聚合物纳米药物用于治疗脑胶质瘤的最新研究进展

脑胶质瘤是颅内最常见的原发性恶性肿瘤,死亡率极高.目前针对脑胶质瘤的治疗手段预后差,难以实现良好的治疗效果.基于高分子聚合物的纳米药物以其良好的生物相容性、便于设计合成、易于靶向修饰以及较高的血脑屏障穿透效率等特性为脑胶质瘤的治疗开辟了新思路.基于高分子聚合物的纳米载体通过包载或键合等方式与小分子抗癌药物、核酸(DNA, siRNA)、蛋白质等治疗类物质结合提高抗肿瘤效果.本文综述了近年来对脑胶质瘤采用的化学治疗、基因治疗、免疫治疗、协同治疗等多种治疗方式及刺激响应性聚合物纳米载体的研究进展,并对其未来发展进行了展望.     

载药纳米粒作为脑靶向给药系统的研究

血脑屏障使大部分的活性药物很难由血液进入脑内发挥作用。载药纳米粒具有脑靶向性,可显著提高药物在脑内浓度,成为药物突破血脑屏障的有效途径。本文综述了近年来载药纳米粒透过血脑屏障的研究进展,并对纳米粒载中药入脑提出展望。     

载药纳米粒作为脑靶向给药系统的研究

血脑屏障使大部分的活性药物很难由血液进入脑内发挥作用。载药纳米粒具有脑靶向性,可显著提高药物在脑内浓度,成为药物突破血脑屏障的有效途径。本文综述了近年来载药纳米粒透过血脑屏障的研究进展,并对纳米粒载中药入脑提出展望。     

脑肿瘤靶向递药策略及其研究进展

脑肿瘤严重威胁人类生命,其特有的屏障结构阻碍了药物有效进入。以脑胶质瘤为例,对现有脑肿瘤主要靶向策略作一简要综述, 并提出了脑肿瘤靶向递药的新理念——系统靶向（或全过程靶向）递药,即集脑肿瘤发生发展各阶段特征靶向策略于一体,设计对脑肿瘤 发生发展各阶段具有靶向功能的纳米递药系统,以实现更为有效的脑肿瘤靶向治疗目标。     

RGD修饰包载超顺磁性氧化铁纳米粒用于脑胶质瘤的靶向研究

目的：采用PLGA-PEG为聚合材料,制备RGD修饰包载超顺磁性四氧化三铁纳米粒子（RGD-NP—Fe3O4）,用于脑胶质瘤细胞靶向核磁共振成像纳米探针。方法：采用沉淀法制备RGD修饰的栽超顺磁性纳米粒,考察纳米粒的粒径,电位等理化指标以及细胞毒性。通过细胞以及肿瘤球摄取实验,考察RGD．NP—Fe304的脑胶质瘤细胞靶向性。结果：制备得到的RGD-NP-Fe3O4粒径在85±7．5nm,电位为18＋1．15mV。纳米粒浓度在300μg/mL范围内,对脑胶质瘤细胞均无显著毒性。经过RGD修饰后脑胶质瘤细胞U87对纳米粒的摄取效率大大提高,纳米粒穿透肿瘤球能力显著增强。结论：RGD修饰包载超顺磁性氧化铁纳米粒是一种潜在的高效的脑胶质瘤细胞靶向诊断纳米探针和靶向给药系统。     

无机纳米材料在神经胶质瘤诊疗中的应用与特点

神经胶质瘤是中枢神经系统中恶性程度与侵袭性最高的肿瘤之一,其难治性和高致死性亟需尽快开发新的诊疗方法。近年来,各种无机纳米材料独特的内在物化特性的探索应用,为神经胶质瘤的早期诊断和靶向治疗带来了新希望。该文系统地介绍了当前已应用于神经胶质瘤诊疗研究的一些重要无机纳米材料,包括纳米金、纳米银、超顺磁性氧化铁、石墨烯、碳纳米管、介孔硅、半导体量子点、上转换纳米材料、层状双氢氧化物以及二硫化钼。在神经胶质瘤诊断方面,超顺磁性氧化铁、量子点和上转换纳米材料等无机纳米材料,具有优异的肿瘤组织成像性能,能提高诊断的灵敏性,可实现对神经胶质瘤的早期诊断和实时监测;在治疗方面,大多数无机纳米材料进行功能性修饰后用作靶向药物载体,可加载多种抗癌的药物、基因和抗体等,提高靶向输送能力,以实现对胶质瘤的靶向治疗,延长药物在体内的半衰期,同时减少全身副作用;其中,纳米金和纳米银还可用于神经胶质瘤放射增敏治疗,碳纳米管和超顺磁性氧化铁可分别用于神经胶质瘤光热治疗和磁热治疗,达到安全特异的治疗效果。这些无机纳米材料尽管在体内降解、靶向可控性、个体化等技术性问题上还需要进一步解决,但其探索应用已为神经胶质瘤治疗研究提供了新的方向。     

