CN111481510A - 一种包裹细胞分泌组的纳米颗粒及其制备方法和应用 - Google Patents
一种包裹细胞分泌组的纳米颗粒及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种包裹细胞分泌组的纳米颗粒及其制备方法和应用,其特点在于通过物理挤出技术,在形成纳米脂质体的过程中进行细胞分泌组的包裹,不对所包裹的细胞活性成分产生任何影响,并且能够延长细胞分泌组在体内循环时间,提高靶向能力,实现细胞分泌组的定向缓慢释放。制备方法包括制备分泌组溶液,制备脂质分子膜和制备包裹分泌组的纳米脂质体颗粒。能够精确控制载药剂量,不造成原材料浪费,适用于任何通过分泌发挥作用的细胞分泌组,是一种充分利用细胞全部活性成分的联合用药方式,用于非细胞活性成分的靶向递送和缓慢释放。
Description
技术领域
本发明所属领域为细胞因子治疗和再生医学,具体说是一种包裹细胞分泌组的纳米颗粒及其制备方法和应用。
技术背景
干细胞疗法在治疗危重疾病的再生医学中展现出良好的前景。细胞主要通过细胞的旁分泌作用、免疫调控作用和非常有限的分化作用发挥治疗功能,高度依赖细胞活性。现有数据报道,细胞进入机体后会发生严重的失剿凋亡,同时大量细胞聚集在肺脏毛细血管极易引发肺栓塞而造成严重的副作用。细胞条件培养基不但表现出类似的治疗作用,而且有效避免了细胞进入机体后造成的免疫排斥、失剿凋亡等问题,说明干细胞在发挥治疗作用时主要依赖其分泌组进行。但是经***给药方式移植的细胞条件培养基作用时间短暂,需要多次给药;而且药物不具有靶向作用,会造成药物有效利用率较低。纳米仿生载体在药物递送方面体现出越来越多的优势。脂质体纳米载体不但具有优良的生物相容性,而且模拟细胞膜磷脂双分子层的特点能有效的避免机体免疫***的攻击。本发明的目的在于利用纳米脂质体载体对细胞分泌组进行包裹,使细胞分泌组纳米化,对活性因子起到保护作用,同时实现细胞因子治疗的靶向性和缓释效果。
发明内容
本发明所述纳米颗粒是采用纳米挤出技术制备的包裹有细胞分泌组的脂质体颗粒;所述细胞分泌组是指间充质干细胞经过不同功能化方式获得的细胞分泌组,所述细胞类型包括脂肪间充质干细胞、骨髓间充质干细胞、脐带间充质干细胞、宫血间充质干细胞、胎盘间充质干细胞、巨噬细胞中的一种或几种的混合物。其具体制备方法包括以下步骤:
1)制备细胞分泌组溶液:106个细胞传代培养于T75细胞培养瓶中,培养48h,后换成基础培养基,培养24h收集细胞上清,获得原始浓度细胞分泌组。经冷冻干燥获得终蛋白浓度10mg/mL的细胞分泌组悬液;
2)制备脂质分子膜:1,2-二棕榈酰-锡-甘油基-3-磷酸胆碱(DPPC)、1,2-二硬脂酰-锡-甘油基-3-磷酸胆碱(DSPC)、1,2-二油酰-锡-甘油基-3-磷酸胆碱(DOPC)和胆固醇(Avanti Polar Lipids)分别以5∶1∶3∶1的摩尔比溶解在丙酮和氯仿(3∶1 v/v)的混合溶剂中,溶液通过旋转蒸发器蒸发形成薄膜;
3)制备包裹分泌组的纳米脂质体颗粒:用细胞分泌组悬液(1∶300蛋白与脂质的质量比例)对步骤2)中形成的膜进行水化,45℃条件下涡旋3min,组装成脂质体;用脂质体挤出器(Mini Extruder)将脂质体悬浮液在45℃条件下通过不同孔径的醋酸纤维素膜挤压20-40次;收集挤膜完成的混悬液,于4℃,120000g离心1h,弃上清,所得沉淀用400μLPBS重悬得到包裹有细胞分泌组的纳米脂质体。
包裹细胞分泌组的纳米脂质体颗粒能够缓释间充质干细胞的有效治疗成分,优选用于靶向、长效的作用。
该制备方法具有如下显著优势:
1)制备工艺上,本发明采用物理方法对细胞分泌组进行纳米包封,保护生物活性成分不受损伤,充分保证治疗的有效性;通过调节合适的脂质蛋白比例,能够精确控制载药剂量,不造成原材料浪费;该工艺适用于任何通过分泌发挥作用的细胞分泌组。
2)在功能上,本发明制备的纳米颗粒将细胞的所有分泌成分作为一个组合进行药物制剂制备,属于联合用药,通过精准的尺径调控实现靶向联合药物递送,同时实现药物缓释,延长作用时间的目的。
3)在原材料上,脂质体制备原材料均为与细胞膜磷脂双分子层高度类似的分子,充分模拟细胞的表面特性,逃避机体的免疫识别机制。
