：评价RGD介导的阿魏酸脂质体体内抗氧化活性。方法：采用大鼠局部脑缺血再灌注为动物模型,川芎嗪为阳性对照药物,以SOD活力、MDA含量、T-AOC含量为指标,评价阿魏酸载入RGD脂质体后的抗氧化活性。结果：SOD活力测定结果表明,阿魏酸普通脂质体组提高SOD活力的作用强于川芎嗪注射液组,RGD阿魏酸脂质体组SOD活力比普通脂质体组高3倍,比阳性药物组高3.38倍;T-AOC含量测定结果表明,普通脂质体组提高T-AOC含量的能力显著高于阳性药物对照组,RGD阿魏酸脂质体组T-AOC含量分别为阿魏酸注射液组5倍,普通脂质体组3倍,川芎嗪组3.4倍;MDA含量测定结果表明,RGD脂质体组降低MDA含量能力显著高于阿魏酸注射液组、阿魏酸普通脂质体组及阳性药物对照组。结论：将阿魏酸载入RGD介导的脂质体可显著提高其抗氧化活性,对脑缺血再灌注具有比普通脂质体及阳性药物更显著的保护效果。     

Microemulsion-based drug delivery system for transnasal delivery of Carbamazepine: preliminary brain-targeting study

This study reports the development and evaluation of Carbamazepine (CMP)-loaded microemulsions (CMPME) for intranasal delivery in the treatment of epilepsy. The CMPME was prepared by the spontaneous emulsification method and characterized for physicochemical parameters. All formulations were radiolabeled with ^99mTc (technetium) and biodistribution of CMP in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging in rats was also performed to determine the uptake of the CMP into the brain. CMPME were found crystal clear and stable with average globule size of 34.11?±?1.41?nm. ^99mTc-labeled CMP solution (CMPS)/CMPME/CMP mucoadhesive microemulsion (CMPMME) were found to be stable and suitable for in vivo studies. Brain/blood ratio at all sampling points up to 8?h following intranasal administration of CMPMME compared to intravenous CMPME was found to be 2- to 3-fold higher signifying larger extent of distribution of the CMP in brain. Drug targeting efficiency and direct drug transport were found to be highest for CMPMME post-intranasal administration compared to intravenous CMP. Rat brain scintigraphy also demonstrated higher intranasal uptake of the CMP into the brain. This investigation demonstrates a prompt and larger extent of transport of CMP into the brain through intranasal CMPMME, which may prove beneficial for treatment of epilepsy.     

Trends and developments in liposome drug delivery systems

Since the discovery of liposomes or lipid vesicles derived from self-forming enclosed lipid bilayers upon hydration, liposome drug delivery systems have played a significant role in formulation of potent drugs to improve therapeutics. Currently, most of these liposome formulations are designed to reduce toxicity and to some extent increase accumulation at the target site(s) in a number of clinical applications. The current pharmaceutical preparations of liposome-based therapeutics stem from our understanding of lipid-drug interactions and liposome disposition mechanisms including the inhibition of rapid clearance of liposomes by controlling size, charge, and surface hydration. The insight gained from clinical use of liposome drug delivery systems can now be integrated to design liposomes targeted to tissues and cells with or without expression of target recognition molecules on liposome membranes. Enhanced safety and heightened efficacy have been achieved for a wide range of drug classes, including antitumor agents, antivirals, antifungals, antimicrobials, vaccines, and gene therapeutics. Additional refinements of biomembrane sensors and liposome delivery systems that are effective in the presence of other membrane-bound proteins in vivo may permit selective delivery of therapeutic compounds to selected intracellular target areas.     

脂质体经皮给药研究进展

目的:分析总结近年来国外脂质体经皮或黏膜给药研究的特点和应用进展。方法:对近年来脂质体药物特点,主要对在皮肤疾病和美容方面,对局部伤口的治疗,在皮肤损伤和保护中的应用,在眼科疾病中的应用进行综述。结果与结论:脂质体是一种很好的定向药物载体,它的应用范围将越来越广     

环糊精包合物脂质体给药系统的研究进展

目的介绍环糊精包合物脂质体给药系统的研究进展。方法根据近年来的21篇文献资料进行归纳整理、分析评述。结果环糊精包合物脂质体能够提高脂质体载药量,改善脂质体中药物泄漏,提高药物在血浆中的稳定性和药效。结论环糊精包合物脂质体是一种新型的药物载体,具有广阔的研究与应用前景。     

