CN106470706A - 用于预防或治疗神经退行性疾病的基于石墨烯纳米结构体的药物组合物 - Google Patents
用于预防或治疗神经退行性疾病的基于石墨烯纳米结构体的药物组合物 Download PDFInfo
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- CN106470706A CN106470706A CN201580018344.8A CN201580018344A CN106470706A CN 106470706 A CN106470706 A CN 106470706A CN 201580018344 A CN201580018344 A CN 201580018344A CN 106470706 A CN106470706 A CN 106470706A
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Abstract
本发明涉及含有石墨烯纳米结构体(graphene nanostructure)作为有效成分的用于预防或治疗神经退行性疾病的药物组合物。
Description
技术领域
本发明涉及含有石墨烯纳米结构体(graphene nanostructure)作为有效成分的用于预防或治疗神经退行性疾病的药物组合物。
背景技术
已知蛋白质的错误折叠(misfolding)不仅引起蛋白质的功能丧失,而且由于非正常蛋白质在细胞内蓄积而产生毒性,由此引发阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩侧索硬化症、癌、囊包性纤维症、II型糖尿病等多种疾病。即,由于蛋白质稳态(proteostasis)失衡,而导致蛋白质的错误折叠和细胞内的非正常蓄积。
目前为止,神经退行性疾病的发病原因还没有百分之百地被揭晓,但是已知神经蛋白质的聚集是其主要原因。纤丝结构构成的蛋白质逐渐转移(transmission)至周边的神经元,最终使大脑特定部位的神经元全部坏死,从而使得该部分负责的功能无法执行。至于帕金森病,病情随着产生叫做多巴胺的神经递质的神经元逐渐坏死而发展。现在给帕金森病患者开出的处方中最常见的药物是叫做信尼麦(Sinemet)的药物,诸如此类的其他帕金森病治疗剂仅仅是通过投入在神经细胞内变为多巴胺的左旋多巴(Levodopa,L-DOPA)而暂时缓解症状而已,并不具有从根本上治疗或延缓的功能。最终药物的效果随着病情的发展而减少,直至死亡。
所进行的蛋白质的错误折叠相关的研究中,作为抗淀粉样蛋白化合物(anti-amyloid compound)的种类中的一种的刚果红(Congo Red)等虽然具有防止由蛋白质的错误折叠引起的纤丝形成的效果,但是具有如下缺陷:对人体的毒性大,且不具有抑制错误折叠的蛋白质的转移以延缓疾病的发展的效果。此外,现有的药物具有尺寸均匀的一种特定形态,因此从热力学方面(熵)来讲对疾病的治疗并不表现出特别的好处。
从而,虽然为治疗蛋白质的错误折叠而进行了很多研究(韩国公开专利第10-2009-0019790号),但是就无人体毒性且表现出优异的抑制性能的治疗剂而言,还没有显著成果。
发明内容
技术问题
本发明旨在提供一种含有石墨烯纳米结构体作为有效成分的用于神经退行性疾病或治疗的药物组合物。
但是本发明所要解决的技术问题不限于以上所述的技术问题,本领域技术人员通过下面的记载能够明确地理解没有记载的其他技术问题。
技术方案
本发明的一方面,提供一种含有石墨烯纳米结构体作为有效成分的用于预防或治疗神经退行性疾病的药物组合物。
发明效果