具体实施方式
实施例1:
1)制备细胞分泌组溶液:106个脂肪间充质干细胞传代培养于T75细胞培养瓶中,培养48h,后换成基础培养基,培养24h收集细胞上清,获得原始浓度细胞分泌组。经冷冻干燥获得终蛋白浓度10mg/mL的细胞分泌组悬液;
2)制备脂质分子膜:1,2-二棕榈酰-锡-甘油基-3-磷酸胆碱(DPPC)、1,2-二硬脂酰-锡-甘油基-3-磷酸胆碱(DSPC)、1,2-二油酰-锡-甘油基-3-磷酸胆碱(DOPC)和胆固醇(Avanti Polar Lipids)分别以5∶1∶3∶1的摩尔比溶解在丙酮和氯仿(3∶1 v/v)的混合溶剂中,溶液通过旋转蒸发器蒸发形成薄膜;
3)制备包裹分泌组的纳米脂质体颗粒:用细胞分泌组悬液(1∶300蛋白与脂质的质量比例)对步骤2)中形成的膜进行水化,45℃条件下涡旋3min,组装成脂质体;用脂质体挤出器(Mini Extruder)将脂质体悬浮液在45℃条件下通过400nm孔径的醋酸纤维素膜挤压20次,再通过200nm孔径的醋酸纤维素膜挤压20次;收集挤膜完成的混悬液,于4℃,120000g离心1h,弃上清,所得沉淀用400μL PBS重悬得到包裹有细胞分泌组的纳米脂质体。
实施例2:
1)制备细胞分泌组溶液:106个脐带间充质干细胞传代培养于T75细胞培养瓶中,在正常培养基中贴壁6h后换成炎症诱导培养基(20ng/mL INFγ、10ng/mL TNFα),之后再换成基础培养基,培养24h,收集细胞上清,获得原始浓度细胞分泌组。经冷冻干燥获得终蛋白浓度10mg/mL的细胞分泌组悬液;
2)制备脂质分子膜:1,2-二棕榈酰-锡-甘油基-3-磷酸胆碱(DPPC)、1,2-二硬脂酰-锡-甘油基-3-磷酸胆碱(DSPC)、1,2-二油酰-锡-甘油基-3-磷酸胆碱(DOPC)和胆固醇(Avanti Polar Lipids)分别以5∶1∶3∶1的摩尔比溶解在丙酮和氯仿(3∶1 v/v)的混合溶剂中,溶液通过旋转蒸发器蒸发形成薄膜;
3)制备包裹分泌组的纳米脂质体颗粒:用细胞分泌组悬液(1∶300蛋白与脂质的质量比例)对步骤2)中形成的膜进行水化,45℃条件下涡旋3min,组装成脂质体;用脂质体挤出器(Mini Extruder)将脂质体悬浮液在45℃条件下通过400nm孔径的醋酸纤维素膜挤压20次,再通过200nm孔径的醋酸纤维素膜挤压20次;收集挤膜完成的混悬液,于4℃,120000g离心1h,弃上清,所得沉淀用400μL PBS重悬得到包裹有细胞分泌组的纳米脂质体。
实施例3:
1)制备细胞分泌组溶液:106个巨噬细胞细胞传代培养于T75细胞培养瓶中,培养基中加入300nM PMA诱导24h后更换含20ng/mL IL-6,20ng/mLIL-13的诱导培养基培养48h,诱导M2型巨噬细胞出现,然后换成基础培养基,培养24h,收集细胞上清,获得原始浓度细胞分泌组。经冷冻干燥获得终蛋白浓度10mg/mL的细胞分泌组悬液;
2)制备脂质分子膜:1,2-二棕榈酰-锡-甘油基-3-磷酸胆碱(DPPC)、1,2-二硬脂酰-锡-甘油基-3-磷酸胆碱(DSPC)、1,2-二油酰-锡-甘油基-3-磷酸胆碱(DOPC)和胆固醇(Avanti Polar Lipids)分别以5∶1∶3∶1的摩尔比溶解在丙酮和氯仿(3∶1 v/v)的混合溶剂中,溶液通过旋转蒸发器蒸发形成薄膜;
3)制备包裹分泌组的纳米脂质体颗粒:用细胞分泌组悬液(1∶300蛋白与脂质的质量比例)对步骤2)中形成的膜进行水化,45℃条件下涡旋3min,组装成脂质体;用脂质体挤出器(Mini Extruder)将脂质体悬浮液在45℃条件下通过400nm孔径的醋酸纤维素膜挤压20次,再通过200nm孔径的醋酸纤维素膜挤压20次;收集挤膜完成的混悬液,于4℃,120000g离心1h,弃上清,所得沉淀用400μL PBS重悬得到包裹有细胞分泌组的纳米脂质体。
实施例4:
1)制备细胞分泌组溶液:106个骨髓间充质干细胞传代培养于T75细胞培养瓶中,培养48h,后换成基础培养基,培养24h收集细胞上清,获得原始浓度细胞分泌组。经冷冻干燥获得终蛋白浓度10mg/mL的细胞分泌组悬液;