脑靶向非病毒基因递释系统的研究进展

脑靶向非病毒基因递释系统可有效介导基因药物跨越血脑屏障,到达病变部位发挥疗效,已成为研究热点之一。多项研究结果显示,通过适当机制如配体-受体特异性结合作用可显著提高非病毒基因递释系统在脑部的蓄积量,从而提高所携带外源基因在脑部的表达量。本文主要从受体介导和吸附介导两种机制入手,综述脑靶向非病毒基因递释系统的最新研究进展。     

包合物脂质体靶向系统在给药中的应用

近年来,包合物和脂质体作为药物的载体被广泛用于药物制剂领域,各自发挥着自身的优势。将环糊精包合物应用于脂质体给药系统——这一新型的药物载体,能够更好地提高靶向给药效果。本文通过概述包合物及脂质体的优势,阐明包合物脂质体这一新型给药系统能提高药物的载药量,增加脂质体的稳定性,对提高药物的吸收和临床疗效等方面具有重要意义,对于靶向给药系统的进一步发展具有新的参考价值。     

Benzamide analogue-conjugated polyethylenimine for brain-targeting and gene delivery

In this study, a small molecule, benzamide analogue, p-hydroxybenzoic acid (p-HA), was used as a novel ligand for brain-targeting gene delivery. p-HA was conjugated to polyethylenimine and further labeled with a near infrared dye, IR820, for in vivo and ex vivo imaging study. Significant fluorescent signal was detected in brain from 0.5 to 24?h after injection compared with unmodified PEI. Then nanoparticles were prepared with p-HA-PEI to encapsulate pEGFP and pGL2 as reporter genes and characterized on the cell level. In 5y cells green fluorescent protein expression could be observed by fluorescent microscopy and significant higher expression of firefly luciferase was detected in p-HA-PEI/pGL2 group than in PEI/pGL2 group. For in vivo gene expression study, comparable high expression of green fluorescent protein in brain sections was confirmed using both confocal fluorescent microscopy and in vivo fluorescent imaging. All these results suggested that p-HA-PEI could be potentially used for brain targeted gene delivery.     

Evolution of blood–brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Blood–brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (e.g., intranasal treatment) for BBB bypassing are not included in this review.     

Evolution of blood–brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Blood–brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer''s disease, Parkinson''s disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (e.g., intranasal treatment) for BBB bypassing are not included in this review.KEY WORDS: Blood–brain barrier, Brain diseases, Brain-targeting, Drug delivery systems, Nanoparticles-tryptophan, BACE1, β-secretase 1, BBB, blood–brain barrier, BDNF, brain derived neurotrophic factor, BTB, blood–brain tumor barrier, CMT, carrier-mediated transportation, DTPA-Gd, Gd-diethyltriaminepentaacetic acid, EPR, enhanced permeability and retention, Gd, gadolinium, GLUT1, glucose transporter-1, ICAM-1, intercellular adhesion molecule-1, K_ATP, ATP-sensitive potassium channels, K_Ca, calcium-dependent potassium channels, LAT1, L-type amino acid transporter 1, LDL, low density lipoprotein, LDLR, LDL receptor, LFA-1, lymphocyte function associated antigen-1, LRP1, LDLR-related protein 1, MFSD2A, major facilitator superfamily domain-containing protein 2a, MMP9, metalloproteinase-9, MRI, magnetic resonance imaging, NPs, nanoparticles, PD, Parkinson''s disease, PEG, polyethyleneglycol, PEG-PLGA, polyethyleneglycol-poly(lactic-co-glycolic acid), P-gp, P-glycoprotein, PLGA, poly(lactic-co-glycolic acid), PSMA, prostate-specific membrane antigen, RAGE, receptor for advanced glycosylation end products, RBC, red blood cell, RMT, receptor-mediated transcytosis, ROS, reactive oxygen species, siRNA, short interfering RNA, TBI, traumatic brain injury, TfR, transferrin receptor, TJ, tight junction, tPA, tissue plasminogen activator, VEGF, vascular endothelial growth factor, ZO1, zona occludens 1     