肿瘤靶向纳米载药系统的设计与构建

近年来将纳米载药系统应用于肿瘤靶向递药的研究层出不穷。与正常组织相比,肿瘤组织具有较低的pH环境、大量新生血管生成、 不规则的血流灌注、局部缺氧等特异性的微环境,利用这些特点进行合理的纳米载药系统设计能够实现肿瘤部位的高效递药及深层穿透, 显著提高肿瘤治疗效果。针对现有的肿瘤靶向纳米载药系统的构建与设计方法进行综述,以阐述纳米载药系统在肿瘤靶向传递中的研究进展     

磁性氧化铁纳米药物载体的研究进展

近年来,磁性氧化铁靶向纳米载体作为载药系统引起了人们的关注。磁性靶向载药系统和靶向药物治疗的目的是药物载体载药后,在外部磁场的作用下直接靶向富集在肿瘤或病损组织,杀伤病损细胞,对人体无害或减少毒副作用。本文介绍了影响磁纳米颗粒在体内作用的设计参数,并总结了被广泛应用于氧化铁纳米颗粒的制备,表面修饰,功能化的方法及氧化铁纳米载体在靶向载药体系中的应用。     

磁性氧化铁纳米药物载体的研究进展

近年来,磁性氧化铁靶向纳米载体作为载药系统引起了人们的关注。磁性靶向载药系统和靶向药物治疗的目的是药物载体载药后,在外部磁场的作用下直接靶向富集在肿瘤或病损组织,杀伤病损细胞,对人体无害或减少毒副作用。本文介绍了影响磁纳米颗粒在体内作用的设计参数,并总结了被广泛应用于氧化铁纳米颗粒的制备,表面修饰,功能化的方法及氧化铁纳米载体在靶向载药体系中的应用。     

基于核酸适配体的DNA纳米结构在肿瘤研究中的应用进展

DNA纳米结构具有强大的分子载带量、良好的稳定性、可编辑性和生物相容性等特点,是纳米材料领域的研究热点。核酸适配体是一段短的寡核苷酸序列(RNA或ss DNA),能够折叠成特定的三维结构与靶标高特异性、高亲和力的结合。将核酸适配体的分子识别特性和DNA纳米结构相结合,可将靶向识别、生物成像及药物递送等特点集于一体,在生命科学研究领域,尤其是肿瘤领域,有着良好的应用前景。本文介绍了DNA纳米结构和核酸适配体的特点与优势,对近年来核酸适配体-DNA纳米结构在肿瘤标志物检测、靶向成像以及药物靶向递送的研究进展进行了综述,并对其发展前景进行了展望,期待核酸适配体-DNA纳米结构能为肿瘤的靶向诊疗提供新的策略。     

Mechanisms of enhanced antiglioma efficacy of polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles by focused ultrasound

The presence of blood‐brain barrier (BBB) greatly limits the availability of drugs and their efficacy against glioma. Focused ultrasound (FUS) can induce transient and local BBB opening for enhanced drug delivery. Here, we developed polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles (PS‐80‐PTX‐NPs, PPNP) and examined the enhanced local delivery into the brain for glioma treatment by combining with FUS. Our result showed PPNP had good stability, fast drug release rate and significant toxicity to glioma cells. Combined with FUS, PPNP showed a stronger BBB permeation efficiency both in the in vitro and in vivo BBB models. Mechanism studies revealed the disrupted tight junction, reduced P‐glycoprotein expression and ApoE‐dependent PS‐80 permeation collectively contribute to the enhanced drug delivery, resulting in significantly stronger antitumour efficacy and longer survival time in the tumour‐bearing mice. Our study provided a new strategy to efficiently and locally deliver drugs into the brain to treat glioma.     

The role of peptides in blood-brain barrier nanotechnology.

The blood-brain barrier (BBB) regulates the passage of molecules between the bloodstream and the brain. Overcoming the difficulty of delivery drugs to specific areas of the brain is a major challenge. The BBB exerts a neuroprotective function as it hinders the delivery of diagnostic and therapeutic agents to the brain. Here, we provide an overview of the way in which peptides and nanotechnology are being exploited in tandem to address this problem. Peptides can be used as specialised coatings able to transport nanoparticles with specific properties, such as targeting. The nanoparticle can also carry a peptide drug. Furthermore, peptides can be used in less conventional approaches such as all-peptide nanoparticles. In summary, the combined use of peptides and nanotechnology offers tremendous hope in the treatment of brain disorders.     

