CN113456576B - 纳米材料用于制备鼻腔纳米制剂脑靶向递送肠道药物应用 - Google Patents
纳米材料用于制备鼻腔纳米制剂脑靶向递送肠道药物应用 Download PDFInfo
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Abstract
本发明公开了一种纳米材料用于制备鼻腔纳米制剂脑靶向递送肠道药物应用,属于生物医药工程技术领域。包括介孔二氧化硅纳米粒子、Ca‑MOF和四氧化三铁等递送载体,可被递送具有神经保护作用或肠道抗炎症的小分子、蛋白质、抗体和微生物等物质;提供了以上述纳米材料用于制备鼻腔纳米制剂脑靶向递送至系统药物的应用。本发明通过鼻腔滴注功能性物质长距离运输至肠道,灵活、安全和高效地将药物经过某些神经环路长距离传输到胃肠道。
Description
技术领域
本发明属于生物医药工程技术领域,更具体地,涉及一种纳米材料用于制备鼻腔纳米制剂脑靶向递送肠道药物应用。
背景技术
肠道系统是一个复杂的微生态循环系统,对人体健康起着关键作用。近年来,肠道菌群研究不断有所突破,大量实验不断证实肠道菌群失调与中枢神经系统疾病存在联系,如抑郁症,自闭症,阿尔兹海默症,帕金森和多发性硬化。将脑-肠轴的概念扩展为微生物-脑-肠轴,该轴神经系统和中枢神经系统用神经-内分泌-免疫系统联系起来,形成一条双向的信号通路。
阿尔茨海默病,是一种复杂的神经退行性疾病,受遗传或环境因素的影响,或同时受这两种因素的影响。与蛋白质错误折叠的淀粉样蛋白-β(Aβ)原纤维和寡聚体以及由高磷酸化tau蛋白组成的神经原纤维缠结在大脑皮层和其他大脑区域的积累有关。特别地,肠道微生物的改变可以激活促炎因子、增加肠道的通透性、浸润脑组织和增加脑内炎症,这与AD疾病的发生发展密切相关。此外,肠道微生物组可将淀粉样蛋白,脂多糖(LPS)和其他微生物分泌物的免疫原性混合物排泄到周围环境中。细菌淀粉样蛋白也会激活已知在神经变性和AD发病机理中起作用的信号通路,因此,肠道微生物组会增强对Aβ大脑积聚的炎症反应。
最近一些研究发现,在AD小鼠模型中发现了微生物菌群的变化,与幼鼠相比,老年鼠肠道中的双歧杆菌数量明显减少,而幼鼠中肠道中双歧杆菌和乳酸菌处于优势地位并加以维持。在无菌动物模型中,益生菌或抗生素以及粪便菌移植调控宿主肠道菌群,可以影响宿主的认知行为。益生菌是可以改善宿主微生态平衡并发挥有益作用的活性微生物,其中,双歧杆菌是一种厌氧细菌,由法国学者蒂西尔(Tissier)于1899年从80个泌乳期婴儿的粪便中分离出来。它具有多种功能,例如抗菌,抗衰老,增强免疫力,抗癌等。据报道AD患者肠道菌群中的双歧杆菌数量明显减少。然而,目前的普遍现象是通过口服途径对人体补充双歧杆菌,但是胃酸对双歧杆菌的致死率几乎是100%。此外,由于血脑屏障,向AD的药物输送受到限制,分别限制了小分子和大分子药物的98%和100%的大脑渗透率。
为了克服这些问题,纳米药物输送系统和通过鼻腔途径的药物输送是最优的选择。其中,鼻腔给药是一种实用且无创的脑部给药方式,已经成为脑部递药研究的热点。现已经证实血管紧张素-Ⅱ、缩胆囊素、胰岛素和血管内皮生长因子等大分子蛋白多肽类药物及间充质干细胞等可绕过血脑屏障,经过嗅觉神经和三叉神经通路迅速均可以通过鼻腔到脑部发挥作用,不良反应较少。但是,目前,经鼻腔递送的药物报道只是仅仅限于说是避开肝脏摄取,提高了药物生物学利用度,但是否可以将药物经过某些神经环路长距离传输到胃肠道尚无报道,借此技术是否可传递益生菌调节肠道菌群的丰富度改善神经退行性疾病进程需要进一步推敲。
发明内容
针对现有技术还无将药物经过神经环路长距离传输到胃肠道的纳米材料,本发明提供了一种鼻腔纳米制剂脑靶向递送肠道的应用,其目的在于灵活、安全和高效地将药物经过某些神经环路长距离传输到胃肠道。