Virosomes: evolution of the liposome as a targeted drug delivery system

The drug delivery system (DDS) is attractive as a therapeutic method. Liposomes are of particular interest as a DDS because they can reduce drug toxicity, and offer promise as gene carriers. An evolution has occurred in the construction of liposomes in the effort to develop efficient vectors for in vivo use. To avoid uptake by the reticuloendothelial system (RES); Lipid components have been optimized. To enhance tissue targeting, liposome surface has been modified with antibodies or ligands recognized by specific cell types. To enhance the efficiency of gene delivery by the introduction of molecules directly into cells, virosomes have been developed by combining liposomes with fusiogenic viral envelope proteins. Liposomes are now being used in the treatment of intractable human diseases such as cancer and monogenic disorders. In the future, many medical procedures will be performed using liposomes.     

Dermal drug delivery by liposome encapsulation: clinical and electron microscopic studies

The fate of liposomes and the encapsulated drug was studied after topical application on the skin. Lidocaine applied on the forearm of human volunteers produced greater local anaesthetic effect in the liposomal form than in the cream form (p less than or equal to 0.001 after 1 h application). Autoradiography demonstrated higher concentration (p less than or equal to 0.01) of 14C-lidocaine in the epidermis and dermis of guinea pigs treated with liposome-encapsulated lidocaine as opposed to lidocaine in Dermabase cream. Electron microscopic observations, using colloidal iron as an electrodense marker, indicated that intact liposomes penetrated into the skin and deposited in the dermis where they acted as a slow release depot system. On the basis of results in the human volunteers and animals, a hypothetical model for liposome-skin interaction is proposed.     

Barriers to remember: brain-targeting chemical delivery systems and Alzheimer's disease

Brain-targeted chemical delivery systems (CDSs) represent rational drug design attempts not only to deliver but also to target drugs to their site of action. Using a sequential metabolism approach, the special bidirectional properties of the blood-brain barrier can be exploited to smuggle the precursors of therapeutic compounds across the barrier and lock them inside the brain ready for sustained release of the active drugs. Many potential therapeutic applications can be envisioned for such CDSs; here, the potential of brain-targeted estradiol for the prevention and treatment of Alzheimer's disease is reviewed in detail.     

难溶性药物美洛昔康脂质体温敏凝胶眼用制剂的研究

目的制备美洛昔康脂质体温敏型眼用凝胶剂,考察其包封率、胶凝性质、离体角膜透过性和眼部刺激性。方法采用薄膜旋蒸法制备美洛昔康脂质体,并对其包封率和理化性质等进行了测定;将美洛昔康脂质体制备成温敏型眼用凝胶制剂,通过搅拌子法,考察了其胶凝行为;采用活体成像系统对比了制剂的角膜滞留特性;采用卧式扩散池,考察了其离体角膜透过性;多次给药后裂隙灯显微镜观察角膜组织考察了其眼部刺激性。结果美洛昔康脂质体包封率可达(77.9±3.10)%,zeta电位为+(35.1±3.62)m V,平均粒径为141.9 nm。美洛昔康脂质体凝胶的胶凝温度为31.7℃。活体成像实验结果显示原位凝胶延长了药物的眼部滞留时间。离体角膜透过结果为美洛昔康脂质体凝胶的透过速率最优。眼部刺激性实验多次给药后,观察日本大耳白兔眼角膜无浑浊,虹膜和结膜未见红肿、充血、肿胀等异常现象,提示多次给药对兔眼角膜无刺激。结论采用薄膜旋蒸法制备的美洛昔康脂质体有较高的包封率,且美洛昔康脂质体温敏型眼用制剂在眼部温度下可自发形成凝胶,延长眼部滞留时间,无眼部刺激性。     

生物技术药物的脂质体给药系统研究进展

脂质体给药系统可降低药物的毒性、增加药物在靶点的聚集并提高药物的疗效。近年来随着对脂质 药物相互作用和脂质体分布机理的深入理解 ,通过控制脂质体大小、电荷和表面水合作用以抑制脂质体的快速清除 ,使脂质体药物制剂有了进一步发展 ,尤其是靶向脂质体的研制 ,提高了多种药物的安全性和疗效。此文对脂质体体内分布机制以及在疫苗给药和基因治疗等方面的研究新进展作一综述     

Evaluation of brain-targeting for the nasal delivery of estradiol by the microdialysis method

