纳米材料制造的最新状态及其在神经疾病管理中的潜在应用

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背景

纳米材料 (NM) 表示为具有 1-100 nm 范围内典型尺寸的材料。基本上，它们是基于复合材料（将 NM 与其他 NM 或更大的块状材料结合）、基于树枝状聚合物（由支链单元构建的纳米尺寸聚合物）、基于碳（富勒烯、纳米管）和基于金属（量子点、纳米银、纳米金和金属氧化物，即氧化铈、氧化钛、氧化铁和氧化锌）材料。在这个前沿的世纪中，这些具有所需粒径和形状的纳米粒子 (NPs) 一个一个或多个的制造在药物基因传递、疾病管理、药物、化妆品、食品、光子晶体、涂料、油漆、催化、生物修复、材料科学、植物生长和/或其生产和保护 [1,2,3,4,5,6,7,8,9,10,11,12]。

NMs 在商业和工业层面的使用已大大增加，例如每年生产约 3000 吨 TiO2 NPs [13]，超过 50% 用于个人护理产品，如防晒霜 [14]。同样，银和金 NPs 已广泛用于医学、疾病诊断、传感器技术、生物整平、制药和许多其他生物医学应用 [2, 11, 15,16,17,18]。根据其磁性，铁和氧化铁 NPs 已广泛用于癌症治疗、药物输送、MRI、催化和从饮用水系统中去除杀虫剂 [11]。铂纳米粒子被用作抗氧化剂和催化剂[10, 19]，而钯纳米粒子被广泛用作催化剂和癌症治疗[10]。

近年来，这些 NMs 被用作纳米药物，并在全球众多神经系统疾病的诊断和治疗中发挥着至关重要的作用。因此，纳米医学是一个新兴领域，工程纳米技术用于检测、治疗和预防多种疾病，包括神经系统疾病。纳米药物由具有较高药物生物利用度的纳米级分子组成。通常，NM 被设计为不与身体防御机制相互作用。 NMs 的尺寸较小，它们可以很容易地储存在外周组织中，以便在体内长期使用 [20]。 NMs 可以在分子和超分子水平上与生理系统相互作用。它们可以重新设计，以对细胞环境作出反应，并在细胞和组织中触发所需的生物活性，同时减少不利影响。新型纳米技术发明正在为治疗和减少危及生命的疾病以及神经系统疾病做出宝贵的治疗贡献 [21]。

几乎所有的神经系统疾病都与中枢和外周神经系统有关。大脑、脊髓和神经控制着身体系统的整个工作。如果神经系统出现任何问题，随后通常会检测到与说话、吞咽、呼吸、学习等相关的问题。神经系统疾病的治疗和管理选择非常有限，因为血脑屏障 (BBB) 限制了治疗分子和所需药物通过口服途径的交叉和溶解度差。为了克服这个问题，纳米技术以纳米管、纳米线、纳米球、机器人、微型、纳米悬浮液、纳米药物、纳米凝胶、纳米乳剂、纳米载体、微粒 (MP)、纳米颗粒、聚合物和固体脂质纳米颗粒的形式提供了新的技术发明机会(SLNs)、固体脂质载体、液晶 (LCs)、脂质体、微乳液 (MEs) 和水凝胶，用于有效和靶向的药物递送系统和各种疾病的诊断和管理 [22]。

目前，致力于神经系统疾病的各个研究小组正在不断努力，通过使用纳米药物来有效控制和管理神经系统疾病，开发用于靶向给药的纳米药物。最常报告的神经系统疾病是阿尔茨海默病 (AD)、帕金森病 (PD)、肌萎缩侧索硬化 (ALS)、多发性硬化 (MS)、神经系统肿瘤和缺血性中风 [23]。其中，AD根据记忆丧失、词汇访问丧失和判断障碍进行分类。它是一种与年龄相关的疾病，随着年龄的增长（60-85 岁）而增加。除了老年，肥胖、糖尿病和心血管疾病是人类健康迅速恶化和 AD 发病的主要因素。基因突变已被描述为导致早发型家族性 AD 的原因，已知它们在 21 号染色体上编码淀粉样前体蛋白 (APP) [24]、在 14 号染色体上编码早老素 1 (PS1) [25] 和早老素 2 ( PS2) 在 1 号染色体上 [26]。 AD的迟发散发形式包含超过90%的所有疾病。疾病的病因在 65 岁以后每年增加一倍，并在 85 岁达到 50% [27]。散发性 AD 的遗传风险是由于载脂蛋白 E 的 ε4 等位基因的遗传所致，该等位基因位于染色体 19q13 [27]。这种蛋白质可以影响疾病的进展和神经细胞损伤的程度 [27, 28]。有鉴于此，已经假设了许多机制来阐明载脂蛋白 E 在阿尔茨海默病患者大脑中的影响 [28]。该蛋白质还具有轻度认知障碍 (MCI) 发展的风险因素，该障碍可能在以后转化为 AD 发展 [29]。 AD 导致 80% 以上的痴呆症，现在它已被归类为世界上最具破坏性的疾病 [20, 30,31,32]。环境污染是 AD 和 PD 进展的主要原因。来自不同来源的金属和金属氧化物被吸入并沉积在肺/大脑中。例如，CeO2 和 TiO2 已证明在长期暴露后会在组织中积累 [33, 34]。已经证实，TiO2 NPs 在斑马鱼幼虫和 PC 12 细胞系中诱导了 PD 样症状。它会导致过早孵化并干扰它们的运动 [35]。斑马鱼脑组织中的 TiO2 NPs 已被证明可诱导 ROS 产生，导致下丘脑区域的细胞死亡。这些 NPs 也会影响神经元功能。在最近的一项研究中，Yoo 等人。 [36] 已经证明金纳米颗粒能够在存在电磁场的情况下产生用于PD治疗的诱导多巴胺神经元。

