聚焦超声联合微泡开放血脑屏障增强脑靶向递送研究进展

血脑屏障(blood-brain barrier, BBB)是药物脑靶向递送的最主要屏障,聚焦超声和微泡联合应用为跨BBB脑靶向递送提供了一种新途径,其主要机制为空化效应.本综述概括了近年来采用聚焦超声联合微泡增强BBB通透性实现药物脑靶向递送的相关研究,详细论述了聚焦超声及其作用机制;商品化微泡种类、常用微泡膜材、内...     

Limitations to effect of alpha-MSH on permeability of blood-brain barrier to IV 99mTc-pertechnetate

The effects of several variables on the permeability of the blood-brain barrier (BBB) to 99mTc-labeled sodium pertechnetate after IV administration of alpha-MSH were investigated. Doses of alpha-MSH of about 200 micrograms/kg were generally more effective in increasing the brain:blood ratio of radioactivity than the smaller doses that had previously been shown to affect behavior and the EEG. Pulsatile administration of a total of 200 micrograms/kg alpha-MSH over 90 min did not change the permeability of the BBB to the pertechnetate anion. Infusion of the same dose over 90 min significantly increased the brain:blood ratio of radioactivity in one of two experiments: no significant effects were seen with infusion for shorter times, lower concentrations, or with a 4-9 analog (Org 2766). In another experiment, bolus injection of 200 micrograms/kg alpha-MSH resulted in a significantly increased ratio 90 min later as compared with controls. Although the effects of a peptide on the permeability of the BBB to other compounds remains intriguing, limitations appear to exist in experiments with 99mTc-pertechnetate.     

CSF,blood-brain barrier,and brain drug delivery

ABSTRACT

Introduction: There are 2 misconceptions about the cerebrospinal fluid (CSF), the blood-brain barrier (BBB), and brain drug delivery, which date back to the discovery of a barrier between blood and brain over 100 years ago. Misconception 1 is that drug distribution into CSF is a measure of BBB transport. Misconception 2 is that drug injected into the CSF compartment distributes to the inner parenchyma of brain.

Areas Covered: Drug distribution into the CSF is a function of drug transport across the choroid plexus, which forms the blood-CSF barrier, and not drug transport across the BBB, which is situated at the microvascular endothelium of brain. Drug injected into CSF undergoes rapid efflux to the blood compartment via bulk flow. Drug penetration into brain parenchyma from the CSF is limited by diffusion and drug concentrations in brain decrease exponentially relative to the CSF concentration.

Expert Opinion: The barrier between blood and brain was discovered in 1913, when it was believed that the BBB was localized to the choroid plexus, and that nutrient flow from blood passed through the CSF en route to brain. These misconceptions are still widely held, and hinder progress in the development of technology for BBB drug delivery.     

Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3

BackgroundDelivery of viral vectors as gene therapies to treat neurodegenerative diseases has been hampered by the inability to penetrate the blood brain barrier (BBB) and invasive or non-targeted delivery options prone to inducing immune responses. MR guided focused ultrasound (MR-g-FUS) and microbubbles have demonstrated safe, temporary, targeted BBB permeabilization clinically.MethodsWe developed clinically scalable, microbubble drug conjugates (MDCs) for the viral gene therapy, AAV.SIRT3-myc [adeno-associated virus expressing myc-tagged SIRT3], which has previously been shown to have disease modifying effects in animal models of Parkinson’s disease (PD). The lipid shells of the perfluorocarbon gas MDCs were covalently conjugated to antibodies with binding specificity to AAVs. Following systemic (iv) delivery of AAV.SIRT3-myc MDCs, MR-g-FUS was used to deliver SIRT3-myc to brain regions affected in PD. SIRT3-myc expression was determined post mortem, using immunohistochemistry.ResultsAn in vitro, SH-SY5Y cell culture model was used to show that the localized destruction of MDCs using ultrasound exposures within biological safety limits dissociated AAV2-GFP (green fluorescent protein) from the MDCs in the targeted area while maintaining their transduction capacity. In rats, MR-g-FUS resulted in BBB permeabilization in the striatum and substantia nigra (SNc). SIRT3-myc was expressed in the striatum, but not the SNc.ConclusionThese studies demonstrate that MDCs combined with MR-g-FUS are an effective method for delivery of viral vector gene therapies, such as AAV.SIRT3, to brain regions affected in PD. This technology may prove useful as a disease-modifying strategy in PD and other neurodegenerative disorders.     