2)制备脂质分子膜:1,2-二棕榈酰-锡-甘油基-3-磷酸胆碱(DPPC)、1,2-二硬脂酰-锡-甘油基-3-磷酸胆碱(DSPC)、1,2-二油酰-锡-甘油基-3-磷酸胆碱(DOPC)和胆固醇(Avanti Polar Lipids)分别以5∶1∶3∶1的摩尔比溶解在丙酮和氯仿(3∶1 v/v)的混合溶剂中,溶液通过旋转蒸发器蒸发形成薄膜;
3)制备包裹分泌组的纳米脂质体颗粒:用细胞分泌组悬液(1∶300蛋白与脂质的质量比例)对步骤2)中形成的膜进行水化,45℃条件下涡旋3min,组装成脂质体;用脂质体挤出器(Mini Extruder)将脂质体悬浮液在45℃条件下通过500nm孔径的醋酸纤维素膜挤压20次,再通过300nm孔径的醋酸纤维素膜挤压30次;收集挤膜完成的混悬液,于4℃,120000g离心1h,弃上清,所得沉淀用400μL PBS重悬得到包裹有细胞分泌组的纳米脂质体。
实施例5:
取200μL细胞分泌组纳米脂质体和等量细胞分泌组重悬液分别置于-20℃保存1w,2w,4w,在各个时间点取样品进行BCA定量蛋白分析。具体操作为:按BCA试剂:Cu试剂体积比为50∶1配置BCA工作液,准备0.5mg/mL BSA标准品,并按标准品0、2、4、6、8、10、12、16、20μL加到96孔板标准品孔中,加PBS补足至20μL,加20μL样品到96孔板样品孔中,各孔加入200μLBCA工作液,37℃反应25min。用酶标仪测定A562nm读值,根据标准曲线计算样品蛋白浓度。
实施例6:
取200μL分泌组脂质体纳米颗粒或分泌组与空白脂质体混合物加入到3.8mL PBS中置于垂直混悬仪上,37℃条件下检测VEGF释放效率,分别于4h、12h、24h、2d、4d、7d取反应液200μL补充PBS 200μL。反应结束后,用VEGF ELISA试剂盒检测反应液中VEGF浓度。结果如表1显示,VEGF经细胞膜纳米囊泡包裹后具有缓释作用,释放作用能够持续7d。
实施例7:
20mg/kg顺铂诱导小鼠急性肾损伤,诱导24h后取200μL细胞分泌组纳米脂质体(包裹有FITC)或等量细胞分泌组重悬液(混合有FITC)经尾静脉注入小鼠体内,注射6h后过量麻醉处死小鼠分别取小鼠的心脏、肝脏、肺脏、脾脏、肾脏,并用小动物活体成像仪检测各个器官的荧光信号分析纳米脂质体的靶向能力。注射4d后取小鼠血液检测血清尿素氮和血清肌酐含量,并取肾脏进行冷冻切片和Prohibitin免疫荧光染色,以观察肾小管上皮细胞线粒体完整性。
结果:经纳米脂质体包裹后细胞分泌组能更有效的聚集在受损组织内部,靶向效率提高30%;经纳米脂质体包裹的细胞分泌组的治疗效果更优,血清尿素氮和肌酐水平几乎回落至正常水平,线粒体结构更完整,说明肾小管上皮细胞功能得到了改善。以上结果证明本发明制备的脂质体包裹的细胞分泌组能靶向运输细胞活性成分到特定部分发挥治疗效果。
表1.脂质体包裹分泌组与分泌组悬液性质比较
Claims (3)
1.包裹细胞分泌组的纳米颗粒是采用纳米挤出技术制备的包裹有细胞分泌组的脂质体颗粒;细胞分泌组是指间充质干细胞经过不同功能化方式获得的细胞分泌组;细胞类型包括脂肪间充质干细胞、骨髓间充质干细胞、脐带间充质干细胞、宫血间充质干细胞、胎盘间充质干细胞、巨噬细胞中的一种或几种的混合物。
2.纳米细胞膜载药制备方法,包括以下步骤:
1)制备细胞分泌组溶液:106个脂肪间充质干细胞传代培养于T75细胞培养瓶中,培养48h,后换成基础培养基,培养24h收集细胞上清,获得原始浓度细胞分泌组,经冷冻干燥获得终蛋白浓度10mg/mL的细胞分泌组悬液;
2)制备脂质分子膜:1,2-二棕榈酰-锡-甘油基-3-磷酸胆碱(DPPC)、1,2-二硬脂酰-锡-甘油基-3-磷酸胆碱(DSPC)、1,2-二油酰-锡-甘油基-3-磷酸胆碱(DOPC)和胆固醇(AvantiPolar Lipids)分别以5∶1∶3∶1的摩尔比溶解在丙酮和氯仿(3∶1 v/v)的混合溶剂中,溶液通过旋转蒸发器蒸发形成薄膜;
3.包裹细胞分泌组的纳米脂质体颗粒能够缓释间充质干细胞的有效治疗成分,优选用于靶向、长效的作用。
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