Blood-brain barrier and new approaches to brain drug delivery.

Morbidity caused by brain dysfunction affects more than 50 million persons in the United States. Although new neuropharmaceuticals have the potential for treating specific brain diseases, they may not effectively enter brain from blood. Safe strategies are needed for drug delivery through the brain capillary wall, which makes up the blood-brain barrier in vivo. Two of these strategies are reviewed, as are related new developments in the molecular and cell biology of the brain capillary endothelium. The production of chimeric peptides represents a physiologic-based strategy for drug delivery. It entails the covalent coupling of the neuropharmaceutical to a brain transport vector, allowing transportation through the blood-brain barrier. Another strategy is biochemical opening of the blood-brain barrier: intracarotid leukotriene infusion is a method for selectively increasing blood-brain barrier permeability in brain tumors without affecting barrier permeability in normal brain tissue.     

肿瘤颅内外转移机理的实验性探讨

众所周知,胶质瘤很少发生颅外转移,但许多肿瘤却容易转移入颅内,本文以动物实验方法探讨这种现象发生机理。ＢＡＬＢ／Ｃ裸小鼠给予左侧颈内动脉注射人脑胶质瘤及黑色素瘤株细胞（１－２×１０／ｍｌ细胞悬液）后饲养观察。半月处死全部裸小鼠并对其进行大体及组织学检查。黑色素瘤颅内转移瘤成瘤率达１００％。而有部分胶质瘤却只能在颅外成瘤后少数破坏颅骨才能进入颅内,对照组采用胶质瘤作腹腔注射,结果８例中有５例发生肺部转移。本实验说明黑色素瘤只有很强的通过血脑屏障能力而胶质瘤细胞本身具有穿透血脑屏障以外的其它血管壁的浸润转移能力,而原发于颅内的胶质瘤不发生颅外转移很可能与其不能通过血脑屏障有关。     

Uptake mechanism of ApoE-modified nanoparticles on brain capillary endothelial cells as a blood-brain barrier model

Background

The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood.

Methodology/Principal Findings

In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different in vitro co-incubation experiments were performed with competing ligands of the respective receptor.

Conclusions/Significance

This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier.     

In Vitro Drug Response and Efflux Transporters Associated with Drug Resistance in Pediatric High Grade Glioma and Diffuse Intrinsic Pontine Glioma

Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of cancer-related death in children. While it is clear that surgery (if possible), and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.     

β-elemene combined with temozolomide in treatment of brain glioma

Temozolomide (TMZ) is a widely used chemotherapeutic agent for malignant glioma. β-Elemene has been reported to have the ability of passing through the blood-brain barrier and reverse multidrug resistance. In the present study, transport of drugs through the in vitro blood-brain barrier (BBB) model also suggested that β-elemene can assist in TMZ transport to the brain. Plasma and brain pharmacokinetics demonstrated that when β-elemene is used in combination with TMZ, the metabolic rate of TMZ in plasma is slowed, and mean residence time (MRT) in brain is prolonged. The brain tissue distribution at 1 h indicated that the combination of TMZ and β-elemene promotes the distribution of β-elemene in the brain but slightly reduces the distribution of TMZ in the brain. Furthermore the antitumor effect and toxicity in vivo were also investigated. The combination of β-elemene and TMZ was well tolerated and significantly inhibited tumor growth in glioma xenografts. In summary, the present study indicates a synergistic antitumor effect of β-elemene and TMZ in glioma.     

Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain.

The brain is partially protected from chemical insults by a physical barrier mainly formed by the cerebral microvasculature, which prevents penetration of hydrophilic molecules in the cerebral extracellular space. This results from the presence of tight junctions joining endothelial cells, and from a low transcytotic activity in endothelial cells, inducing selective permeability properties of cerebral microvessels that characterize the blood-brain barrier. The endothelial cells provide also, as a result of their drug-metabolizing enzymes activities, a metabolic barrier against potentially penetrating lipophilic substances. It has been established that in cerebrovascular endothelial cells, several families of enzymes metabolize potentially toxic lipophilic substrates from both endogenous and exogenous origin to polar metabolites, which may not be able to penetrate further across the blood-brain barrier. Enzymes of drug metabolism present at brain interfaces devoid of blood-brain barrier, like circumventricular organs, pineal gland, and hypophysis, that are potential sites of entry for xenobiotics, display higher activities than in cerebrovascular endothelial cells, and conjugation activities are very high in the choroid plexus. Finally, xenobiotic metabolism normally results in detoxication, but also in some cases in the formation of pharmacologically active or neurotoxic products, possibly altering some blood-brain barrier properties.