抗转铁蛋白受体抗体选择性穿越血脑屏障

多肽类神经药物在体内效果欠佳的原因是难以穿越毛细血管内皮细胞壁形成的血脑屏障,改进的办法是将此多肽偶联于正常情况下能进入血脑屏障的蛋白形成嵌合蛋白,后者经受体或吸附介导作用而进入脑内。已研究的载体有胰岛素、转铁蛋白和阳离子化白蛋白等,但是分别由于低血糖副作用,血中内源性物质浓度过高和肾脏吸收较强等不足,因此使其应     

泊洛沙姆在药物穿越血脑屏障中的重要作用

泊洛沙姆是一种具有药理活性的多功能药用辅料，在药剂学中应用广泛。近年来，研究发现泊洛沙姆可以通过多种作用机制帮助药物穿越血脑屏障，抑制血脑屏障上的P-糖蛋白、多药耐药相关蛋白等外排泵系统；吸附血浆中的不同载脂蛋白后，通过与血脑屏障上相应受体的结合，使泊洛沙姆包被的纳米粒主动转运入脑；连接各种配体及单克隆抗体等导向性分子，使其通过受体介导的转运进入脑部。本文综述了泊洛沙姆在促进药物穿越血脑屏障的重要作用，对设计脑靶向药物传递系统具有重要意义。     

伊立替康治疗脑胶质瘤的研究进展

目前治疗恶性脑胶质瘤的方案都无法显著改善患者总生存期。伊立替康可透过血脑屏障,强烈杀伤恶性胶质瘤细胞。近年来,伊立替康在单用或联用其他药物治疗恶性脑胶质瘤方面取得了较多的进展,但相关的临床研究结果尚未进行归纳总结,本文对此作一综述。从目前的研究结果看,伊立替康单药治疗恶性脑胶质瘤效果不甚理想,具有临床应用前景的联合用药选择有替莫唑胺、塞来昔布和舒尼替尼等。     

新化学类型的多巴胺受体阻滞剂——千金藤立定

左旋千金藤立定是新化学类型的多巴胺受体阻滞剂,它对D_1和D_2 受体均有亲和力;并具有一定的镇静效应,其作用性质与脑内阿片受体无关.药物动力学和毒理研究显示,该药吸收快,符合二室模型;急性和慢性应用对心、肝、肾功能无明显影响。该药试用于血管性头痛,药物诱发的多动症,儿童秽语多动综合征等,取得了良好的效益.     

冰片辅助胶质瘤治疗的临床前研究进展

胶质瘤是一种常见的原发性恶性脑肿瘤,目前临床主要治疗手段为手术切除联合放化疗,但由于血脑屏障的选择通透性和肿瘤细胞的多药耐药性特点,使得治疗效果并不理想。近年来,研究发现冰片具有开放血脑屏障以及促进化疗药物渗透的作用,冰片与化疗药物联用或共载,化疗药物能更多地靶向胶质瘤组织,增加疗效。本文就近年来冰片与化疗药物联合应用的临床前研究进行综述,以期为胶质瘤的治疗提供有益参考。     

骨形成蛋白7及骨形成蛋白受体IA在脑胶质瘤中的表达

目的 探讨骨形成蛋白7（BMP-7）及骨形成蛋白受体IA（BMPR-IA）在胶质瘤中的表达及其与预后的相关性。方法 应用免疫组织化学方法检测60例脑胶质瘤标本（Ⅰ型8例、Ⅱ型24例、Ⅲ型16例、Ⅳ型12例）和5例正常脑组织标本BMP-7和BMPRIA表达情况,对表达丰度进行半定量差异分析。结果 BMP-7和BMPR-IA在脑胶质瘤中表达丰度均随肿瘤恶性程度增加而增加。肿瘤1年生存率与BMP-7和BMPR-IA表达旱负相关。Ⅰ、Ⅱ、Ⅲ和Ⅳ型组的1年生存率分别为100．0％、66．6％、43．7％和25．0％。结论 BMP-7和BMPRIA在脑胶质瘤中表达丰度随着恶性程度增加而增加,且与预后呈负相关,提示BMP-7和BMPR-IA与脑胶质瘤的形成、生物学行为相关。     

非离子表面活性剂在脑靶向传递系统中的研究进展

由于血脑屏障的存在,限制了很多药物脑靶向的使用及疗效。研究者们使用非离子表面活性剂与载体偶联,通过吸收血液中的载脂蛋白促进受体介导的内吞作用,以及抑制P-糖蛋白外排等机制,或者用非离子表面活性剂连接相应配体和单克隆抗体等方法,可以增加脑部对药物的摄取。本文综述了血脑屏障的结构特点,以及如何通过非离子表面活性剂的修饰使药物穿过血脑屏障,对实现脑靶向给药有重要意义。     