根据本发明的第一方面,提供了了一种纳米材料用于制备鼻腔纳米制剂脑靶向递送至肠道药物的应用,所述纳米材料为纳米载体装载具有治疗作用的物质;所述纳米载体用于将所述具有治疗作用的物质经过神经环路传输至肠道。
优选地,所述具有治疗作用的物质为缓解神经退行性疾病的疾病进程的药物。
优选地,所述具有治疗作用的物质为治疗阿尔兹海默症的药物。
优选地,所述具有治疗作用的物质用于使β-淀粉样蛋白减少、促炎因子表达下降以及抗炎因子表达升高。
优选地,所述具有治疗作用的物质为小分子化合物、蛋白质或微生物。
优选地,所述小分子化合物为抗炎物质;所述蛋白质为抗体;所述微生物为能够改善肠道微生物的细菌;
优选地,所述抗炎物质为姜黄素,所述抗体为抗hAβ1-42单克隆抗体,所述细菌为双歧杆菌。
按照本发明的另一方面,提供了一种纳米材料用于制备鼻腔纳米制剂脑靶向递送至肠道成像探针的应用,所述纳米材料为纳米载体装载探针分子;所述纳米载体用于将所述探针分子经过神经环路传输到肠道。
优选地,所述纳米载体为介孔二氧化硅纳米粒子、四氧化三铁纳米粒子或纳米级的金属有机框架材料。
优选地,所述纳米级的金属有机框架材料为纳米级的Ca-MOF;所述介孔二氧化硅纳米粒子的粒径为50nm-400nm;所述四氧化三铁纳米粒子的粒径为50nm-200nm。
优选地,所述装载为化学连接或物理吸附。
总体而言,通过本发明所构思的以上技术方案与现有技术相比,主要具备以下的技术优点:
(1)本发明通过鼻腔滴注功能性物质长距离运输至肠道,灵活、安全和高效地将药物经过某些神经环路长距离传输到胃肠道。
(2)本发明优选地,利用介孔二氧化硅纳米粒子作为载体经鼻腔到肠道进行物质递送,可利用介孔二氧化硅纳米粒子表面进行NHS修饰,与BSA蛋白和1F12单克隆抗体发生酯化反应结合,也可以利用介孔二氧化硅纳米粒子多孔结构特点对Cy3小分子物质和双歧杆菌进行物理装载,根据实际需要或实际医疗条件选择装载方式,可极大提高装载物质到肠道递送的灵活性和利用度。另外,本发明所提出的肠道快速递送物质技术,是借助鼻腔给药进行滴注,通过鼻腔递送纳米材料载物进入胃肠道,全面综合纳米粒子载药特性、鼻腔递送无侵袭性和益生菌调节肠道微生物均衡的优势,本发明在一定程度上解决的益生菌递送的问题,具有操作简便、快捷和无需特殊设备等特点,适用于广泛推广应用。
(3)本发明优选地,利用介孔二氧化硅纳米粒子装载的微生物可将微生物快速到达肠道,并能通过改变肠道内微生物菌群丰富度,缓解神经退行性疾病如阿尔茨海默症的疾病进程,与对照组相比,经鼻腔进行滴注介孔二氧化硅纳米粒子装载的微生物,会导致APP/PS1小鼠的外周血和脑中β-淀粉样蛋白显著的减少、促炎因子表达下降、抗炎因子表达升高和行为学也得到极大的改善,在神经退行性疾病如阿尔茨海默症治疗中有潜在的应用价值。因此,本发明通过鼻腔递送介孔二氧化硅纳米粒子装载的双歧杆菌,通过提高肠道益生菌丰富度,来改善生物体的行为能力和减缓大脑中的β-淀粉样蛋白负担。
(4)本发明优选地,以金属有机框架材料作为纳米载体。MOFs的孔道结构规则、孔隙率高、生物可降解性、结构组成和功能可调等特点使其具有广泛的应用价值。其中,Ca-MOF可利用其苯环间π键作用力吸附和富集病理性蛋白、多肽和有毒小分子物质。因此,本发明优选采用Ca-MOF功能纳米粒子。
(5)本发明优选地,以四氧化三铁粒子作为纳米载体。四氧化三铁(Fe3O4)纳米粒子又以其大比表面积、低毒性和良好的生物相容性等物理化学性质而得到全世界生物医用领域的广泛关注,如磁共振成像、作为增强显影剂和造影剂,实现诊疗一体化研究。因此,本发明优选采用四氧化三铁纳米粒子。