根据本发明实施方式的含有石墨烯纳米结构体作为有效成分的用于预防或治疗神经退行性疾病的药物组合物,是将石墨烯纳米结构体用于神经退行性疾病的预防和治疗的首次尝试。石墨烯纳米结构体对人体无毒性,也不会在体内蓄积,还表现出对蛋白质的错误折叠引起的纤丝形成抑制80%等卓越的效果,在抑制错误折叠的蛋白质的转移以延缓病情的发展的方面也很有效。此外,于现有的治疗剂不同,石墨烯纳米结构体不局限于一种特定形态,各个石墨烯纳米结构体的分子量、分子式、形态等均不同,从热力学方面来说从根本上阻碍结晶的形成,因此使得疾病的根本性的治疗变得可能。不仅如此,石墨烯纳米结构体在UV-vis(紫外-可见)区域产生荧光,且具有如下优点:当适当调节这种荧光强度时,能够追踪(tracking)待作用为药物的石墨烯纳米结构体在体内如何移动。此外,由于在与石墨烯纳米结构体的末端结合的功能团上连接以神经蛋白质为靶标的物质,因此具有能够追踪神经蛋白质的优点。当通过上述方法将石墨烯纳米结构体诱导至神经蛋白质附近后照射对细胞损害较小的远红外激光时,可以通过石墨烯纳米结构体的光热效应来抑制纤丝化和聚集现象。
附图说明
图1是根据本发明一实施例的石墨烯量子点的TEM(透射电子显微镜)和AFM(原子力显微镜)图像。
图2是根据本发明一实施例的石墨烯量子点的PL(光致发光)分析结果图表。
图3是根据本发明一实施例的石墨烯量子点的FT-IR(傅里叶变换红外)分析结果图表。
图4是根据本发明一实施例的石墨烯量子点的ZETA(界达)电位测定结果图表。
图5是根据本发明一实施例的石墨烯量子点抑制纤丝化的效果的示意图。
图6a和图6b分别是根据本发明实施例的石墨烯纳米结构体的神经元存活率的分析结果的图像(a)和图表(b)。
图7a和图7b分别是表示根据本发明实施例的石墨烯纳米结构体对活性氧簇生成的抑制活性的8-OHG(核算氧化8-羟基鸟苷)染色分析结果的图像(a)和图表(b)。
图8a和图8b分别是用于确认根据本发明一实施例的石墨烯纳米结构体对a-syn(α-突触核蛋白)转移的抑制的实验模拟图(a)及其结果的图像(b)。
图9是根据本发明实施例的石墨烯纳米结构体对纤丝化的抑制的TEM分析结果的示意图。
图10是根据本发明一实施例的石墨烯量子点对纤丝化的抑制的AFM分析结果的示意图。
图11a和图11b分别是根据本发明实施例的石墨烯纳米结构体对纤丝化的抑制的高清晰TEM分析结果示意图。
图12是采用BN-PAGE(蓝绿温和胶聚丙烯酰胺凝胶电泳)分析注入根据本发明一实施例的石墨烯纳米结构体后的PFFs(预形成的纤丝)状态的结果示意图。
图13是根据本发明一实施例的石墨烯纳米结构体和和刚果红的发光特性的示意图。
图14是根据本发明一实施例的石墨烯纳米结构体的光热特性的图表。
图15是根据本发明一实施例制备的样品的FT-IR图谱。
图16是根据本发明一实施例制备的样品的荧光发光测定结果的示意图。
具体实施方式
下面结合附图详细说明本发明的实施方式和实施例,以使本领域技术人员能够容易实施本发明。
但是本发明能够以各种不同形态实施,并不限于在此说明的实施方式和实施例。此外,为了明确说明本发明,在附图中省略了与说明无关的部分,且在说明书全文中对类似的部分使用了类似的附图标记。
本发明说明书全文中,记载某一部件位于其他部件之“上”时,不仅包括该部件与其他部件相接的情况,还包括这两个部件之间存在另一其他部件的情况。
本发明说明书全文中,记载某一部分“包含”某一构成要素时,在没有特别的相反说明的情况下,意味着还可以包含其他构成要素,而不是排除其他构成要素。本说明书中使用的表示程度的“约”、“实质上”等用语,在已给出所提及的含义所固有的制造及物质允许误差的情况下,解释为该数值或接近该数值的含义,以防止某些非善意的侵权人对为了帮助理解本发明而提及准确或绝对的数值的公开内容的不当使用。此外,本发明说明书全文中“~的步骤”不表示“为~的步骤”。
本发明说明书全文中,马库什形式的表达中包含的用语“它们的组合”表示在马库什形式表达所记载的构成要素组成的组中选择的一个以上的混合或组合,即表示包含从上述构成要素组成的组中选择的一个以上。