如上所述，神经系统中药物和其他治疗化合物的生物利用度和有效递送受到两个屏障的限制，即 BBB 和血脑脊液屏障 (BCSFB) [20, 37,38,39,40]。 BBB 在保护血液传播的病原体（如细菌、病毒、寄生虫和毒素）进入方面发挥着重要作用 [41]。虽然 BBB 有助于保护大脑，但它也干扰了许多神经系统疾病的治疗。因此，必须开发一种良性有效的药物递送系统，该系统可以穿过 BBB 到达靶细胞而不会产生任何副作用。瓦希斯特等人。 [42] 曾报道 BBB 降低了到达作用部位的药物浓度，并降低了其治疗目标疾病的能力；因此，更高浓度的药物加强了开发基于纳米材料的药物递送系统的必要性。该研究还强调了纳米凝胶制备的最新趋势及其在药物递送系统中的重要性。重要的是要注意亲脂性分子或低分子量分子（低于 400-600 Da）穿过 BBB；因此，神经系统疾病治疗需要谨慎选择药物。 AD 可能是家族性或散发性、认知障碍和导致神经元细胞死亡的脑中斑块沉积。建议防止功能神经元的损失或替换受损的神经元。已发现神经干细胞（NSC）移植可改善 AD 动物模型的认知和突触传导性 [43]。

张等人。 [44] 报道了 NMs 在干细胞治疗几种神经系统疾病中的重要性。作者发现 NM 在体内和体外促进干细胞增殖和分化，并在干细胞成像和跟踪中发挥主导作用。崔克等人。 [45] 还报道了间充质干细胞 (MSCs) 治疗缺血性中风的重要性；然而，它们向目标的系统交付仍然是一个挑战。用葡聚糖包被的 MNP 标记的 MSC 在大脑中传播到脑损伤风险增加的区域，并显示出更好的功能恢复。该研究报道，尽管静脉给药途径是良性的，但穿过 BBB 的 MSC 数量有限。

本综述重点介绍了常用的金属螯合剂NMs/NPs及其在神经系统疾病管理给药系统中的应用现状。

神经系统疾病和管理

总之，与 CNS 相关的主要挑战是缺乏智能诊断工具和有效药物无法穿越 BBB。为了克服这些问题，NMs/NPs 的各种配方在药物递送中显示出广泛而有前景的应用，以对抗神经系统疾病的治疗和管理（图 1）。 NMs/NPs在AD、PD、ALS、MS、神经肿瘤、缺血性脑卒中等神经系统疾病中的具体应用如下。

不同类型NPs及其在神经系统疾病治疗和管理中的应用

阿尔茨海默病

目前，AD 已影响超过 3500 万人，预计到 2050 年，全球病例数将增加 [22]。目前，AD的治疗以对症和血管预防为主，使用胆碱酯酶抑制剂和N -甲基-D-天冬氨酸拮抗剂。纳米技术在 AD 诊断和治疗中的应用已显示出有希望的结果。多个 NM 被用于 AD 诊断和治疗。许多方法已被用于制备 NP，例如聚合物聚合、离子凝胶乳液、溶剂蒸发、溶剂扩散、纳米沉淀、喷雾干燥和非润湿模板中的粒子复制。 AD 的病情可以通过使用与淀粉样蛋白 β (Aβ) 形式具有良好亲和力的 NPs 来改善，从而诱导“下沉效应”。通过使用超灵敏的基于NP的生物条形码、免疫传感器和扫描显微镜程序，AD的诊断和Aβ1的检测已达到先进阶段[46]。

