CN111557913A - 靶向癫痫细胞的纳米光敏复合物及调控检测系统 - Google Patents
靶向癫痫细胞的纳米光敏复合物及调控检测系统 Download PDFInfo
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Abstract
一种纳米靶向光敏复合物,其中所述纳米靶向光敏复合物包括纳米脂质体,包裹在脂质体内部的光敏药物,以及连接在纳米脂质体外表面的靶向分子基团。本发明还公开了所述纳米靶向光敏复合物的制备方法和应用其建立的调控检测系统,纳米靶向光敏复合物生物相容性强,提高所包裹药物的利用率,并且能够对病灶区神经细胞进行靶向调控。应用所述复合物制备的神经调控检测系统可实现靶向调控下神经信号同步记录,具有良好的时空分辨率。
Description
技术领域
本发明涉及生物医学基础研究、靶向纳米药物调控与神经信号检测领域,尤其涉及一种调控癫痫病灶神经细胞的纳米靶向光敏复合物及应用其建立的调控检测系统。
背景技术
癫痫是仅次于脑血管疾病的第二大中枢神经系统疾病,引发癫痫的因素通常较为复杂,而且不同类型的癫痫的病灶区不尽相同。癫痫会持续影响患者的心理认知和基本生理功能,造成严重的心理障碍和机能损害,甚至引发死亡,对患者的家庭和社会带来极大的压力。目前临床上治疗癫痫的方法主要包括药物治疗、手术切除和脑部刺激疗法,但是这些方法存在副作用大、再次伤害、精确度低等问题,缺乏具有高时空分辨率的靶向治疗方法。癫痫的发病特点是脑部神经细胞过度放电和放电节律紊乱,因此亟需一种能够对癫痫病灶的神经细胞活动进行靶向调控的药物,和探究一种能够实现神经细胞电生理信号同步检测、靶向药物递送和控制药物释放的调控系统平台,这有助于实现癫痫病灶的精准定位、癫痫发病过程的实时监测和癫痫的靶向精准调控。开发靶向调控药物对于深入理解癫痫疾病的发病机制、探索癫痫闭环治疗方法具有重要的意义。
发明内容
有鉴于此,本发明的主要目的在于提供一种调控癫痫细胞的纳米靶向光敏复合物及调控检测系统,以期部分地解决上述技术问题中的至少之一。
为了实现上述目的,作为本发明的一方面,提供了一种纳米靶向光敏复合物,包括纳米脂质体,包裹在脂质体内部的光敏药物,以及连接在纳米脂质体外表面的靶向分子基团。
其中,所述光敏药物能够在特定波长光刺激下,释放出活性分子对神经细胞进行调控;所述光敏药物是笼锁谷氨酸或笼锁γ-氨基丁酸。
其中,所述纳米脂质体,其双分子层包含胆固醇、二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰乙醇胺-聚乙二醇2000;所述胆固醇、二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰乙醇胺-聚乙二醇2000分子的摩尔比例为(1-5)∶(15-25)∶(1-5)。
其中,所述二硬脂酰磷脂酰乙醇胺-聚乙二醇2000分子上连接有活性基团,从而能够通过巯基交联反应或酰胺反应与靶向分子基团结合;所连接的活性基团是三苯甲酸酯、碳酸琥珀酰亚胺、羰基二咪唑、乙烯基砜或马来酰亚胺。
其中,所述靶向分子基团是多肽、DNA片段、适配体或抗体。
作为本发明的另一方面,提供了一种制备如上所述的纳米靶向光敏复合物的方法,包括以下步骤:
将胆固醇、二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰乙醇胺-聚乙二醇2000按比例溶解在有机溶剂中,然后旋转蒸发除去有机溶剂以在反应容器壁上形成单层脂质薄膜;
加入光敏药物溶液进行水化,在超声水浴中使所述单层脂质薄膜脱离,然后用滤膜推滤法使所得乳浊液通过高分子滤膜,形成包裹光敏药物的纳米脂质体;
进行表面修饰,将靶向分子基团连接在纳米脂质体表面,制得纳米靶向光敏复合物。
其中,所述二硬脂酰磷脂酰乙醇胺-聚乙二醇2000连接的活性基团为马来酰亚胺,即所用分子为DSPE-PEG2000-Maleimide;所述胆固醇、DPPC和DSPE-PEG2000-Maleimide的摩尔比例为4∶20∶1;和/或