本发明说明书全文中,“石墨烯量子点(graphene quantum dots,GQDs)”是指氧化石墨烯(graphene oxides)或还原的氧化石墨烯(reduced graphene oxides)的纳米尺寸的片段。
本发明说明书全文中,用语“石墨烯”表示复数个碳原子相互通过共价键连接而形成多环芳香族分子,上述共价键连接的碳原子形成6元环的基本重复单元,但是也可以进一步包括5元环和/或7元环。
本发明说明书全文中,用语“氧化石墨烯”还可以称为石墨烯氧化物(grapheneoxides),可简称为“GOs”。石墨烯上可以包括结合有羧基、羟基或环氧基等含氧功能团的结构,但不限于此。
本发明说明书全文中,用语“还原氧化石墨烯”是指经过还原过程而氧比重减少的氧化石墨烯,也称为还原的石墨烯氧化物(reduced graphene oxides),可简称为“rGOs”,但不限于此。
下面,详细说明本发明的实施方式,但本发明可不限于此。
本发明的第一方面提供含有石墨烯纳米结构体(graphene nanostructure)作为有效成分的用于预防或治疗神经退行性疾病的药物组合物。
根据本发明一实施方式,所述药物组合物可以进一步包含药学上可接受的载体或赋形剂,但可不限于此。所述药学上可接受的载体或赋形剂只要能够用于药物组合物就不受限制,例如,可以包含选自由凡士林、绵羊油、聚乙二醇、醇及它们的组合组成的组中的一种,但可不限于此。
根据本发明一实施方式,所述神经退行性神经疾病是有关蛋白质的错误折叠的疾病,例如,可以选自由阿尔茨海默病、帕金森病、亨廷顿病、艾滋病痴呆症、脑卒中、老年全身性淀粉样变病、原发性全身性淀粉样变病、继发性全身性淀粉样变病、II型糖尿病、肌萎缩性淀粉样变病、血液透析-相关淀粉样变病、传染性海绵状脑病及多发性硬化症组成的组中,但可不限于此。
根据本发明一实施方式,所述石墨烯纳米结构体可以包括石墨、石墨烯或石墨烯量子点,但可不限于此。
所述石墨烯量子点例如可以为约1~20nm、约5~20nm、约10~20nm、约15~20nm、约1~15nm、约1~10nm或约1~5nm范围的大小,但可不限于此。
根据本发明一实施方式,所述石墨烯纳米结构体例如可以包括约1~100nm、约10~100nm、约30~100nm、约50~100nm、约70~100nm、约90~100nm、约1~90nm、约1~70nm、约1~50nm、约1~30nm或约1~10nm范围的不同尺寸的石墨烯纳米结构体,但可不限于此。
根据本发明一实施方式,所述石墨烯纳米结构体能够抑制蛋白质的错误折叠(misfolding)引起的纤丝形成,此外,还能够抑制错误蛋白质的转移(transmission),但可不限于此。
根据本发明一实施方式,所述石墨烯纳米结构体不会在体内蓄积,对人体不显示毒性。
根据本发明一实施方式,所述石墨烯纳米结构体可以通过防止纤丝状态的蛋白质引起的线粒体功能障碍的机制,抑制神经元内的活性氧簇生成,但可不限于此。
根据本发明以实施方式,所述石墨烯纳米结构体的末端的官能团可以结合以神经蛋白质为靶标的物质,例如作为抗淀粉样变病的物质的刚果红或作为淀粉样变病探测染料(detecting dye)的硫黄素(thioflavin)T或S等,但可不限于此。
根据本发明的所述官能团可以是含有氧原子的官能团,例如-OH、-COOH、-C=O等,但可不限于此。
根据本发明一实施方式,所述石墨烯纳米结构体可以在远红外激光照射下产生光热效应,但可不限于此。
根据本发明一实施方式,本发明的药物组合物由于在石墨烯纳米结构体的末端结合的官能团上连接以神经蛋白质为靶标的物质,因此具有能够追踪神经蛋白质的优点。当通过上述方式将石墨烯纳米结构体诱导至神经蛋白质附近后,照射对细胞损害较小的远红外激光时,能够通过石墨烯纳米结构体的光热效应抑制纤丝化和聚集现象。