(6)本发明优选地,纳米载体装载双歧杆菌。双歧杆菌属的细菌是人和动物肠道菌群的重要组成成员之一,双歧杆菌属于益生菌在抗衰老和调节肠道微生物菌群等诸多优势,本发明在一定程度上解决的益生菌改善肠道微生物菌群和抗炎的问题,提高生物体内肠道菌群的丰富度和β-淀粉样蛋白的清除,减缓脑内炎症的发生发展和脑内β-淀粉样蛋白斑块的形成。为减缓阿兹海默综合症的疾病进程提供了新技术来源。
(7)本发明优选地,纳米载体装载Cy3小分子。Cy3属于菁染料是性能优良的荧光标记染料,摩尔吸光系数在荧光染料中是最高的,其琥珀酰亚胺酯是最常用的脂肪氨基标记试剂,广泛用于蛋白、抗体、核酸及其他生物分子的标记和检测,广泛应用于小动物活体成像领域,实现递送物质的追踪。
(8)本发明优选地,纳米载体装载牛血清白蛋白。牛血清白蛋白(BSA),是牛血清中的一种球蛋白,包含607个氨基酸残基,分子量为66.45kDa,等电点为4.7。牛血清白蛋白在生化实验中作为蛋白质一种代表,广泛应用于发挥维持渗透压、pH缓冲和载体作用。
(9)本发明优选地,纳米载体装载抗hAβ1-42单克隆抗体。hAβ1-42单克隆抗体在脑内清除脑中β-淀粉样蛋白,极大加快了脑内β-淀粉样蛋白含量的降低速度,为阿兹海默综合症的临床快速清除β-淀粉样蛋白和降低β-淀粉样蛋白的毒性提供了新技术来源。
附图说明
图1为本发明技术原理图。
图2为Ca-MOF和Fe3O4经鼻腔对蛋白质大分子物质到肠道的递送图;其中,A图为本发明Ca-MOF偶联BSA蛋白的SDS-PAGE图;B图为本发明Ca-MOF偶联BSA-Cy3蛋白的荧光图;C图为本发明Ca-MOF-BSA-Cy3鼻腔递送后6h肠道荧光图;D图为本发明Ca-MOF-BSA-Cy3鼻腔递送后6h肠道切片共聚焦荧光图,红色为Ca-MOF-BSA-Cy3信号,20X;E图为本发明Fe3O4偶联BSA蛋白的SDS-PAGE图;F图为本发明Fe3O4偶联BSA-Cy3蛋白的荧光图;G图为本发明Fe3O4-BSA-Cy3鼻腔递送后6h肠道荧光图;H图为本发明Fe3O4-BSA-Cy3鼻腔递送后6h肠道切片共聚焦荧光图,20X。
图3为MSN为载体经鼻腔对物质到肠道的递送图;其中,A图为MSN透射电镜图;B图为MSN对Cy3小分子物质装载后荧光检测图;C图为MSN-Cy3经鼻腔递送后6h小鼠肠道荧光图;D图为MSN-Cy3经鼻腔递送后脑冰冻切片共聚焦成像图;红色为MSN-Cy3,10X;E图为本发明MSN偶联BSA蛋白的SDS-PAGE图;F图为本发明MSN偶联BSA-Cy3蛋白的荧光图;G图为本发明MSN-BSA-Cy3鼻腔递送后6h肠道荧光图;H图为本发明MSN-BSA-Cy3鼻腔递送后6h肠道切片共聚焦荧光图,红色为MSN-BSA-Cy3信号,10X;I图为本发明MSN偶联1F12抗体的SDS-PAGE图;J图为本发明MSN偶联1F12抗体SDS-PAGE图;K图为本发明MSN-1F12-Cy3鼻腔递送后6h肠道荧光图;L图为本发明MSN-1F12-Cy3鼻腔递送后6h肠道切片共聚焦荧光图,10X。
图4为MSN经鼻腔对微生物到肠道的递送结果图;其中,A图为20μg/μL MSN装载双歧杆菌后的释放检测图;B图为MSN装载双歧杆菌后在小肠体液的生存活力检测图;C图为双歧杆菌后在含有胃蛋白酶的小肠体液的生存活力检测图;D图为双歧杆菌后不含有胃蛋白酶的小肠体液的生存活力检测图。
图5为MSN-双歧杆菌经鼻腔到肠道的递送减缓AD小鼠炎症进程的检测图;其中,A图为实验前4月龄AD小鼠血液中Aβ的检测结果图;B图为4月龄AD小鼠完成第四次递送后血液中Aβ的检测结果图;C图为8月龄AD小鼠治疗后脑组织中抗炎因子IL-4检测结果图;D图为8月龄AD小鼠治疗后脑组织中抗炎因子IL-10检测结果图;E图为8月龄AD小鼠治疗后脑组织中促炎因子IFN-γ检测结果图;F图为8月龄AD小鼠治疗后脑组织中促炎因子IL-6检测结果图。