所述有机溶剂为氯仿、甲醇、丙酮和乙腈的至少一种;优选地,所述有机溶剂为氯仿与甲醇混合溶剂;和/或
所述旋转蒸发温度为30-37℃,蒸发时长为10-20分钟;和/或
所述光敏药物为光笼解锁药物,浓度为2-10毫摩尔每升;和/或
所述纳米脂质体的粒径为50-200纳米。
其中,所述靶向分子基团为大麻素I型受体抗体;所述表面修饰方法包括以下具体步骤:
将抗体分子用剪切酶处理获得抗体片段,然后经过还原剂处理得到硫醇化抗体片段;最后利用巯基交联反应,将硫醇化抗体片段和纳米脂质体混合连接形成纳米靶向光敏复合物。
其中,所述剪切酶是木瓜蛋白酶、胃蛋白酶、IdeS免疫球蛋白酶或IdeZ免疫球蛋白酶;优选地,所述剪切酶为IdeZ免疫球蛋白酶;和/或
反应浓度为1国际单位蛋白酶与1微克抗体反应,反应条件25-37℃,反应时间为30-60分钟;和/或
所述还原剂是二硫苏糖醇、β-巯基乙醇或三(2-羧乙基)膦;优选地,所述还原剂为二硫苏糖醇;和/或
反应浓度为0.1-0.5毫摩尔每升,反应温度25-37℃,反应时间30-60分钟;和/或
所述混合连接反应为浓度为1毫克纳米脂质体和20-25毫克抗体片段混合,反应温度室温,反应时长1.5-2.5小时。
作为本发明的再一方面,提供了一种应用如上所述的纳米靶向光敏复合物调控和检测癫痫病灶神经细胞的系统,包括:
纳米靶向光敏复合物,用于向神经细胞靶向递送光敏药物;
微注射药管,通过微量注射器将纳米靶向光敏复合物注射到动物脑内;
微纳电极阵列,在调控过程中同步检测癫痫病灶神经细胞的电生理活动信号;
光纤及光源,利用光刺激系统提供刺激光源,激活所述纳米靶向光敏复合物中的光敏药物,实现对癫痫病灶神经细胞活动的调控。
基于上述技术方案可知,本发明的纳米靶向光敏复合物及其制备方法相对于现有技术至少具有如下有益效果之一或其中的一部分:
(1)纳米靶向光敏复合物生物相容性强,降低生物组织的免疫反应,减少所包裹药物的弥散和损失。表面靶向分子基团修饰可提高与癫痫病灶区神经细胞的特异结合,能够将药物递送至病灶区神经细胞表面,进行靶向调控。
(2)光敏药物只有在光刺激之后才可释放活性分子,对周围神经细胞进行调控,保证了药物作用的精确性,减少对非病灶区神经细胞的调控作用,降低副作用。结合光调控技术,通过对光源的控制,能够实现药物释放的实时控制。
(3)应用所述纳米靶向光敏复合物与微纳电极阵列等电生理信号检测手段结合,可同步记录神经细胞电生理信号的变化,能够及时反映癫痫发病以及复合物调控的过程,根据电生理信号变化可以判断何时打开或关闭刺激光源,调控光敏药物的激活,进一步提高调控系统的时空分辨率。
附图说明
图1为本发明的实施例所述调控癫痫病灶神经细胞的纳米靶向光敏复合物示意图;
图2为本发明的实施例所述光敏药物示意图;
图3为本发明的实施例所述制备纳米靶向光敏复合物的工艺流程图;
图4为本发明的实施例所述神经细胞调控系统示意图。
上述附图中,附图标记含义如下:
1、纳米脂质体; 2、光敏药物; 3、靶向分子基团;
4、纳米靶向光敏复合物; 5、微注射药管; 6、微纳电极阵列;
7、光纤及光源。
具体实施方式
本发明公开了一种调控癫痫病灶神经细胞的纳米靶向光敏复合物及调控检测系统,能够实现对癫痫病灶区神经细胞靶向调控,同时可以实现靶向调控下神经细胞电生理信号同步检测,具有较高的时空分辨率,为癫痫疾病的治疗提供了新药物和新方法。
为使本发明的目的、技术方案和优点更加清楚明白,以下结合具体实施例,并参照附图,对本发明作进一步的详细说明。
如图1所示,为本发明的实施例所述调控癫痫病灶神经细胞的纳米靶向光敏复合物示意图;包括纳米脂质体1,包裹在脂质体内部的光敏药物2,以及连接在纳米脂质体外表面的靶向分子基团3。
其中,所述光敏药物能够在特定波长光刺激下,释放出活性分子对神经细胞进行调控;所述光敏药物是笼锁谷氨酸或笼锁γ-氨基丁酸。所述纳米脂质体,其双分子层包含胆固醇、二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰乙醇胺-聚乙二醇2000;所述胆固醇、二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰乙醇胺-聚乙二醇2000分子的摩尔比例为(1-5)∶(15-25)∶(1-5)。所述二硬脂酰磷脂酰乙醇胺-聚乙二醇2000分子上连接有活性基团,从而能够通过巯基交联反应或酰胺反应与靶向分子基团结合;所连接的活性基团是三苯甲酸酯、碳酸琥珀酰亚胺、羰基二咪唑、乙烯基砜或马来酰亚胺。所述靶向分子基团是多肽、DNA片段、适配体或抗体。