实施本发明的形式
下面通过实施例进一步具体地说明本发明,但本发明的范围并不限于这些实施例。
[实施例]
制备例1
参考2012年发表于纳米快报(Nano Letters)上的论文[Nano lett,12,844-849(2012)]制备了GQDs。将碳纤维加入到以3:1的比例混合有硫酸和硝酸的溶液中,在80℃下加热24小时(热氧化工艺,thermo-oxidation process)。反应完成后,经透析过程、真空过滤等进行纯化,用旋转蒸发仪最终获得粉末形态的GQDs。由此获得的GQDs的形态为在结构上具有非常多样的尺寸(约5~20nm)的粒子(参照图1)。制备的GQDs的其他特征还有:在UV(紫外光)灯下产生了荧光(发射:490nm和550nm)(JASCO FP-8300荧光分光仪)(参照图2),且当照射808nm NIR激光时,产生了光热(photothermal)效应。通过观察FT-IR分析图谱(Thermo Scientific Nicolet iS 10FT-IR分光仪),GQDs末端的羧基(-COOH)在1724cm-1,芳香族C=C峰在1614cm-1被观测到(参照图3)。最后,通过ZETA电位(Malvern ZetasizerNano ZS)分析的表面电荷显示为在约-20mV(参照图4)。
制备例2
通过下列反应式的反应,制备了在上述制备的石墨烯纳米结构体(GQDs)末端的官能团上结合有作为以神经蛋白质为靶标的物质的刚果红的物质。通过将所述刚果红的量分别设置为不同(100微克/m、250微克/ml和500微克/ml)而制备了样品1、2和3。
试验例1
使用叫做PFFs(pre-formed fibrils)的α-突触核蛋白(alpha-synuclein)实验模型确定石墨烯量子点对纤丝化的抑制效果。具体地,在神经元中注入PFFs后经一周的时间就会形成纤丝,这最终导致了神经元的坏死。纤丝化会引起α-突触核蛋白的磷酸化,这可以通过如图5中所示的染色的图像来确认。可确认到,向神经元仅注入PFFs(1微克/ml)时茂密的p-α-syn(磷酸化的α-突触核蛋白)在注入GQDs(1微克/ml)之后消失到几乎没有注入任何试剂的水平(参照图5)。如图5所示,将p-α-syn减少了约80%,实际上这可以被解释为达到了完全抑制了纤丝化的水平。此外,神经元的存活率也增加了约20%(参照图6b)。仅注入GQDs时的神经元的存活率(用TUNEL(末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记)检测分析)相比仅注入PBS(磷酸盐缓冲液)培养基的情况,反而显示更好的效果,从而确认GQDs对神经元没有毒性(参照图6a及图6b)。图6a中左侧表示受损细胞染色为红色的TUNEL检测,中间部分是细胞核内的DNA染色为蓝色的DAPI(4′,6-二脒基-2-苯基吲哚)染色,右侧是它们的定量(quantification)。
此外,作为有关所使用的石墨烯纳米结构体通过防止纤丝状态蛋白质所引起的线粒体功能障碍的机制而抑制神经元内的活性氧簇的生成的实验,用8-OHG(作为DNA氧化的主要产物的核酸氧化8-羟基鸟苷(8-oxo-2’-deoxyguanosine))对预培养的神经元染色后进行分析(参照图7a)。如图7a所示,由于加入石墨烯纳米结构体,受活性氧簇的影响而生成的8-OHG的量显著降低。有关线粒体功能障碍的实验是通过细胞的基础呼吸速率(basalrespiratory rate)、最大呼吸速率(maximal respiratory rate)和线粒体的Complex I(复合物-I)活性分析而确认的(参照图7b)。如图7b的图表所示,向神经元仅注入PFFs时的线粒体的呼吸速率显著降低,且Complex I活性也减少;但是GQDs和PFFs一同注入到神经元时,恢复到正常水平。在该试验例中的对线粒体功能障碍的分析结果被认为是与图6a的神经元存活率相符合的重要结果。