脑恶性胶质瘤术后放疗联合紫杉醇同步化疗临床疗效观察

目的 观察脑恶性胶质瘤术后放疗联合紫杉醇每周方案同步化疗的治疗效果和毒副作用,探讨有效的治疗方案,以提高脑恶性胶质瘤的疗效,延长患者生存期.方法 经病理证实的脑恶性胶质瘤21例,术后2～6周接受放射治疗,其中常规放疗14例,调强适形放疗7例,放疗中位剂量61.2Gy(58～69Gy);放疗过程予紫杉醇60mg/M2每周一次同步增敏化疗方案,连用6周.结果 21例患者放化疗后疗效达完全缓解(CR)2例、部分缓解(PR)12例、无变化(NC)4例、进展(PD)3例,总有效率达66.7%(14/21).中位生存时间24.4个月,1、2、3年生存率分别达75.0%、41.0%和9.0%.放化疗过程主要毒性反应为消化道反应(Ⅰ度10例,Ⅱ度2例)和骨髓抑制(Ⅰ度7例,Ⅱ度8例),未发现肝肾功能损害以及除病变因素以外的其他颅神经损害表现.结论 脑恶性胶质瘤术后患者采用放疗联合同步紫杉醇增敏化疗安全、有效,为脑恶性胶质瘤术后的综合治疗提供了新方案,值得进一步研究.     

脑胶质瘤中表皮生长因子受体磷酸化AKT的表达及临床意义

目的探讨不同病理级别脑胶质瘤中表皮生长因子受体(EGFR)及磷酸化AKT(PAKT)的表达及临床意义。方法收集经手术切除的65例脑胶质瘤标本和5例正常脑组织,行免疫组织化学方法染色,检测EGFR与PAKT表达水平。结果脑胶质瘤组织中EGFR和PAKT的阳性表达率分别为73.84%和63.08%;EGFR和PAKT在Ⅲ~Ⅳ级脑胶质瘤的表达率为80.85%和72.34%,均显著高于Ⅰ~Ⅱ级的55.56%和38.89%(P<0.05)。EGFR与PAKT的表达水平呈正相关(r=0.68,P<0.01)。结论 EGFR与PAKT在脑胶质瘤中存在过表达与共表达,且与胶质瘤的恶性程度相关;检测两者表达水平对胶质瘤的早期诊断、靶向治疗及预测患者的预后有重要价值。     

超声微泡用于脑胶质瘤靶向药物递送

本文用超声微泡可逆地有限开放血脑屏障(blood-brain barrier,BBB),为抗肿瘤药物的脑内靶向递送打下基础。建立脑胶质瘤大鼠模型,探索低频超声(1 MHz)结合微泡对脑胶质瘤部位BBB开放的影响,并与非超声条件下伊文思蓝(Evans blue,EB)渗透BBB对比。考察超声的时机和时长对BBB渗透和脑组织的损伤作用。考察脑胶质瘤生长期对BBB渗透性的影响。结果表明,脑胶质瘤对BBB渗透性影响非常有限;而超声微泡可短暂有限开放BBB,并具有可逆性,可促进EB和核磁增强造影剂渗透BBB。超声时长30 s最合适,可开放BBB,并且对脑组织不会造成明显损伤。药物需在超声前注射才能借助BBB开放进入脑。超声微泡可安全有效开放BBB,控制时机和时长,能促进药物进入脑胶质瘤和脑组织。     

Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2

Background and purpose:Paclitaxel is highly efficacious in the treatment of breast, head and neck, non-small cell lung cancers and ovarian carcinoma. For malignant gliomas, paclitaxel is prevented from reaching its target by the presence of the efflux pump P-glycoprotein (P-gp) at the blood-brain barrier. We investigated the utilization of a new drug delivery system to increase brain delivery of paclitaxel.Experimental approach:Paclitaxel molecules were conjugated to a brain peptide vector, Angiopep-2, to provide a paclitaxel-Angiopep-2 conjugate named ANG1005. We determined the brain uptake capacity, intracellular effects and antitumour properties of ANG1005 in vitro against human tumour cell lines and in vivo in human xenografts. We then determined ANG1005 activity on brain tumours with intracerebral human tumour models in nude mice.Key results:We show by in situ brain perfusion that ANG1005 enters the brain to a greater extent than paclitaxel and bypasses the P-gp. ANG1005 has an antineoplastic potency similar to that of paclitaxel against human cancer cell lines. We also demonstrate that ANG1005 caused a more potent inhibition of human tumour xenografts than paclitaxel. Finally, ANG1005 administration led to a significant increase in the survival of mice with intracerebral implantation of U87 MG glioblastoma cells or NCI-H460 lung carcinoma cells.Conclusions and implications:These results demonstrate the antitumour potential of a new drug, ANG1005, and establish that conjugation of anticancer agents with the Angiopep-2 peptide vector could increase their efficacy in the treatment of brain cancer.British Journal of Pharmacology (2008) 155, 185-197; doi:10.1038/bjp.2008.260; published online 23 June 2008.     