Low permeability of the blood-brain barrier to nanomolar concentrations of immunoreactive alpha-melanotropin

The permeability of the blood-brain barrier (BBB) to immunoreactive alpha-melanotropin (-MSH) was quantified in rats pretreated with monosodium l-glutamic acid to deplete their CNS stores of endogenous -MSH. The methodology, suitable for poorly permeable substances, monitored blood and brain tissue concentrations of -MSH over 15 min following intravenous injection of 30 nmol synthetic -MSH. Rate constants for entry of -MSH into brain tissue were estimated from separate nonlinear least-squares fits of connecting two- and one-compartment open models to plasma and extravascular brain tissue concentration data, respectively. Comparisons were made to rate constants measured similarly for ¹⁴C-inulin. The BBB had a low permeability to immunoreactive -MSH, consistent with peptide penetrating the barrier by passive diffusion dependent upon the lipid solubility of the molecule.     

高强度聚焦超声治疗肝脏肿瘤近期疗效观察

目的探讨高强度聚焦超声（high—intensityfocusedultrasound,HIFU）治疗肝脏肿瘤的近期疗效。方法对118例接受HIFU治疗的肝癌患者,分析治疗前后临床症状、AFP、肝功能、影像学变化以及术后并发症的发生情况。结果HIFU治疗后,临床症状缓解率54．5％（42／77）;59．4％（41／69）的患者血清AFP下降;91．6％（99／108）的患者术后早期影像学检查提示治疗有效,主要表现为治疗区域出现不同程度的组织坏死,血供消失或减少;术后并发症少。结论HIFU治疗肝脏肿瘤是有效和可行的,为临床治疗肝脏肿瘤提供一种新的治疗手段。     

The aluminum-induced increase in blood-brain barrier permeability to delta-sleep-inducing peptide occurs throughout the brain and is independent of phosphorus and acetylcholinesterase levels

The effect of aluminum on levels of inorganic phosphorus and acetylcholinesterase in blood and brain and on permeability of the blood-brain barrier (BBB) in different regions of the brain to the neuropeptide deltasleep-inducing peptide (DSIP) was studied in adult rats. Aluminum (100 mg/kg) significantly increased the permeability of the BBB to intracarotid ¹²⁵I-N-Tyr-DSIP so that levels of radioactivity in whole brain were 45% higher than in control animals. The pattern of regional distribution of radioactivity in the brain was, however, unaffected, demonstrating that the affect of aluminum occurs throughout the BBB. Aluminum also significantly decreased inorganic phosphorus levels in the serum by 19%, but this effect did not correlate with BBB permeability to DSIP. Aluminum did not decrease brain levels of phosphorus despite the drop in blood levels of phosphorus nor affect brain or blood levels of acetylcholinesterase. Experiments with radioactive ³²P reinforced the finding that blood but not brain levels of phosphorus are reliably affected by aluminum. The lack of correlation between changes in BBB permeability and decreased levels of inorganic phosphorus in the blood suggests that the effect of aluminum may not be mediated by its effects on phosphorus metabolism. Also, the change in BBB permeability after administration of aluminum does not appear to depend on changes in brain cholinergic activity but does occur throughout the brain.     

Ethanol enhancement of blood-brain barrier permeability to catecholamines in chicks

The effect of ethanol (EtOH) on permeability of the blood-brain barrier (BBB) to parenteral catecholamines was investigated in neonate chicks. Animals simulataneously administered EtOH, 2 g/kg, and norepinephrine (NE), 5 mg/kg, or epinephrine (E), 5 mg/kg, entered a roosting state which was more pronounced than that observed after either amine alone. Roosting chicks were killed 2 min after NE + EtOH and 10 min after E + EtOH for whole brain amine analysis. NE + EtOH treatment resulted in a 220% increase in whole brain NE over controls receiving this amine alone, whereas E + EtOH produced a 29% increase in brain E. EtOH alone did not alter endogenous levels of either amine in brain. Results indicate that EtOH, a solvent whose solubility characteristics allow it to penetrate easily both aqueous and lipoid membrane components, facilitates entry of E and NE into the brain of the neonate chick across an imperfect BBB present at hatching.     

Peptide-mediated drug delivery across the blood-brain barrier for targeting brain tumors

Introduction: Transportation of the nutrients and other substances from the blood to the brain is selectively controlled by the brain capillary endothelial cells that form a restrictive barrier, so-called blood-brain barrier (BBB). Currently, there is no unimpeachable approach to overcome the BBB obstructiveness because the existing options are either invasive or ineffective.

Areas covered: This review delineates the biological impacts of BBB on brain drug delivery and targeting. The nanoscaled multifunctional shuttles armed with the targeting entities (e.g., antibodies and peptides) are discussed. Important insights are remarked into the combinatorial screening methodologies used for the identification of de novo peptides capable of crossing BBB and targeting the brain.