试验例2
虽然单纯地抑制纤丝化并提高神经元的存活率也重要,但是为了神经退行性疾病的治疗及缓解疾病的发展速度,防止向周边的神经元转移(transmission)也非常重要。为了确认这一事实,安装微流控装置(microfluidic device),观察在将GQDs放入哪一腔室时能够阻断转移过程。图8a是简单的实验的模拟图,图8b示出该实验的结果。至于C1(腔室1),向第一个腔室的神经元注入GQDs;至于C2(腔室2),向第二个腔室的神经元注入GQDs,然后确认到α-突触核蛋白的纤丝化向周边的神经元扩散。至于仅有PFFs而没有GQDs的阳性对照组,观察到已纤丝化的α-突触核蛋白从第一个腔室转移至第三个腔室。至于向第一个腔室的神经元加入GQDs的第二个装置,观察到纤丝化程度一开始就不大,由此在第二和第三腔室的神经元中也几乎没有α-突触核蛋白的纤丝化。至于向中间的腔室的神经元加入GQDs的最后一个装置,观察到虽然在第一个腔室中进行了一定程度的纤丝化,但是加入GQDs的第二个腔室的神经元开始其纤丝化的量显著减少,接下来的最后的腔室的神经元中几乎没有发生纤丝化。在该装置中初期的纤丝化程度与作为阳性对照组仅加入PFFs的装置不同的原因被认为在于,由于设备自身的误差而在设备中无法为各神经元完全分离GQDs。
试验例3
按照与细胞内实验相同的方式进行取样(在37℃对1微克/ml的GQDs和1微克/ml的PFFs进行孵化后在二氧化硅基材上点样),并通过OM(optical microscope,光学显微镜)分析GQDs对纤丝化的抑制,结果仅孵化PFFs时观察到推测为纤丝聚集的大团块(参照图9的(a)和(b)),相反与GQDs一同孵化时观察到了疑似GQDs和α-突触核蛋白的低聚体聚集的图像(参照图9的(c)和(d))。上述结果中的总α-突触核蛋白和GQDs的量有些过量,且没有获得能够明确他们的结构的清晰图像,但是可以确认的是上述两个样品的结果明显不同。
按照与OM分析相同的取样方式准备样品,通过AFM(atomic force microscope,原子力显微镜)分析GQDs对纤丝化的抑制,结果仅孵化PFFs时观察到纤丝和PFFs聚集的路易小体(lewy body)的形成(参照图10的(b)),相反与GQDs一同孵化时观察到了疑似GQDs和α-突触核蛋白的低聚体聚集的图像(参照图10的(d))。
按照与上述OM和AFM分析相同的方法,在TEM(transmission electronmicroscopy,透射电子显微镜)格子(grid)上点样,通过高分辨率电子显微镜(highresolution-transmission electron microscope)进行分析。图11a是在TEM格子上仅点样PFFs后分析的数据。从图像中可以看出,形成了又厚又长的纤丝束。相反一同放入GQDs的样品中,如AFM图像中所示,可以获得疑似GQDs和α-突触核蛋白聚集的图像(参照图11b)。
虽然如图9至图11所示的图像中显示在PFFs中注入GQDs时和没有注入GQDs时的显著的差异,但是这些图像是在干燥的状态下所获得的,因此在显示注入GQDs后的准确的PFFs状态方面具有局限性。为了更详细的分析而进行了BN-PAGE(blue nativepolyacrylamide gel electrophoresis,蓝绿温和胶聚丙烯酰胺凝胶电泳)分析的结果,确认到惊人的事实(参照图12)。在图12中,1号列是空白对照组,即仅加入GQDs的情况;2号和4号列是仅加入PFFs的情况;3号和5号列是将作为同时加入PFFs和GQDs的样品的凝胶放入的情况,结果可确认到,加入GQDs时在对应于α-突触核蛋白单体(14.46kDa)的区域中检测到的量较多。这是表明在PFFs中加入GQDs的话不仅能够阻断PFFs纤丝化,而且还使其返回为单体的重要数据。