治疗的主要重点是针对蛋白质和 Aβ 肽的代谢功能障碍和聚集。 Aβ蛋白的斑块形成如下图1所示：

β淀粉样蛋白形成斑块

大脑中细胞内过度磷酸化的神经原纤维缠结和淀粉样斑块（Aβ 肽的细胞外沉积物）是 AD 的主要原因。还提出了 AD 进展的其他原因，即胆碱能系统失调和脑中 Aβ 肽沉积 [31]。 NFT 会破坏轴突完整性和神经递质运输 [47]。因此，应配制具有可穿过 BBB 的显着特征的药物。 BBB 保护大脑免受各种病原体的侵害。亲脂性分子、O2 和 CO2 以及其他分子量 <600 g/mol 的分子很容易通过 BBB 扩散。氨基酸、葡萄糖和胰岛素通过特定受体介导的内吞作用进入大脑 [48]。许多设备已经通过在药物运输中使用多种方法来穿过 BBB 并到达 AD 患者的脑组织。一种这样的方法是将活性化合物与纳米载体结合。聚合物胶束、脂质体、脂质和与 BBB 具有高度关联的聚合物纳米颗粒。因此，纳米载体与脑营养转运系统的相互作用使药物能够到达目标部位。例如，洛克曼等人。 [49] 报道了用硫胺素包覆的 NPs 将颗粒靶向 BBB 硫胺素转运蛋白。因此，药物通过 BBB 转运 [50]。可生物降解的材料作为载体有助于将药物运输到使用部位。这些治疗有望保护、修复和调节中枢神经系统 (CNS) 组织的损伤 [51]。

亲水、带电、荧光标记物 ThT 已被用作检测 AD 淀粉样蛋白 β 斑块的探针 [52]。哈蒂格等人。 [53] 已经通过海马内注射将含有 PBCA 的封装 ThT NPs 递送到小鼠大脑中。在这项研究中，TEM 图像显示小胶质细胞和神经元中存在 NP。因此，利用该技术可以完成对AD的检测。

AD 患者大脑的生化研究表明，胆碱乙酰转移酶 [54] 的新皮质缺陷是乙酰胆碱 (Ach) 合成的原因。它还有助于学习和增强记忆力。因此，预计基底前脑中胆碱能神经元的产生和大脑皮层中神经传递的丧失会导致 AD 患者认知功能的恶化。用 ACh 毒蕈碱受体拮抗剂东莨菪碱治疗大鼠，降低了 ACh 的水平，同时损害了空间记忆 [55]。然而，已经观察到增加乙酰胆碱释放的物质，即。利诺哌啶，改善阿托品诱导的记忆力减退[56]。

聚合物 NPs 被制成并用放射性标记的 125I-氯碘羟喹进行封装，以增强其向大脑的转运和 125I-CQ 的淀粉样蛋白斑块保留。已观察到这些 NPs 是体内单光子发射计算机断层扫描的合适载体 [22, 57]。另一种被称为磁性氧化铁的 NP 正被有效利用，因为它具有更大的表面积和磁性效应，而且毒性更小。金纳米粒子已被用作 Aβ 肽聚集动力学研究的宝贵工具。此外，通过融合含有钴 (II) 磁核和铂壳的金 NPs 合成了异二聚体 NPs。这些纳米颗粒通过用硫辛酸-PEG 包被稳定，并在 AD 中显示出有希望的结果 [58]。此外，前哨淋巴结通常是球形脂质核心基质，可以有效地溶解亲脂性分子。 SLNs可以穿过血脑屏障，药物/治疗分子可以通过内吞作用有效地输送到大脑中[22, 59]。

脂质体是另一种类型的药物递送载体，包含一个或多个磷脂双层以携带亲脂性或亲水性药物。利凡斯的明脂质体和细胞穿透肽修饰脂质体被配制用于改善在大脑中的分布并减少副作用，从而增强药效学。结果表明，在进入大脑 8 小时后，血脑屏障中的利凡斯的明浓度更高 [60]。基于表面活性剂的药物递送系统通过在水的存在下聚集表面活性剂分子以形成基于表面活性剂浓度、盐的存在和温度的结构，为药物递送提供了另一种选择。 ME 通常是热力学稳定的。因此，可以生成具有不同几何形状的微乳液、纳米乳液和溶致液晶中间相[22]。

两种类型的纳米颗粒，如聚山梨酯 80 涂层聚 (n 氰基丙烯酸丁酯）和另一个涂有聚山梨酯 80 的材料是使用乳液聚合制备的，以处理 AD [61]。开发了一种双功能 NP，用于基于 PEG 化聚（乳酸）聚合物和两个靶向肽 TGN（由 12 个氨基酸组成的配体：TGNYKALHPNHGC）和 QSH（d D-对映体肽：QSHYRHISPAQVC）通过在NPs 的表面并用于 AD [62]。 TGN 用于靶向 BBB 配体，而 QSH 与 Aβ 斑块有效关联。这些 NPs 通过在 AD 小鼠大脑中的靶向递送直接发送到 Aβ 斑块。因此，NPs的应用有望成为AD诊断和治疗的重要工具[22]。

AD 患者脑组织的死后研究表明有两种类型的病变，即老年斑 (SP) 和神经原纤维缠结 (NFT)。已发现 AD 患者大脑中的 SP 增加了铜、锌和铁。据认为，金属与金属和蛋白质相互作用，这可能会影响淀粉样蛋白-β (Aβ) 的聚集，从而导致毒性。多项临床研究表明，锌、铜和铁可补充转基因小鼠的 Aβ 斑块 [63,64,65,66]。在含 NFT 的神经元中已检测到锌和铁。铁 (III) 和铜 (II) 可以与蛋白质螯合并改变其基本构象，促进磷酸化和聚集。金属优先与蛋白质中的各种原子结合，例如 N、O 和 S。因此，金属螯合物可用于治疗 AD，并且可以通过与蛋白质配位去除 SP 中多余的金属。 Aβ 还原铜 (II) 和铁 (III) 离子并通过双电子转移至 O2 生成 H2O2 [66]。