Expert opinion: Depending on the physicochemical properties of small molecules and macromolecules, they may cross the BBB and get into the brain either through passive diffusion or active/facilitated transportation and transcytosis in a very selectively controlled manner. Phage-derived shuttle peptides can specifically be selected against BBB endocytic machinery and used in engineering novel peptide-drug conjugates (PDCs). Nanoscaled multitargeting delivery systems encompassing PDCs can overcome the BBB obstructiveness and deliver drugs specifically to diseased cells in the brain with trivial side effects.     

全颅常规外照射对大鼠血脑屏障通透性的影响及相关机制研究

目的探讨全颅常规外照射增加大鼠血脑屏障药物通透性的产生机制,为临床对颅内肿瘤寻找合适的化疗时机提供理论依据。方法 60只正常成年Wistar大鼠随机分为5组,分别采用0、10、20、30、40Gy,^60Coγ射线进行全脑常规分割外照射,2Gy/次、1野/次,5次/周。各组完成照射计划后16h经尾静脉注射氨甲喋呤（MTX）25mg/kg,2h后采集脑脊液,用RP-HPLC法检测其中的MTX浓度。之后所有大鼠均断头取脑,40g/L中性甲醛固定24h,石蜡包埋,采用免疫组化法检测各组大鼠血脑屏障上P-gp的表达情况。结果对照组P-gp阳性表达最强,10Gy组与对照组,20Gy与30Gy组,40Gy组分别与20Gy、30Gy组比较无统计学意义（P〉0.05）,其余各组比较均有统计学意义（P〈0.05）。各组大鼠脑脊液中的MTX平均浓度分别为：0.06、0.08、0.19、0.24、0.23mg/L。经方差分析及秩和检验,10Gy组与对照组,20Gy与30Gy组,40Gy组分别与20Gy、30Gy组比较无统计学意义（P〉0.05）,其余各组比较均有统计学意义（P〈0.05）。结论一定剂量的放射线可能通过降低血脑屏障上P-gp的表达,增加其对药物的通透性,并且在放射剂量达到20Gy的时候化疗效果最好。     

血脑屏障上的P-糖蛋白与药物转运功能

目的：综述脑毛细血管内皮细胞上的Ｐ－糖蛋白药物外排功能。方法：根据对有关的资料的分析,归纳,总结得出Ｐ－糖蛋白与脑内药物转运的关系。结果：血脑屏幕上的Ｐ－糖蛋白具有ＡＴＰ依赖性的药物外排泵的功能,能降低脑内药物的浓度。结论：利用多药耐药性逆转剂有可能提高脑内的药物转运或者降低药物的通透性减少中枢神经系统的不良反应。     

高强度超声聚焦治疗子宫肌瘤的临床观察

目的探讨高强度超声聚焦治疗子宫肌瘤的有效性及安全性。方法选择不愿意行手术切除子宫肌瘤的育龄期已生育患者335例，应用FEP—BYO1型高强度超声聚焦治疗机进行治疗，治疗后定期随访观察。结果335例患者经高强度超声聚焦治疗后近期总有效率为97％（疗效显著30例、有效195例、部分有效100例），无效10例（3％）。结论高强度超声聚焦是无创治疗子宫肌瘤的有效方法。     

血脑屏障上的P-糖蛋白与药物转运功能

目的 :综述脑毛细血管内皮细胞上的P -糖蛋白药物外排功能。方法 :根据对有关的资料的分析、归纳、总结得出P -糖蛋白与脑内药物转运的关系。结果 :血脑屏障上的P -糖蛋白具有ATP依赖性的药物外排泵的功能 ,能降低脑内药物的浓度。结论 :利用多药耐药性逆转剂有可能提高脑内的药物转运或者降低药物的通透性减少中枢神经系统的不良反应     

高能超声聚焦刀治疗晚期胰腺癌临床观察

目的 观察高能超声聚焦刀治疗晚期胰腺癌临床效果和安全性.方法 选择失去手术机会的胰腺癌病人应用FEP-BY01型高能超声聚焦治疗机,治疗后定期随访观察.结果 36例患者经高强度超声治疗后近期有效率为63.8%,中位生存期为21月.结论 高强超声聚焦是无创治疗胰腺癌的有效方法.     