Co-delivery of doxorubicin and siRNA for glioma therapy by a brain targeting system: angiopep-2-modified poly(lactic-co-glycolic acid) nanoparticles

It is very challenging to treat brain cancer because of the blood–brain barrier (BBB) restricting therapeutic drug or gene to access the brain. In this research project, angiopep-2 (ANG) was used as a brain-targeted peptide for preparing multifunctional ANG-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), which encapsulated both doxorubicin (DOX) and epidermal growth factor receptor (EGFR) siRNA, designated as ANG/PLGA/DOX/siRNA. This system could efficiently deliver DOX and siRNA into U87MG cells leading to significant cell inhibition, apoptosis and EGFR silencing in vitro. It demonstrated that this drug system was capable of penetrating the BBB in vivo, resulting in more drugs accumulation in the brain. The animal study using the brain orthotopic U87MG glioma xenograft model indicated that the ANG-targeted co-delivery of DOX and EGFR siRNA resulted in not only the prolongation of the life span of the glioma-bearing mice but also an obvious cell apoptosis in glioma tissue.     

A novel synergetic targeting strategy for glioma therapy employing borneol combination with angiopep-2-modified,DOX-loaded PAMAM dendrimer

Glioma is the most common primary malignant brain tumour and the effect of chemotherapy is hampered by low permeability across the blood–brain-barrier (BBB). Borneol is a time-honoured ‘Guide’ drug in traditional Chinese medicine and has been proved to be capable of promoting free drugs into the brain efficiently, but there are still risks that free drugs, especially anti-glioma drugs, may be disassembled and metabolised before penetrating the BBB and caused the whole brain distribution. The purpose of this paper was to investigate whether borneol intervention could facilitate the BBB penetration and assist glioma treatment by combining with doxorubicin (DOX) loaded PAMAM dendrimers drug delivery system modified with Angiopep-2 (a ligand of the low-density lipoprotein receptor-related protein, which overexpress both in the BBB and gliomas). The results demonstrated that Angiopep-2 modification could actually enhance the affinity between the dendrimers and the targeting cells and finally increase the cell uptake and boost the anti-tumour ability. Borneol physical combination could further enhance the anti-tumour efficiency of this targeting drug delivery system (TDDS) after penetrating BBB. Compared with free DOX solution, this TDDS illustrated obviously sustained and pH-dependent drug release. This suggested that this synergetic strategy provided a promising way for glioma therapy.     

Uptake of ANG1005, A Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer

Purpose

We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport.

Methods

The transfer coefficient (K_in) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB-231BR metastases of breast cancer.

Results

The BBB K_in for ¹²⁵I-ANG1005 uptake (7.3?±?0.2?×?10^-3 mL/s/g) exceeded that for ³H-paclitaxel (8.5?±?0.5?×?10^-5) by 86-fold. Over 70% of ¹²⁵I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain ¹²⁵I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of ¹²⁵I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of ¹⁴C-paclitaxel by 4–54-fold.

Conclusions

The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel.     

Ligand-modified homologous targeted cancer cell membrane biomimetic nanostructured lipid carriers for glioma therapy

The main treatment measure currently used for glioma treatment is chemotherapy; the biological barrier of solid tumors hinders the deep penetration of nanomedicines and limits anticancer therapy. Furthermore, the poor solubility of many chemotherapeutic drugs limits the efficacy of antitumor drugs. Therefore, improving the solubility of chemotherapeutic agents and drug delivery to tumor tissues through the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) are major challenges in glioma treatment. Nanostructured lipid carriers (NLCs) have high drug loading capacity, high stability, and high in vivo safety; moreover, they can effectively improve the solubility of insoluble drugs. Therefore, in this study, we used solvent volatilization and ultrasonic melting methods to prepare dihydroartemisinin nanostructured lipid carrier (DHA-NLC). We further used the glioma C6 cancer cell (CC) membrane to encapsulate DHA-NLC owing to the homologous targeting mechanism of the CC membrane; however, the targeting ability of the CC membrane was weak. We accordingly used targeting ligands for modification, and developed a bionanostructured lipid carrier with BBB and BBTB penetration and tumor targeting abilities. The results showed that DHA-loaded NGR/CCNLC (asparagine–glycine–arginine, NGR) was highly targeted, could penetrate the BBB and BBTB, and showed good anti-tumor effects both in vitro and in vivo, which could effectively prolong the survival time of tumor-bearing mice. Thus, the use of DHA-loaded NGR/CCNLC is an effective strategy for glioma treatment and has the potential to treat glioma.     