这种 Aβ 诱导的细胞培养中的氧化应激和毒性由蛋氨酸和酪氨酸适度调节 [67, 68]。自由基介导的反应在许多神经系统疾病的衰老和生理学中起着重要作用。发现抗氧化剂如多酚化合物（白藜芦醇、姜黄素、儿茶素）对 AD 治疗非常有帮助 [69]。这些化合物表现出强大的抗氧化和抗炎特性（表 1），并且大量体外研究表明绿茶多酚可以保护神经元免受 Aβ 诱导的损伤 [70,71,72]。绿茶多酚在中风/脑缺血、AD 和 PD 的动物模型中表现出积极的影响。绿茶含有表没食子儿茶素没食子酸酯（EGCG）作为活性成分，可作为抗 Aβ 的神经保护剂。

姜黄素是姜黄中的一种活性成分，可作为有效的抗氧化和抗炎剂。当它被喂给老年 Tg2576 小鼠时，观察到 Aβ 水平和斑块显着降低 [83]。它还在体外阻断 Aβ 聚集和原纤维形成（IC50 =0.8 μM），从而减少淀粉样蛋白斑块 [83]。姜黄素可能螯合氧化还原活性铁和铜 [94]。由于其在水中的溶解度非常低，在碱性 pH 值下会快速全身消除、吸收和降解，因此即使在较高剂量下也是安全的 [95, 96]。杨等人。 [96] 报道了 10 mg kg ⁻¹ 给大鼠静脉注射姜黄素产生的最大血清姜黄素水平为 0.36 ± 0.05 μg ml ^-1 ，而高 50 倍的口服姜黄素剂量仅产生 0.06 ± 0.01 μg ml ^-1 血清水平。然而，Ravindranath 和 Chandrasekhara [97] 报道了更高的剂量并没有导致更高的吸收。在生理 pH 值下未电离的药物分子是亲脂性的，分子量低，可以通过扩散穿过 BBB。神经肽、氨基酸和己糖通常需要特定的载体才能扩散到大脑中 [98]，尽管肽和蛋白质可以通过饱和转运系统穿过 BBB [99]。

聚合物纳米载体是很有前景的候选者，因为它们可以打开 BBB 的紧密连接 (Tjs)，延长药物释放，并保护它们免受酶促降解 [41]。小于 100 nm 的亲水性 NPs 是非常有效的药物载体。生物分布随着纳米颗粒尺寸的减小而增加。注射的金 NP（15、50 和 100 纳米）在小鼠体内的分布显示，在胃、脑、心脏、肺、肝脏、脾脏、肾脏和血液中，15 纳米粒径的 NP 含量更高。较大的颗粒在胃、胰腺、大脑和血液中的吸收量较小 [100]。许多因素负责通过 BBB 快速运输治疗药物/分子，例如，药物的分子量、分子电荷、结构构象、浓度梯度溶解度、使用的聚合物以及药物与某些供体位点结合的亲和力/细胞蛋白[101]。 BBB 在体外和原位均未出现毒性表明 NPs 可能通过内吞作用/转胞吞作用或什至通过扩散通过屏障运输。它们可能被脑内皮细胞吸收 [102]。然而，在用作载体之前检查 NP 的毒性是必不可少的。表 2 总结了测试用于治疗 AD 的载药纳米粒。

非甾体类药物，即苯丝氨酸、他汀类药物、tarenflurbil、曲米磷酸和沙利普登，均未在治疗神经系统疾病方面表现出令人满意的疗效 [124,125,126]。然而，众所周知，高胆固醇水平与 AD 风险增加有关。动物研究证实，高胆固醇血症会促进 Aβ 的产生和沉积。目前，还有两类药物被批准用于 AD 治疗。胆碱酯酶抑制剂 (ChEI) 多奈哌齐 (Aricept)、加兰他敏 (Reminyl) 和卡巴拉汀 (Exelon) 用于治疗轻度至中度 AD。 N -甲基-D-天冬氨酸拮抗剂美金刚是治疗中重度痴呆的唯一药物。过量的铁、锌和铜离子会导致 Aβ 沉淀，从而导致产生有毒的 Aβ 低聚物 [127]。如果上述金属离子与无毒配体如二铁肟或 D-青霉胺螯合，形成可从生命系统中去除的可溶性复合物，则可以轻松防止 Aβ 低聚物的形成。将与去铁酮结合的 240 nm 聚苯乙烯 NP 施用于体外培养的人皮层神经元，通过阻止 Aβ 聚集显示出细胞毒性降低 [128]。然而，生物利用度和毒性限制了它们在人体系统中的应用。纳米载体通过螯合剂与它们的结合来促进这一特性。