如图2所示,所用光敏药物为光笼解锁药物ruthenium-bipyridine-triphenylphosphine-γ-aminobutyric acid(RuBi-GABA),化学式为C42H39F6N5O2P2Ru,IUPAC命名为(bis(2,2′-Bipyridine-N,N′)triphenylphosphine)-4-aminobutyric acidruthenium hexafluorophosphate complex。在特定波长光刺激下能够释放出抑制性神经递质γ-氨基丁酸(GABA)。RuBi-GABA溶解在生理盐水中,使用浓度为5毫摩尔每升。
如图3所示,为本发明的实施例所述制备纳米靶向光敏复合物的工艺流程图;其具体步骤如下:
(1)将高分子有机材料胆固醇、DPPC和DSPE-PEG2000-Maleimide按比例在氯仿与甲醇配比溶剂中混合均匀。高分子有机材料摩尔浓度比例为(胆固醇∶DPPC∶DSPE-PEG2000-Maleimide)4∶20∶1。溶剂中氯仿与甲醇的混合体积比例为5∶2。
(2)经旋转蒸发成单层脂质薄膜,反应条件为37℃,蒸发时长15分钟。
(3)随后加入所包载的光笼解锁药物溶液进行水化,在超声水浴中使脂质薄膜脱离。
(4)将所得乳浊液通过滤膜推滤法进行均一化处理。本实施例中,推滤系统包括推滤器两个,聚碳酸酯膜,以及固定器。推滤次数为30次以上,得到粒径均一的脂质体。
(5)对脂质体进行表面抗体修饰。将大麻素I型受体抗体用IdeZ蛋白酶处理,反应浓度为1国际单位(unit)蛋白酶与1微克抗体反应,反应条件37℃,反应时间为30分钟,从而获得抗体片段。
(6)然后经过二硫苏糖醇还原剂处理,反应浓度为0.5毫摩尔每升,反应温度室温,反应时间30分钟,得到硫醇化抗体片段。
(7)最后利用巯基交联反应,将硫醇化抗体片段和所述脂质体混合连接,混合浓度为1毫克脂质体和25微克抗体片段混合反应,反应温度室温,反应时长2小时,形成纳米靶向光敏复合物。
如图4所示,为应用所述纳米靶向光敏复合物构建的神经调控系统,包括:纳米靶向光敏复合物4,用于向神经细胞靶向递送光敏药物;微注射药管5,通过微量注射器将纳米靶向光敏复合物注射到动物脑内;微纳电极阵列6,被植入到实验动物脑内,在调控过程中同步检测癫痫病灶神经细胞的电生理活动信号;光纤及光源7,将光纤植入到实验动物脑内,利用光刺激系统提供刺激光源,激活所述纳米靶向光敏复合物中的光敏药物,实现对癫痫病灶神经细胞活动的调控。
结合本实施例,所述神经细胞调控方法的具体操作为:
(1)将实验癫痫大鼠麻醉后固定在手术实验平台上,通过外科手术在目标脑区上方颅骨钻孔,随后将微纳电极阵列、微注射药管和光纤的植入。微纳电极阵列用于检测神经电生理信号。微注射药管用于注射纳米靶向光敏复合物。光纤与光源连接,用于激活光敏药物。
(2)在检测到神经细胞电生理活动信号后,随后通过微量注射系统,在海马区处注射25微升纳米靶向光敏复合物。等待1小时,让复合物靶向基团与目标细胞膜受体靶向结合。
(3)观察微纳电极阵列检测到的神经细胞电生理信号,当癫痫发作时,能够观察到神经细胞电生理信号发放突然密集,局部场电位的波动幅值显著增加,此时打开光刺激系统激发光源,激活RuBi-GABA释放抑制性神经递质。随后可观察到电生理信号发放减弱,逐渐恢复正常,说明神经细胞癫痫活动被成功抑制。
以上所述的具体实施例,对本发明的目的、技术方案和有益效果进行了进一步详细说明,应理解的是,以上所述仅为本发明的具体实施例而已,并不用于限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种纳米靶向光敏复合物,其特征在于,包括纳米脂质体,包裹在脂质体内部的光敏药物,以及连接在纳米脂质体外表面的靶向分子基团。