图6为MSN-双歧杆菌经鼻腔到肠道的递送改善AD小鼠行为能力结果图;其中,A图为治疗后8月龄AD小鼠和C57鼠嗅觉灵敏度检测结果图;B图为治疗后8月龄AD小鼠和C57鼠感知能力检测结果图;C图为治疗后8月龄AD小鼠和C57鼠跳台记录仪记录小鼠5min内被处罚时间结果图;D图为治疗后8月龄AD小鼠和C57鼠跳台记录仪记录小鼠潜伏期1时间结果图;E图为治疗后8月龄AD小鼠和C57鼠筑巢行为学检测结果图。
图7为MSN-双歧杆菌经鼻腔到肠道的递送对脑内β-淀粉样蛋白的清除结果图;其中,A图为MSN-双歧杆菌治疗组与对照组APP/PS1小鼠的脑组织中硫磺素反染后脑组织切片荧光图;B图为MSN-双歧杆菌治疗组与对照组APP/PS1小鼠的脑组织中β-淀粉样蛋白斑块数量统计结果;C图为MSN-双歧杆菌治疗组与对照组APP/PS1小鼠的脑组织中β-淀粉样蛋白斑块面积统计结果。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。此外,下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
为便于指代,现将主要缩写的含义解释如下:
四氧化三铁纳米粒子装载BSA-Cy3:简写为Fe3O4-BSA-Cy3;
金属有机骨架化合物(Metal Organic Frameworks):简写为MOF;
Ca-MOF装载BSA-Cy3:简写为Ca-MOF-BSA-Cy3;
介孔二氧化硅纳米粒子(Mesoporous Silica Nanoparticles):简写为MSN;
介孔二氧化硅纳米粒子装载Cy3:简写为MSN-Cy3;
介孔二氧化硅纳米粒子装载BSA-Cy3:简写为MSN-BSA-Cy3;
介孔二氧化硅纳米粒子装载1F12-Cy3:简写为MSN-1F12-Cy3;
介孔二氧化硅纳米粒子装载双歧杆菌:简写为MSN-Bi。
一些实施例中,所述物质载体为介孔二氧化硅纳米粒子。物质载体不限于介孔二氧化硅,还可以是四氧化三铁包裹介孔二氧化硅、树枝状介孔二氧化硅、生物可溶性介孔二氧化硅、生物材料修饰(如PLGA、血小板、多巴胺和金属框架材料等)的介孔二氧化硅、复合介孔二氧化硅、不同结构的二氧化硅微球以及具有相似生物学功能性质的纳米粒子,而其中由于介孔二氧化硅纳米粒子在生物医学上已经批准,是生物安全的,因此,本发明优选采用介孔二氧化硅纳米粒子。
一些实施例中,所述功能纳米粒子为MOF支架。
一些实施例中,所述MOF支架为Ca-MOF。
一些实施例中,所述功能纳米粒子为四氧化三铁纳米粒子。
一些实施例中,所述递送物质为小分子物质。
一些实施例中,所述小分子物质为Cy3。
一些实施例中,所述物质载体介孔二氧化硅纳米粒子中,介孔二氧化硅纳米粒子的尺寸为400nm,该尺寸物质的载量和经鼻腔到肠道递送的生物利用率最高。
一些实施例中,所述递送物质为蛋白质。
一些实施例中,所述蛋白质为牛血清白蛋白。
一些实施例中,所述蛋白质为抗hAβ1-42单克隆抗体1F12。
作为本发明的进一步优选,所述递送物质为微生物。
作为本发明的进一步优选,所述微生物为双歧杆菌。
本发明提供了一种用于肠道快速递送物质技术,物质载体优选地,纳米粒子为介孔二氧化硅纳米粒子。其中,物质载体优选地为小分子化合物(以Cy3为例)、蛋白质(以牛血清白蛋白为例)、抗Aβ抗体(以抗Aβ单克隆抗体1F12为例)和微生物(以益生菌双歧杆菌为例)。
本发明利用介孔二氧化硅纳米粒子作为载体经鼻腔到肠道进行物质递送,可利用介孔二氧化硅纳米粒子表面进行NHS修饰,与BSA蛋白和1F12单克隆抗体发生酯化反应结合,也可以利用介孔二氧化硅纳米粒子结构特点对Cy3小分子物质和双歧杆菌进行物理装载,根据实际需要或实际医疗条件选择装载方式,可极大提高装载物质到肠道递送的灵活性和利用度。