同样，已知 5-chloro-7-iodo-8-hydroxyquinoline（一种醌醇衍生物）对锌和铜离子具有高亲和力。用这种醌醇治疗 AD 转基因小鼠可阻止 Aβ 聚集 [129]。低浓度的可溶性复合制剂可防止金属与其他连接蛋白的相互作用。用聚山梨醇酯 80 包被的 PBCA NPs 封装可以提高羟基喹啉的效率和生物利用度。据报道，这些羟基苯酚 NPs 在野生型小鼠中可以穿过 BBB，表明其具有治疗 AD 的潜力[129]。

在 AD 治疗中也提出了天然存在的分子。例如，姜黄中的姜黄素和水果和蔬菜中的槲皮素类黄酮在本质上具有抗炎、抗氧化和抗癌作用。由姜黄素-磷脂偶联物制备的 170 nm 脂质体已证明在体外与 Aβ 原纤维具有高亲和力，而与 Aβ 单体的亲和力非常低 [130]。脂质体作为载体在 AD 患者中传递治疗分子。同样，槲皮素也被证明可以保护原代大鼠海马神经元免受 Aβ 细胞毒性、蛋白质氧化、脂质过氧化和细胞凋亡 [131]。小鼠口服槲皮素可改善学习和记忆能力，但其在肠道中的吸收率低并导致其快速消除[132]。当脂质体包裹的槲皮素经鼻给药时，它抑制了 AD 大鼠模型中海马神经元的退化 [133]。 AD中蛋白质的确认起着重要作用。肽可以采用β-折叠确认或卷曲形成。已经观察到小鼠大脑中不溶性和可溶性 Aβ 肽的显着减少。然而，在AD的治疗中，构象变化是显着的。金纳米粒子常用于在电磁场下治疗 AD。如下图2所示；负载药物的纳米颗粒被光热切除，吸收光能转化为热能，提高纳米颗粒的温度，破坏靶细胞，而不损害正常健康细胞。

金纳米粒子在阿尔茨海默病治疗中的作用

帕金森病

PD 是一种神经退行性疾病，每年每 100 名 65 岁以上的人中就有一人受到影响。这种疾病通过影响神经炎症反应导致患者身体运动的严重并发症。纳米技术的使用可能是缓解 PD 的有力工具。工程化 NMs 可以促进受影响神经元的再生和保护，还可以增强药物和小分子通过 BBB 的传递。为了克服 PD 常规疗法的副作用，目前正在对许多策略和技术的开发进行广泛的研究，例如用于生物特征模拟和优化的纳米支架设备以及直接和有针对性地输送到大脑中。目前，肽和肽 NPs 不仅用于 PD，还用于其他 CNS 疾病的诊断和治疗。但是，迫切需要进一步开发具有改进和有效性能的纳米药物，以将纳米药物输送到 CNS 和脑组织 [46]。掺有金和二氧化钛的纳米管阵列使用光电化学免疫传感器识别 a-syn [134]。与纳米神经技术相结合的 AFM 研究可以识别单个 a-syn 分子的蛋白质错误折叠。使用过氧化氢酶包装的聚乙烯亚胺 NPs 可有效减少神经元内的神经炎症和神经变性。此外，抗α-syn-共轭聚氰基丙烯酸丁酯纳米粒有助于神经元a-syn清除[23, 135, 136]。

肌萎缩侧索硬化

它是一种运动神经元疾病，会导致神经肌肉控制丧失，并导致致命后果 [137]。运动神经元的退化发生在下部和上部神经元中。主要在神经元和轴突中检测到蛋白质内含物以及超氧化物歧化酶 1 (SOD1)。与 SOD1 聚集体相结合的 SOD 涂层金 NP 可用作 ALS 诊断的比色检测系统 [138]。神经保护病理可以通过使用带有 SOD 的羧基富勒烯纳米管来实现 [139]。使用碳纳米颗粒可以有效、准确地将谷氨酸抑制剂利鲁唑递送至受影响部位[140, 141]。

多发性硬化

MS 是一种经常致残的 CNS 疾病。最常见的症状是流向大脑以及大脑与身体之间的信息流中断。使用与 N 结合的水溶性富勒烯可以实现疾病进展和髓系神经元浸润 -甲基-D-天冬氨酸受体拮抗剂在患病患者中测试了聚（甲基丙烯酸甲酯）和聚（己内酯）-PEG（PCL-PEG）NP。该药物在小鼠中的治疗效果增加 [142,143,144]。在另一项研究中，PEG 的共聚物用于为细胞加载过氧化氢酶，最后通过静脉给药，观察到炎症大脑的治疗活性增加 [145]。此外，在小鼠中使用载有治疗性 DNA 的聚（乙烯亚胺）降低了疾病的严重程度 [58, 146]。

Neurological Tumors

The treatment of neurological tumors (like brain tumors) has been investigated for many years by using polymeric NPs [147]. For the treatment of most of the tumor, a passive targeting technology using smaller than 100-nm NPs has been used with enhanced permeability, penetration, and retention effect which resulted into better gathering of NPs around the tumor region [143, 144]. The risk of elimination of NP, targeting brain tumor from the blood, can be overcome by engineering the better surface with receptors like folate which facilitate the NP accumulation at their site of action [142, 143]. Cabral and Kataoka [144] have suggested that the use of polymeric NPs for brain tumor study has reached an advanced stage of pre-clinical phase. The BBB was disrupted in many brain tumors except micrometastases or infiltrative gliomas [148]. Paclitaxel-loaded PEGylated PLGA-based NP was designed to target brain gliomas, and it was observed that the life span of mice increased twofolds [58, 145].