The uptake of estradiol into the cerebrospinal fluid (CSF) after intranasal and intravenous administration in rats was investigated to study whether direct nose-CSF transport of estradiol exits or not. Animals received 0.48 mg kg(-1) estradiol randomly methylated beta-cyclodextrin (RAMEB) inclusion complex intranasally and intravenously. Following nasal delivery, estradiol reached a C(max) value (mean+/-S.D.) in plasma (26.70+/-11.37 ng ml(-1)) and CSF (54.76+/-32.84 ng ml(-1)) after 20 min in each case, while after intravenous infusion, estradiol reached a C(max) value in plasma (170.08+/-64.67 ng ml(-1)) and CSF (26.48+/-11.34 ng ml(-1)) at 5 min and 60 min, respectively. The AUC(CSF)/AUC(plasma) ratio (1.60+/-0.67) after intranasal delivery differed significantly from the ratio (0.61+/-0.16) observed after intravenous infusion (P<0.05). All these results indicate that estradiol is transported into CSF via olfactory neurons, and, hence, there is a direct transport route from the nasal cavity into the CSF for estradiol.     

Myristic acid-conjugated polyethylenimine for brain-targeting delivery: in vivo and ex vivo imaging evaluation

To investigate the potential of myristic acid (MC) to mediate brain delivery of polyethylenimine (PEI) as a gene delivery system, a covalent conjugate (MC-PEI) of MC, and PEI was synthesized. A near-infrared fluorescence probe, IR820 was conjugated to MC-PEI to explore its in vivo distribution after intravenous (i.v.) administration in mice. The brain targeting ability of MC-PEI was evaluated by near-infrared fluorescence imaging and analyzed semiquantitatively by fluorescence intensity, respectively. Significant NIR fluorescent signal was detected in the brain 12?h after i.v. administration and further confirmed by imaging the whole brain and brain slices. Semiquantitative results from fluorescence intensity further supported the successful brain delivery of MC-PEI which led to a very significant increase (～200%) in the brain uptake after i.v. injection in comparison with unmodified PEI. The capability of MC-PEI to condense DNA was further confirmed using agarose gel retardation assay, indicating its potential for gene delivery. The significant in vivo and ex vivo results suggest that MC-PEI is a promising brain-targeting drug delivery system, especially for gene delivery.     

Prolonged systemic delivery of streptokinase using liposome

To prolong the biological half-life of streptokinase, a thrombolytic agent, streptokinase-bearing liposome with and distearolyphosphatidyl ethanolamine-N-poly (ethylene glycol) 2000 (DSPE-PEG 2000) was prepared and evaluated. Streptokinase-bearing liposomes composed of distearolyphosphatidylcholine (DSPC), cholesterol and cholesterol-3-sulfate with DSPE-PEG 2000 was prepared by the freeze-thawing method and administered via femoral vein to rats (15000 IU/kg). The activity of streptokinase in plasma was determined by the method based on the amidolytic activity of streptokinase-plasminogen complex. Pharmacokinetic parameters on streptokinase incorporated in liposomes were compared with those of streptokinase alone. The T_1/2 and AUC_∞ of streptokinase incorporated in DSPC-PEG liposome increased 16.3- and 6.1-fold, respectively, compared with those of streptokinase alone. Streptokinase-bearing long-circulating liposome could increase the circulation time of streptokinase in blood and expect longer thrombolytic activity compared with streptokinase alone.     

Human skin sandwich for assessing shunt route penetration during passive and iontophoretic drug and liposome delivery

This work explored the role of skin appendages (shunt route) in passive and iontophoretic drug and liposome penetration. The technique used an epidermis and stratum corneum sandwich from the same skin donor with the additional stratum corneum forming the top layer of the sandwich. Penetration was monitored during occluded passive and iontophoretic (0.5 mA cm(-2)) delivery of mannitol and estradiol solutions, and ultradeformable liposomes containing estradiol. The shunt route had a significant role during passive penetration of mannitol (hydrophilic compound), but was negligible during penetration of estradiol (lipophilic drug) and liposomes. In iontophoresis, the shunt route significantly contributed to the overall flux of all preparations, being highest for mannitol. However, shunts were not the only pathway for iontophoretic drug delivery and evidence was observed for the creation of new aqueous pathways via disorganization of the intercellular lipid domain of stratum corneum. The skin sandwich technique should prove valuable for general studies on routes of skin penetration.