Transferrin receptor targeting segment T7 containing peptide gene delivery vectors for efficient transfection of brain tumor cells

Successful gene therapy for brain tumors are often limited by two important factors, the existence of blood brain barrier (BBB) and inefficient transfection of brain tumor cells. In this study, we designed a series of peptide-based gene delivery vectors decorated with T7 segment for binding the transferrin (Tf) receptors which were highly expressed on brain tumor cells, and evaluated their ability of gene delivery. The physicochemical properties of peptide vectors or peptide/DNA complexes were studied as well. The in vitro transfection efficiency was investigated in normal and glioma cell lines. Among these complexes, PT-02/DNA complexes showed the highest transfection efficiency in glioma cells and low cytotoxicity in normal cell lines, and it could transport DNA across the BBB model in vitro. Furthermore, PT-02/DNA could deliver pIRES2-EGFP into the brain site of zebrafish in vivo. The designed peptide vectors offered a promising way for glioma gene therapy.     

CTX-CNF1 Recombinant Protein Selectively Targets Glioma Cells In Vivo

Current strategies for glioma treatment are only partly effective because of the poor selectivity for tumoral cells. Hence, the necessity to identify novel approaches is urgent. Recent studies highlighted the effectiveness of the bacterial protein cytotoxic necrotizing factor 1 (CNF1) in reducing tumoral mass, increasing survival of glioma-bearing mice and protecting peritumoral neural tissue from dysfunction. However, native CNF1 needs to be delivered into the brain, because of its incapacity to cross the blood–brain barrier (BBB) per se, thus hampering its clinical translation. To allow a non-invasive administration of CNF1, we here developed a chimeric protein (CTX-CNF1) conjugating CNF1 with chlorotoxin (CTX), a peptide already employed in clinics due to its ability of passing the BBB and selectively binding glioma cells. After systemic administration, we found that CTX-CNF1 is able to target glioma cells and significantly prolong survival of glioma-bearing mice. Our data point out the potentiality of CTX-CNF1 as a novel effective tool to treat gliomas.     

VEGF信号通路在缺血性脑损伤中的作用及中药调节的研究进展

缺血性脑损伤常见的并发症为缺血性脑水肿,后者与血脑屏障（BBB）的功能密切相关。体外研究显示血管内皮生长因子（VEGF）能与受体结合从而激活多种细胞信号通路,通过抑制细胞调亡、降低氧化应激而发挥脑保护作用。蝮龙抗栓丸、参附注射液、脑泰通颗粒等中药可通过调控VEGF治疗BBB损伤。围绕VEGF及其相关通路在缺血性脑损伤中的研究进展及中药通过干预VEGF及其相关通路治疗BBB损伤做一综述,为脑缺血异常的临床治疗及新药研发提供理论依据。     

Selective boron drug delivery to brain tumors for boron neutron capture therapy

Malignant glioma is one of the most deadly forms of cancer in humans and remains refractory to presently available treatments. Boron neutron capture therapy (BNCT) is a promising therapeutic modality for the treatment of malignant brain tumors. For successful BNCT, a sufficient quantity of boron atoms must be selectively delivered to individual brain tumor cells while at the same time the boron concentration in the normal brain tissue should be kept low to minimize the damage to normal brain tissue. However, the brain entry of drugs is restricted by the blood-brain barrier (BBB), even though the permeability of the pathological area of this barrier may be partially increased due to the present of brain tumors. Therefore, selective delivery of boron to tumor cells across the BBB is a major challenge to the BNCT of brain tumors. This review briefly discusses four main mechanisms responsible for drug transport across the BBB. Brain tumor-localizing boron compounds are described, such as borocaptate sodium, p-boronophenylalanine, boronated porphyrins and boronated nucleosides. Strategies employed to selectively deliver boron drug into brain tumors are reviewed including hyperosmotic BBB modification, biochemical opening of BBB, electropermeabilization and direct intracerebral delivery of boron drugs. Conjugation of boron drugs to macromolecules like monoclonal antibodies and epidermal growth factor are discussed for active tumor targeting. Boron delivery via microparticles such as liposomes, high density lipoproteins and nanoparticles is also covered for their potential utilization in BNCT of brain tumors.