Ischemic Stroke

Currently, at global level, ischemic stroke is considered as a third root cause of death. It produces structural brain damage. The targeted and effective delivery of drugs and therapeutic compounds in the brain can be achieved by using stereotactic surgery [146]. Ischemic stroke treatment using nanomedicine in the brain has been already demonstrated [149]. CNTs are found to be very useful in brain imaging to identify stroke location and diseased site as well as delivery of drugs/therapeutic molecules to the site of action. The drug delivery by using nanotechnology will be a valuable tool for ischemic stroke and other chronic neurological diseases. Single-walled carbon nanotubes (SWCNTs) functionalized with amine groups increased the neuron tolerance to ischemic injury [147]. Application of nanodrug delivery could be of great benefit in the future for neuroprotection success in chronic neurological diseases including ischemic stroke. Neurotherapy with the use of CNTs would be extremely useful in the treatment of various neurological pathologies including ischemic stroke. Neurotrophin plays a significant role in the development and function of neurons as well as neuroprotection in both CNS and peripheral nervous system, and their delivery into the brain can be performed by using CNTs. The neuronal injury can be protected and functional motor recovery will be enhanced by pre-treatment with amine, functionalized with SWCNTs [20, 150].

Metal Chelators and NMs/NPs Used in Neurological Disease Management

Metal Chelators

Metal chelators or multidentate organic molecules form complexes with metal and are more stable than those formed with monodentate ligands. If these complexes are soluble in aqueous medium, they can easily be removed from the biological system and prevent toxicity. There are several such molecules such as desferrioxamine, an iron chelator, but it has also been used in the depletion of zinc, copper, and aluminum [151] in AD patients. Penicillamine is specifically used for the removal of copper from the brain. Although many transition metals are essential to human subjects in trace amounts, they become toxic when they exceed the tolerance limit and are involved in neuronal damage in neurological diseases. For instance, enhanced quantity of copper (390 μM), zinc (1055 μM), and iron (940 μM) has been observed to be present in AD brain in comparison to the normal adult samples (copper 70 μM, zinc 350 μM, and iron 340 μM) [63, 152, 153].

Nanomaterials

Currently, NMs are being frequently used in tissue engineering and targeted drug delivery. They play a significant role to overcome major problems related to effective and targeted drug delivery into the brain for diagnosis and treatment of neurological disorders [154, 155]. BBB allows free diffusion and transport of lipophilic molecules, oxygen, and carbon dioxide, and transporters or receptor-mediated endocytosis help the entry of other compounds in the brain [48]. Thus, to overcome these barriers and improve the effective delivery of therapeutic compounds in the brain, now, multiple tactics are being used viz. nanocarriers and strong conjugation of valuable drug compounds to the vectors having active transport capacity of drugs through BBB in the brain. Several NMs are produced using nanotechnology that can deliver desirable therapeutic compounds into the brain tissues as well as near the site of drug action in other tissues [32, 50, 51, 156]. Biodegradable materials as a carrier also revealed an effective drug delivery near the site of action. Thus, these preparation and treatments are likely to protect, repair, and regulate the damage of CNS tissues [51]. In addition, many NMs and polymers are extensively being used in the drug delivery system by coating with surfactant polysorbate 80 enabling them to easily cross BBB through receptor-mediated endocytosis. These polymers are known as polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, chitosan, gelatin, and polybutyl cyanoacrylate [39, 154]. These NMs have additional properties as their surface can be manipulated and or engineered with hydrophilic polyethylene glycol layer allowing to protect the drugs from enzymatic degradation and recognition by the immune system [157]. Thus, these significant features enable those compounds to be considered as promising vehicle for AD and other neurological disease diagnosis and treatment [32].

聚合物纳米粒子

Polymeric NPs are solid colloidal particles containing macromolecular materials to attach, adsorb, dissolve, and encapsulate the drugs or therapeutic compounds. Degradable polymeric NPs of 10–100 nm are a common type of drug delivery systems for the neurological disease treatments. These particles exist in two variable units, nanocapsules and nanospheres [58, 148, 158,159,160]. Nanocapsules are made of coreshell NPs, whereas nanospheres contain homogeneous matrices. These particles sizes facilitate fine tuning to acquire desired properties like active compound protection with easy delivery and permeability of drugs into the target cells with higher efficacy and efficiency at low cost preparation [161,162,163]. Moreover, these particles are effective due to suitable degradation rate and their capability to cross BBB and reach the CNS [154]. Coating of suitable polymer with surfactant polysorbate 80 enables them to cross the BBB by adsorption of apolipoprotein E from the blood which is taken up by the cells of BBB by endocytosis [154]. Some modification in the characteristic preparation of NP coated with polymers may occur which protects the drug against immune system/enzymatic degradation [157]. Different signaling pathways are activated when interaction of growth factors (GFs) with their receptors on cell surface occurs. All pathways are different from each other. From animal studies, it has been observed that insulin-like growth factor (IGF), basic fibroblast growth factor (bFGF), and nerve growth factor (NGF) available in the brain exhibit useful influences [155]. It is, however, difficult to deliver GFs due to BBB, enzymatic degradation, clearance, and denaturation in the brain and the blood [164]. Kurakhmaeva et al. [165] revealed from animal studies that NGF-loaded poly (butyl cyanoacrylate) (PBCA) coated with polysorbate 80 improved memory function in mouse model. Intravenous administration of drug is an alternative route of transportation to the brain. It is expected that the drugs/therapeutic molecules are taken up by the olfactory epithelium and transported to the cerebrospinal fluid by passing the BBB [166]. Polymer NP of 120 nm loaded with the bFGF coated with Solanum tuberosum lectin has been shown to improve learning and memory capability in rat model of AD [167]. In addition, many polymeric NPs have been designed to treat brain tumors and neurodegenerative disorders [58]. They may be encapsulated as therapeutic agent and transported into the brain if it crosses the BBB.