高强度超声聚焦刀治疗子宫肌瘤的有效性及安全性探讨

目的：观察高强度超声聚焦刀（ HIFU）治疗子宫肌瘤的有效性及安全性。方法运用HIFU对105例子宫肌瘤患者实施治疗,治疗后1个月、3个月、6个月随访观察患者的临床症状、肌瘤体积及不良反应,评估HFIU治疗的效果。结果治疗前子宫肌瘤体积为（48．1±17．8）cm3,治疗后1、3、6个月瘤体体积分别减小至（30．9±10．2）cm3、（24．5±8．6）cm3、（18．3±7．8）cm3,治疗前后差异均有统计学意义（t＝3．518、5.276、8．119,均P＜0．01）;HIFU治疗6个月后总体的有效率为80．9％,而对于肌层子宫肌瘤、直径小于5 cm的子宫肌瘤HIFU的有效率分别可达到为91．9％、93．8％。结论 HIFU治疗子宫肌瘤的近期疗效确切,且对于肌层及体积较小的肌瘤效率最为显著。     

高强度超声聚焦治疗子宫肌瘤147例临床观察

目的探讨高强度超声聚焦治疗子宫肌瘤的有效性及安全性。方法选择我院2008年4月～2011年5月不愿意行手术切除子宫肌瘤的育龄期已生育患者147例,应用FEP-BYO2型高强度超声聚焦治疗机进行治疗,治疗后定期随访观察患者临床症状、体征及瘤体内超声影像学变化。结果 147例患者经高强度超声聚焦治疗后近期总有效率为93%(疗效显著52例、有效68例、部分有效17例;无效10例7%)。结论高强度超声聚焦是治疗子宫肌瘤的安全、有效方法。     

高强度聚焦超声治疗肝癌的疗效观察

目的探讨高强度聚焦超声(HIFU)对不能手术切除的肝癌患者的疗效、安全性及对肿瘤标志物的影响。方法15例肝癌患者采用平均接受3次高强度聚焦超声(HIFU)治疗,对其进行疗效评价,观察患者的临床受益反应、化学免疫分析法检测CA19-9和AFP浓度。结果15例患者血液检查CA19-9、AFP均有不同程度下降,且有统计学差异(P<0.05或P<0.01)。其中CR3例,PR9例,CR+PR80%,肝脏急性不良反应1级3例,2级1例,无3、4级不良反应。结论高强度聚焦超声能控制肝癌肿瘤进展、改善生活质量、对肿瘤标志CA19-9、AFP有明显下调作用,无明显不良反应。     

高强度聚焦超声治疗子宫肌瘤的临床观察

目的研究高强度聚焦超声治疗子宫肌瘤的临床效果和安全性。方法选取2011年9月～2012年10月本院收治的生育后且具有手术切除子宫指征的子宫肌瘤患者74例,对所有患者采取JC型高强度聚焦超声治疗方法,同时采用B超进行定位。在治疗后的1、3、6个月分别患者进行随访,观察患者的症状、体征、实验室指标以及影像学上的变化,综合评估患者的预后及手术并发症的发生情况。结果经治疗后,患者的尿频、经量增多等临床症状有显著改善,影像学检查显示子宫病灶明显缩小,各项实验室指标明显改善（P〈0．05）;治疗后共有11例患者发生不良反应,占14．9％,主要为腹痛、尿频、发热等症状。结论高强度聚焦超声治疗子宫肌瘤效果显著。而相关不良反应需要临床进一步研究。     

1例心理护理高强度聚焦超声治疗妇科肿瘤患者的体会

目的消除患者和家属对高强度超声聚焦刀治疗的疑虑,获得患者和家属的认同,配合治疗。方法运用心理护理技巧建立良好的护患关系,协助建立良好的社会支持系统;详细介绍HIFU治疗的原理、优势及治疗注意事项,介绍成功病例,增加患者和家属对治疗的信心。结果患者和家属充分了解HIFU治疗的知识,消除对新治疗方式的顾虑,使患者积极配合治疗。结论 HIFU治疗是一种新的治疗方法,患者和家属需要一个认知和接受的过程,建立良好的护患关系有助于护理人员开展HIFU治疗的卫生宣教,及时消除患者和家属的怀疑、恐惧、焦虑的心理,通过心理护理,可以获得患者的认同、家属的支持,患者积极配合治疗。     

神经退行性疾病状态下血-脑屏障变化机制及中药对血脑屏障的影响研究进展

血-脑屏障（BBB）结构和功能的完整性是维持中枢神经系统动态平衡的关键因素。BBB异常伴随神经退行性疾病的发展过程,不同的神经退行性疾病,其BBB异常的病理机制不同,而药物对BBB异常的改善作用也严重影响药物对神经退行性疾病的疗效。本文主要针对神经退行性疾病状态下BBB异常的分子机制及中药的调控作用及其机制两方面进行综述,为神经退行性疾病靶向血脑屏障药物的研发提供基础理论参考