2.根据权利要求1所述的纳米靶向光敏复合物,其特征在于,所述光敏药物能够在特定波长光刺激下,释放出活性分子对神经细胞进行调控;所述光敏药物是笼锁谷氨酸或笼锁γ-氨基丁酸。
3.根据权利要求1所述的纳米靶向光敏复合物,其特征在于,所述纳米脂质体,其双分子层包含胆固醇、二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰乙醇胺-聚乙二醇2000;所述胆固醇、二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰乙醇胺-聚乙二醇2000分子的摩尔比例为(1-5)∶(15-25)∶(1-5)。
4.根据权利要求3所述的纳米靶向光敏复合物,其特征在于,所述二硬脂酰磷脂酰乙醇胺-聚乙二醇2000分子上连接有活性基团,从而能够通过巯基交联反应或酰胺反应与靶向分子基团结合;所连接的活性基团是三苯甲酸酯、碳酸琥珀酰亚胺、羰基二咪唑、乙烯基砜或马来酰亚胺。
5.根据权利要求1所述的纳米靶向光敏复合物,其特征在于,所述靶向分子基团是多肽、DNA片段、适配体或抗体。
6.一种制备权利要求1-5中任一项所述的纳米靶向光敏复合物的方法,其特征在于,包括以下步骤:
将胆固醇、二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰乙醇胺-聚乙二醇2000按比例溶解在有机溶剂中,然后旋转蒸发除去有机溶剂以在反应容器壁上形成单层脂质薄膜;
加入光敏药物溶液进行水化,在超声水浴中使所述单层脂质薄膜脱离,然后用滤膜推滤法使所得乳浊液通过高分子滤膜,形成包裹光敏药物的纳米脂质体;
进行表面修饰,将靶向分子基团连接在纳米脂质体表面,制得纳米靶向光敏复合物。
7.根据权利要求6所述的方法,其特征在于,所述二硬脂酰磷脂酰乙醇胺-聚乙二醇2000连接的活性基团为马来酰亚胺,即所用分子为DSP E-PEG2000-Maleimide;所述胆固醇、DPPC和DSPE-PEG2000-Maleimide的摩尔比例为4∶20∶1;和/或
所述有机溶剂为氯仿、甲醇、丙酮和乙腈的至少一种;优选地,所述有机溶剂为氯仿与甲醇混合溶剂;和/或
所述旋转蒸发温度为30-37℃,蒸发时长为10-20分钟;和/或
所述光敏药物为光笼解锁药物,浓度为2-10毫摩尔每升;和/或
所述纳米脂质体的粒径为50-200纳米。
8.根据权利要求6所述的方法,其特征在于,所述靶向分子基团为大麻素I型受体抗体;所述表面修饰方法包括以下具体步骤:
将抗体分子用剪切酶处理获得抗体片段,然后经过还原剂处理得到硫醇化抗体片段;最后利用巯基交联反应,将硫醇化抗体片段和纳米脂质体混合连接形成纳米靶向光敏复合物。
9.根据权利要求8所述的方法,其特征在于,所述剪切酶是木瓜蛋白酶、胃蛋白酶、IdeS免疫球蛋白酶或IdeZ免疫球蛋白酶;优选地,所述剪切酶为IdeZ免疫球蛋白酶;和/或
反应浓度为1国际单位蛋白酶与1微克抗体反应,反应条件25-37℃,反应时间为30-60分钟;和/或
所述还原剂是二硫苏糖醇、β-巯基乙醇或三(2-羧乙基)膦;优选地,所述还原剂为二硫苏糖醇;和/或
反应浓度为0.1-0.5毫摩尔每升,反应温度25-37℃,反应时间30-60分钟;和/或
所述混合连接反应为浓度为1毫克纳米脂质体和20-25毫克抗体片段混合,反应温度室温,反应时长1.5-2.5小时。
10.一种应用权利要求1-5任一项所述的纳米靶向光敏复合物调控和检测癫痫病灶神经细胞的系统,其特征在于,包括:
纳米靶向光敏复合物,用于向神经细胞靶向递送光敏药物;
微注射药管,通过微量注射器将纳米靶向光敏复合物注射到动物脑内;
微纳电极阵列,在调控过程中同步检测癫痫病灶神经细胞的电生理活动信号;
光纤及光源,利用光刺激系统提供刺激光源,激活所述纳米靶向光敏复合物中的光敏药物,实现对癫痫病灶神经细胞活动的调控。
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