Solid Lipid Nanoparticles

SLNs are also being used as efficient and alternative carriers for drug delivery as they have better advantages with improved characteristics. SLNs are known as an attractive colloidal drug carrier system for brain targeting. The accumulation of SLNs in reticulo endothelial system limits their use for targeted drug delivery in the brain. The lipid matrix is solid at room temperature with unique size and their better advantages to use as nanocarriers which allows better release and stability of drugs without causing cytotoxic effects in the tissue [41]. The SLNs have better advantages of reproducibility by using multiple strategies and larger scale-up feasibility. It is also a good option for other formulations that lack organic solvents. This also reduces the chance of residual contaminations. Based on these characters, SLN provides one of the most promising systems for drug delivery against many neurodegenerative disease and cancer treatment [40, 168, 169]. The drug stability into the blood and their entry through BBB can be enhanced by using NMs with SLN formulations as the polysorbate triggers the serum proteins by acting as anchor for apolipoproteins. The NPs coated with polysorbate provided desirable results for effective delivery of drugs across the BBB. The interaction of lipoproteins with capillary endothelial cell receptors available in brain with apolipoproteins facilitates the crossing of BBB. The phagocytosis can also be prevented by surface modification of SLN by coating with hydrophilic polymers or surfactants [170]. Furthermore, the use of ligands to SLN surface also improves the drug concentration and increased drug stability and availability across BBB for the neurological treatments. However, to date, only few drugs are FDA-approved for AD, known as acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine). Nonetheless, recently, solid NPs having galantamine hydrobromide have been developed to upgrade the drug bioavailability for AD treatment [40, 171].

Liposomes

Liposomes are spherical vesicles made of impermeable lipid bilayer, phospholipids, and cholesterol. They are being considered as an important vehicle for drug delivery due to their non-toxic and biocompatibility characteristics. They can deliver hydrophilic and hydrophobic molecules by carrying the aqueous and lipid parts of the liposomes. Though, they are recognized as foreign particles by the biological system without causing any negative response after their entry into the system, they are non-immunogenic as well as non-carcinogenic, biodegradable, and non-thrombogenic in nature [172]. Liposomes are being used as larger transport nanocarriers as they are capable of encapsulating multiple components. Additionally, they are protected against enzymatic degradation and removal by the reticuloendothelial system. The most important characteristics are capability to fuse with biological membranes, move across cell membrane, and to penetrate the BBB. The half-life of liposome can be easily enhanced by treating their surface with PEG [173]. The Aβ oligomers with high affinity towards liposomes can be used for delivery of therapeutic compounds in animal models [174]. In an in vitro study, using phosphatidylcholine liposomes having omega-3 fatty acid and docosahexaenoic acid into APP-overexpressing cells, it was observed that the cell membrane fluidity increased. The induction of non-amyloidogenic processing of APP resulted into formation of soluble APPα (sAPPα) and further the inhibition of JNK stress signaling pathway by sAPPα-containing cell supernatants; PI3K/Akt survival pathway was activated in cultured neuronal cells and finally resulted into prevention of apoptotic cell death [175]. So, liposomes containing DHA could be used for prevention and treatment of AD [32].