试验例4
对在上述制备例1中制备的GQDs和刚果红溶液(对照组)照射红外线激光后在暗处拍摄了荧光发光现象,其结果如图13所示。
此外,如图14所示,当照射NIR(近红外线)激光时,相比刚果红或蒸馏水(distilled water)表现出更高的光热效应,并且随着GQDs的浓度(500微克/ml、250微克/ml、100微克/ml)增加,温度也增加。
试验例5
使用多种样品(上述制备例1和2中制备的GQDs、样品1、样品2、样品3和作为比较例的刚果红溶液),进行了FT-IR分析、荧光发光测定实验。
参照示出FT-IR分析图谱的图15,可以看到在与刚果红(congo red,CR)的-NH2对应的峰3419cm-1处,峰值随着刚果红的浓度增加而减少;在与GQDs末端的羧基(-COOH)对应的峰1710cm-1处,峰值也是随着刚果红的浓度增加而减少;与肽键(-CONH)对应的峰1660cm-1是随着GQDs和刚果红的结合而逐渐生成;与芳香族C=C对应的峰1614cm-1按照预想的那样在所有的样品中维持。
另外,测定了根据上述样品的波长的荧光发光特性后示于图16中。其中,刚果红作为对照组使用,样品1的荧光发光峰值显示为最高。
上述的本发明的说明仅是示例性的,本领域技术人员应当理解的是,在不变更本发明的技术构思和必要特征的情况下,也可以容易地变型为其他具体形态。因此记载的实施例应当被理解为在任何方面都是示例性的而不是限定性的。例如,以单一型态说明的各个构成要素也可以分布实施,同样,分布说明的构成要素也可以以结合的形态实施。
本发明的范围应由随附的权利要求书来呈现而不是由上述的详细说明来呈现,由权利要求书的含义、范围及其等同概念导出的所有的变更或变形的形态,均应理解为包含在本发明的范围内。
Claims (10)
1.一种用于预防或治疗神经退行性疾病的药物组合物,其含有石墨烯纳米结构体作为有效成分。
2.根据权利要求1所述的用于预防或治疗神经退行性疾病的药物组合物,其中,所述药物组合物进一步包含药学上可接受的载体或赋形剂。
3.根据权利要求1所述的用于预防或治疗神经退行性疾病的药物组合物,其中,所述神经退行性神经疾病选自由阿尔茨海默病、帕金森病、亨廷顿病、艾滋病痴呆症、脑卒中、老年全身性淀粉样变病、原发性全身性淀粉样变病、继发性全身性淀粉样变病、II型糖尿病、肌萎缩性淀粉样变病、血液透析-相关淀粉样变病、传染性海绵状脑病及多发性硬化症组成的组中。
4.根据权利要求2所述的用于预防或治疗神经退行性疾病的药物组合物,其中,所述载体或赋形剂选自由凡士林、绵羊油、聚乙二醇、醇及它们的组合组成的组中。
5.根据权利要求1所述的用于预防或治疗神经退行性疾病的药物组合物,其中,所述石墨烯纳米结构体包括石墨、石墨烯或石墨烯量子点。
6.根据权利要求1所述的用于预防或治疗神经退行性疾病的药物组合物,其中,所述石墨烯纳米结构体抑制由蛋白质的错误折叠引起的纤丝形成。
7.根据权利要求1所述的用于预防或治疗神经退行性疾病的药物组合物,其中,所述石墨烯纳米结构体是抑制错误折叠的蛋白质的转移。
8.根据权利要求1所述的用于预防或治疗神经退行性疾病的药物组合物,其中,所述石墨烯纳米结构体不在体内蓄积。
9.根据权利要求1所述的用于预防或治疗神经退行性疾病的药物组合物,其中,所述石墨烯纳米结构体的末端的官能团结合以神经蛋白质为靶标的物质。
10.根据权利要求1所述的用于预防或治疗神经退行性疾病的药物组合物,其中,远红外激光照射使所述石墨烯纳米结构体产生光热效应。
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