本发明利用四氧化三铁纳米粒子作为载体经鼻腔到肠道进行物质递送,可利用四氧化三铁纳米粒子表面进行-COOH修饰,与BSA蛋白脱水缩合反应,也可以利用四氧化三铁纳米粒子的磁性特性或吸附能力进行物理装载,根据实际需要或实际医疗条件选择装载方式,可极大提高装载物质到肠道递送的灵活性和利用度。
本发明利用Ca-MOF纳米粒子作为载体经鼻腔到肠道进行物质递送,可利用Ca-MOF的孔道结构,吸附和富集的特性,实现对姜黄素小分子药物和BSA蛋白进行物理装载,根据实际需要或实际医疗条件选择装载方式,可极大提高装载物质到肠道递送的灵活性和利用度。
另外,本发明所提出的肠道快速递送物质技术,是借助鼻腔给药进行滴注,通过鼻腔递送纳米材料载物进入胃肠道,全面综合纳米粒子载药特性、鼻腔递送无侵袭性和益生菌调节肠道微生物均衡的优势,本发明在一定程度上解决的益生菌递送的问题,具有操作简便、快捷和无需特殊设备等特点,适用于广泛推广应用;因此,本发明通过鼻腔递送介孔二氧化硅纳米粒子装载的双歧杆菌,通过提高肠道益生菌丰富度,来改善生物体的行为能力和减缓大脑中的β-淀粉样蛋白负担,对医学研究领域具有极大推动作用。
实施例1:Ca-MOF为载体物质经鼻腔到肠道的递送
1.1、姜黄素Ca-MOF的合成
取姜黄素20g,用1000mL乙醇丙酮(体积比4:1)混合溶液溶解,于40~50℃下保温处理2h备用。另取无水氯化钙5g,溶于100mL乙醇中备用;将氯化钙乙醇溶液添加到姜黄素混合溶液中,保温反应2~3h,将氨水调节上述溶液pH至7~8,静置过夜;过滤分离姜黄素Ca-MOF沉淀,用乙醇洗涤3次后,在70~80℃下干燥,即得到姜黄素Ca-MOF。
1.2、Ca-MOF-BSA-Cy3复合体构建
用0.1M Na2CO3调节BSA pH值至8.5~9.0之间。在漩涡的状态下加入NHS-Cy3,室温混匀3h。混匀后,将合成好的荧光探针过PD-10柱,除去未结合的NHS-Cy3;与Ca-MOF进行室温摇晃孵育6h,然后5000rpm,离心5min除去未吸附的BSA-Cy3,使用PBS清洗3次。其偶联后具体结果如附图2中的A和图2中的B所示。
1.3、鼻腔递送至肠道
将上述Ca-MOF-BSA-Cy3,10000rpm,5min离心分离上清进行浓缩,分别得到5μg/μLCa-MOF-BSA-Cy3,取20μL进行鼻腔递送,6h后进行心脏灌流后成像。肠道组织整体荧光成像和冰冻切片后共聚焦成像均可见和Ca-MOF-BSA-Cy3信号,其具体结果如附图2中的C和图2中的D所示。
实施例2:Fe3O4为载体物质经鼻腔到肠道的递送
1.1、Fe3O4-BSA-Cy3复合体构建
取2mg Fe3O4-COOH用800μL反应缓冲液(0.1M MES,0.15M NaCl,pH 6.0)重悬,再加入200μL现配偶联试剂(EDC-HCl溶液),室温旋转混合30min,加入200μL BSA-Cy3(1mg),室温旋转孵育16h,磁性分离去除上清。加入1mL封闭缓冲液(0.2%BSA,0.1MES,0.15M NaCl,pH 6.0)室温封闭2h,磁性分离去除上清。洗涤缓冲液(50mM Tri-HCl,0.15M NaCl,pH 7.2)清洗5次。其偶联后具体结果如附图2中的E和图2中的F所示。
1.2、鼻腔递送至肠道
将上述Fe3O4-BSA-Cy3,磁力分离上清进行浓缩,分别得到5μg/μL Fe3O4-BSA-Cy3,取20μL进行鼻腔递送,6h后进行心脏灌流后成像。肠道组织整体荧光成像和冰冻切片后共聚焦成像均可见和Fe3O4-BSA-Cy3信号,其具体结果如附图2中的G和图2中的H所示。
实施例3:MSN为载体物质经鼻腔到肠道的递送
1.1、400nm MSN的合成