Gold Nanoparticles

Gold NPs are being effectively utilized for drug delivery against various diseases [17]. They have many important characteristics such as better biocompatibility, easy synthesis, and simplistic surface functionalization with easy and effective delivery to target cells and tissues [17, 18]. Some reports have shown that the gold NPs can be utilized in AD disease treatment by destructing and dissolving the Aβ fibrils and plaques with the help of weak microwave field exposure in the brain tissue. Major cases of AD are plaque formation and Aβ fibrils in the brain which can be either prevented or destroyed. Gold NP interaction with fibrils followed by their exposure to weak microwaves causes an increase in the temperature and dissolution of fibrils. Experiment in mice (in vitro) has shown that gold NPs slow down the progression of AD. It is also interesting to note that apparently NPs do not adversely affect the brain [176]. Gold NPs conjugated with some compounds interfering with Aβ fibrils have been used [114, 115].高等人。 [115] have reported that the gold NPs of 22-nm size reduces the cytotoxicity of Aβ fibrils and Aβ-mediated peroxidase activity in vitro. Triulzi et al. [177] have demonstrated the photochemical ablation of Aβ plaques in AD. They have suggested that gold NPs formed complexes with synthesized β-amyloid peptides. Upon irradiation with laser beam, the complex containing NP was stabilized. Gold NP conjugated with ematoporphyrin has been reported to be effective against T cell lines MT-4 and Jurkat cells (human T cell leukemia) [178] in vitro. They have been used as probe to detect neuronal cell activity [148]. Gold NP suspension of drug from nanobubbles can deliver the drug to the target site when the bubble bursts by heating. Based on these results, the use of gold NPs is a better option in AD disease diagnosis, treatment, and management [32, 115]. Overall, the metal NPs have shown a considerable potential in the treatment of neurological diseases.

Microparticles

MPs are basically a heterogenous population of small cell-derived (0.1–1 μm) vesicles and are now being used as an important vehicle for drug delivery and AD treatment. In the CNS, these particles have been detected in the CSF, where they are discharged by almost all types of cells [179, 180]. It is well known that the FDA-approved donepezil drug is being used in the improvement of daily life functioning and cognition of mild-to-moderate AD patients without causing any damage and significant changes in the function of vital organs till> 98 weeks. This medicine is being used as a daily dose but it causes gastrointestinal side effects as well as impaired memory. Nonetheless, this problem could be solved now by using PLGA donepezil-loaded microparticles for long-term use [181]. These particles were implanted subcutaneously in rats which resulted in steady-state plasma levels of donepezil for 4 weeks, and then, this drug was rapidly reduced. In another study, microparticles were used on rat after ligating with common carotid arteries and neuronal loss with reduced learning and memory capabilities was reported. The above result indicates that the use of FDA-approved drugs can be more beneficial with control release strategies for the treatment of AD [32, 182].

Carbon Nanotubes and Fullerenes

The carbon nanotube (CNT) was discovered in 1991 by Iijima [183]. They have many valuable properties such as ultra-light weight, high flexibility, low deposition, low cost, high capability, ultra-strong, and inert with electrical and thermal conductivity. Currently, it has emerged as new promising NMs due to useful and exclusive properties for treatment of neurological disorders viz. in AD, PD, and ischemic stroke [20, 184, 185]. The successful utilization of CNTs as drug delivery vehicles in vivo has been reported in many diseases like bone implants, rheumatoid arthritis, osteoporosis, and cancer [184, 186]. However, very limited preclinical studies have been performed for successful application of CNTs in neurological disorders [187]. Fullerene derivatives have also been investigated for their role as neuroprotective agents [188]. For instance, nanostructures of hydrated C60 fullerene (C60HyFn) showed protection on the CNS in rats against chronic alcoholization [189]. Authors have suggested an indirect participation of C60HyFn in the neurotransmitter metabolism. In addition, some reports have also shown that the fullerene derivatives contain multiple synergistic mechanisms that can be employed for AD treatment [190].

结论

All neurological disorders are associated with the spinal cord and nervous system. AD leads to the cognitive impairment and plaque deposits in the brain leading to neuronal cell death. Hence, it has been suggested to prevent the loss of functional neurons or to replace the damaged neurons. BBB provides protection to the brain, so an important challenge for any drug is to cross the BBB and to reach the CNS with desirable amount. It is therefore crucial to develop a benign and effective drug delivery system with improved efficacy which may effectively cross the BBB and reach the target cells without producing any significant adverse effects. Different NMs and/or NPs have been developed, utilized, and tested and showed promising contribution in the diagnosis, treatment, and management of neurological disorders. Drug-loaded NPs are tested for AD treatment and provided promising results. In addition, the significance of NMs in stem cell therapy for several kinds of neurological diseases is elucidated. NMs are also able to promote stem cell proliferation and differentiation and also contribute dominant roles in stem cell imaging and tracking. Thus, in CNS-related diseases, the use of NMs/NPs in drug delivery is a better option in comparison to the conventional mode of treatments. However, their systematic toxicity investigations are also required for the effective formulation and application in neurological disorders.

缩写

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

APP:

Amyloid precursor protein

Aβ:

Amyloid-β

BBB:

Blood-brain barrier

CNS:

Central nervous system

CNT：

碳纳米管

DHA:

Docosahexaenoic acid

FDA:

Food and Drug Administration

LCs:

Liquid crystals

MEs:

Microemulsions

MS:

Multiple sclerosis

MPs:

Microparticles

MSCs:

Mesenchymal stem cells

NFT:

Neurofibrillary tangles

NMs:

Nanomaterials

NP：

纳米粒子

PBCA:

Poly (butyl cyanoacrylate)

PD:

Parkinson’s disease

PLGA:

Poly(d,l-lactic-co-glycolic acid)

ROS:

Reactive oxygen species

SLN:

Solid lipid nanoparticle

SOD：

超氧化物歧化酶

SWCNTs:

Single-walled carbon nanotubes