将5mL十六院基-三甲基-氯化胺(Cetyltrimethylammonium chloride,CTAC0.274mmol)和5mL的三乙醇胺(Triethanolamine,TEA 51.1mmol)混合并磁力搅拌升温到95℃,1h后,将0.5mL的正硅酸乙(Tetraethylorthosilicate,TEOS 2.23mmol)逐滴加入并保持温度继续磁力搅拌1h。然后,通过离心和乙醇洗涤3次得到MSN。将得到的MSN在1%的盐酸乙醇溶液中60℃搅拌3h,重复3次,离心得到去模板剂CTAC-MSN。其透射电镜图如附图3中的A所示。
1.2、MSN对小分子物质的装载
分别取2mL的1μg/μL MSN与100μg Cy3(Cy3属于氨基反应染料,是一种明亮的橙色荧光染料,可以使用532nm的激光谱线)染料室温混合3h,混匀后,对混合物进行透析过夜处理,以除去未被装载的Cy3染料。得到MSN-Cy3,其荧光图如附图3中的B所示。
1.3、MSN对蛋白物质的装载
MSN-BSA-Cy3复合体构建:
用0.1M Na2CO3调节BSA pH值至8.5~9.0之间。在漩涡的状态下加入NHS-Cy3,室温混匀3h。混匀后,将合成好的荧光探针过PD-10柱,除去未结合的NHS-Cy3。
NHS修饰MSN:5.4x10-6mol NHS加入稀释到3mL MSN样品中反应3h;离心,PBS清洗3次,分散到200μL DI中避光保存。与浓度1μg/μL的MSN-NHS(pH=8.5~9.0)室温混匀3h,然后10000rpm,5min离心分离未结合的BSA-Cy3,使用PBS清洗探针3次,即得到MSN-BSA-Cy3。其具体结果如附图3中的E和图3中的F所示。
1.4、MSN对抗体的装载
MSN-1F12-Cy3复合体构建:
用0.1M Na2CO3调节1F12 pH值至8.5~9.0之间。在漩涡的状态下加入NHS-Cy3,室温混匀3h。混匀后,将合成好的荧光探针过PD-10柱,除去未结合的NHS-Cy3;再与浓度1μg/μL的MSN-NHS(pH=8.5~9.0)室温混匀3h,然后5000rpm,5min离心分离上清中未结合的1F12-Cy3,使用PBS清洗探针3次,即得到MSN-1F12-Cy3。其具体结果如附图3中的I和图3中的J所示。
1.5、MSN对微生物的装载
MSNs对益生菌的装载,我们选择使用益生菌中的1x109双歧杆菌与20μg/μL MSN进行37℃摇晃孵育0.5h,然后5000rpm,离心5min除去未被装载的菌体,得到上清进行离心(10000rpm,10min),使用生理盐水清洗3次,在加入适量培养基。检测结果发现20μg/μL MSN在确保双歧杆菌正常繁殖的情况下。模拟体液环境,在pH 7.2和37℃条件下,可以从MSN中的缓慢释放益生菌,具体检测结果见附图4中的A。
MSN装载双歧杆菌后,双歧杆菌抵抗胃酸的能力,我们将装载有双歧杆菌的MSN和双歧杆菌分别暴露于小肠液体(SIF,pH 7.2),监测2h内双歧杆菌的生存力。其中,MSN装载双歧杆菌后,可适当避免胃酸对双歧杆菌破坏,具体检测结果见附图4中的B;但裸露的双歧杆菌在小肠液体,有无胃蛋白酶的存在下,均很快失去活力。具体检测结果分别见附图4中的C和图4中的D。
1.6、鼻腔递送至肠道
将上述透析过夜后的MSN-Cy3,5000rpm,5min离心分离上清进行浓缩,得到5μg/μLMSN-Cy3,取20μL进行鼻腔递送,6h后进行心脏灌流后整体荧光成像。肠道整体荧光成像均可见明显荧光信号,其具体结果如附图3中的C所示。其次,MSN-Cy3递送后小肠组织冰冻切片后共聚焦成像可见MSN-Cy3信号,其具体结果如附图3中的D所示。
将上述MSN-BSA-Cy3,10000rpm,5min离心分离上清进行浓缩,分别得到5μg/μLMSN-BSA-BSA-Cy3,取20μL进行鼻腔递送,6h后进行心脏灌流后成像。肠道组织整体荧光成像和冰冻切片后共聚焦成像可见和MSN-BSA-Cy3信号,其具体结果如附图3中的G和图3中的H所示。
将上述MSN-1F12-Cy3,10000rpm,5min离心分离上清进行浓缩,分别得到5μg/μLMSN-1F12-Cy3,取20μL进行鼻腔递送,6h后进行心脏灌流后成像。肠道组织整体荧光成像和冰冻切片后共聚焦成像可见和MSN-1F12-Cy3信号,其具体结果如附图3中的K和图3中的L所示。
实施例4:MSN-双歧杆菌经鼻腔到肠道的递送减缓AD小鼠疾病进程
为了检测MSN-双歧杆菌能否减缓APP/PS1小鼠疾病进程,取200μL已经溶于生理盐水中,浓度为1x109双歧杆菌进行灌胃,20μL MSN-双歧杆菌(菌体,1x109)以及等量20μL MSN和20μL生理盐水在4月龄APP/PS1小鼠中进行鼻腔递送,每周递送一次,连续递送4周。实验中4组APP/PS1鼠为同一批次雄性,经ELISA检测血液Aβ无显著差异,具体检测结果见附图5中的A。第四次递送结束后,分别取4组APP/PS1鼠血中的β-淀粉样蛋白进行ELISA检测,与对照组相比,发现鼻腔递送MSN-双歧杆菌可以减缓血液中β-淀粉样蛋白的增加,具体检测结果见附图5中的B。待APP/PS1小鼠到达8月龄时进行各项指标的检测。
1.1、APP/PS1小鼠脑内炎症因子的检测
APP/PS1小鼠到达8月龄时,分别获取治疗组和对照鼠50mg脑组织在1mL TBS缓冲液中研磨进行,获取组织匀浆液,10000rpm,离心10min,获取上清,分别取50μL上清液进行炎症因子检测(试剂盒,BD Cytometric Bead Array(CBA)Mouse Th1/Th2/Th17 CytokineKit)。检测结果发现,与对照组相比,治疗组APP/PS1小鼠鼻腔递送MSN-双歧杆菌一个月治疗后抗炎因子表达升高具体检测结果见附图5中的C和图5中的D。促炎因子的表达降低,具体检测结果见附图5中的E和图5中的F。说明MSN-双歧杆菌对抑制脑内炎症的发生和发展。
1.2、APP/PS1小鼠行为学的改善
嗅觉行为学
APP/PS1小鼠到达8月龄时,检测APP/PS1小鼠的嗅觉灵敏性,选择气味及交叉适应实验筛选小鼠嗅觉灵敏性。气味剂选用庚酮、乙酸异戊酯、柠檬烯和戊酸乙酯混合溶于矿物油中,稀释成1×10-3,将其密封于塑料管中的棉花球,将带有气味的棉花球放入鼠笼一侧的端口,气味连续释放4次,每次20s,间隔30s,以气味源1cm范围内为节点进行测试。连续检测4次,每次间隔24h。结果发现鼻腔递送MSN-双歧杆菌治疗组APP/PS1小鼠一个月治疗后,小鼠嗅觉灵敏度仅次于8月龄期的C57小鼠,显著高于其他三组的小鼠的灵敏度。具体检测结果见附图6中的A。
学习记忆和感知能力
APP/PS1小鼠到达8月龄时,检测APP/PS1小鼠的学习和记忆能力,利用小鼠跳台记录仪监测小鼠的学习和记忆。首先将小鼠放入箱体中适应5min,在首次开通电流后,小鼠初次找到安全平台的时间为小鼠的感知能力,具体检测结果见附图6中的B;说明经鼻腔递送MSN-双歧杆菌治疗组APP/PS1小鼠一个月治疗后小鼠的感知力得到明显提升。间隔48h后,将小鼠放在安全平台上,开通电流后,监测5min中,小鼠在安全平台停留的时间和被点击的时间(惩罚时间)。最终以小鼠惩罚时间的来反应小鼠的记忆和学习能力。结果发现,鼻腔递送MSN-双歧杆菌治疗组APP/PS1小鼠一个月治疗后,小鼠感知能力几乎能同于8月龄期的C57小鼠,且与其他三组先比,学习和记忆能力显著提高。具体检测结果见附图6中的C和图6中的D。
筑巢行为学
APP/PS1小鼠到达8月龄时,检测APP/PS1小鼠筑巢能力,选择质地柔软的纸巾,在4组实验小鼠鼠笼中同一时间点放入4张尺寸大小完全一样的纸巾,经过72h的连续检测,对4组实验小鼠所筑巢穴进行拍照。结果发现治疗组APP/PS1小鼠鼻腔递送MSN-双歧杆菌一个月治疗后,小鼠所筑巢穴优于其他三组的小鼠的巢穴,且仅次于8月龄期的C57小鼠所筑巢穴。具体检测结果见附图6中的E。
1.3、APP/PS1小鼠脑内β-淀粉样蛋白的清除
APP/PS1小鼠到达8月龄时,获取治疗组和对照组鼠脑冠状切片进行硫磺素反染β-淀粉样蛋白的统计分析。结果:与对照组相比,APP/PS1小鼠鼻腔递送MSN-双歧杆菌一个月治疗后β-淀粉样蛋白数量和面积均少于对照组和双歧杆菌直接灌胃组,说明MSN-双歧杆菌可减缓APP/PS1小鼠脑内β-淀粉样蛋白的负担要比双歧杆菌灌胃的效果更好。具体检测结果见附图7中的A、图7中的B和图7中的C。
综上所述,本发明提出的基于Fe3O4、Ca-MOF和MSN载体鼻腔递送小分子物质,蛋白以及微生物能够快速到达肠道,且MSN-双歧杆菌鼻腔递送可进一步减缓脑中β-淀粉样蛋白的负担、痴呆小鼠的学习和记忆能力,其效果显著。发明的一种用于纳米材料介导鼻腔纳米制剂脑靶向递送肠道系统及其制备方法,对于药物精准治疗具有重大意义。
实施例1、2、3和4已经详尽的描述了一种用于纳米材料介导鼻腔纳米制剂脑靶向递送肠道系统及其制备方法,但是本发明所述的技术不限于本专利实施例所述。本发明所描述的MSN纳米粒子不限于介孔二氧化硅和四氧化三铁包裹介孔二氧化硅,还可以是还可以是树枝状介孔二氧化硅、生物可溶性介孔二氧化硅、生物材料修饰(如PLGA、血小板、多巴胺、金属框架材料等)的介孔二氧化硅、复合介孔二氧化硅、不同结构的二氧化硅微球和具有相似生物学功能性质的纳米粒子载体。本发明所描述了一种用于纳米材料介导鼻腔纳米制剂脑靶向递送肠道系统及其制备方法,其所用的小分子物质为Cy3,也可以各种具有功能性的药物或探针。本发明所描述了一种用于纳米材料介导鼻腔纳米制剂脑靶向递送肠道系统及其制备方法,其所用的单克隆抗体为1F12,也可以是多克隆抗体、单链抗体等具有功能性的蛋白和小分子多肽。本发明所描述了一种用于纳米材料介导鼻腔纳米制剂脑靶向递送肠道系统及其制备方法,其所用的微生物为双歧杆菌,也可以是各种细菌和真菌。本发明所描述的技术不限于对β-淀粉样蛋白的清除,也可以是在抗菌、抗氧化或对体内有害蛋白或小分子多肽的降解等治疗方面应用。
本领域的技术人员容易理解,以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (4)
1.一种纳米材料用于制备鼻腔纳米制剂脑靶向递送至肠道药物的应用,所述纳米材料为纳米载体装载具有治疗作用的物质;所述纳米载体用于将所述具有治疗作用的物质经过神经环路传输至肠道;所述具有治疗作用的物质为能够改善肠道微生物的双歧杆菌;
所述纳米载体为介孔二氧化硅纳米粒子,所述介孔二氧化硅纳米粒子的粒径为50 nm-400 nm。
2.如权利要求1所述的应用,其特征在于,所述具有治疗作用的物质用于使β-淀粉样蛋白减少、促炎因子表达下降以及抗炎因子表达升高。
3.一种纳米材料用于制备鼻腔纳米制剂脑靶向递送至肠道成像探针的应用,所述纳米材料为纳米载体装载探针分子;所述纳米载体用于将所述探针分子经过神经环路传输到肠道;
所述纳米载体为介孔二氧化硅纳米粒子、四氧化三铁纳米粒子或纳米级的金属有机框架材料;
所述纳米级的金属有机框架材料为纳米级的Ca-MOF;所述介孔二氧化硅纳米粒子的粒径为50 nm-400 nm;所述四氧化三铁纳米粒子的粒径为50 nm-200 nm。
4.如权利要求1-3任一项所述的应用,其特征在于,所述装载为化学连接或物理吸附。
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