CN115252581A - 癌细胞膜修饰的仿生纳米粒子及其制备和应用 - Google Patents
癌细胞膜修饰的仿生纳米粒子及其制备和应用 Download PDFInfo
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Abstract
本发明公开癌细胞膜修饰的仿生纳米粒子及其制备和应用。选取两亲性聚合物F127包裹光热剂吲哚菁绿(ICG)和免疫抑制剂NLG919制成生物相容性的纳米颗粒(FIN)。再通过共挤出的方法将癌细胞膜包裹FIN制备成仿生纳米复合物(CFNI)。本发明采用F127包裹ICG和NLG919的胶束内核FIN,促进免疫抑制剂NLG919与疏水吲哚菁绿(ICG)发挥协同作用,可以在近红外激光照射下,产生热量杀伤癌细胞诱导癌细胞免疫原性死亡,释放出损伤相关分子模式,从而增强NLG919介导的免疫疗法,实现抗肿瘤的效果。
Description
技术领域
本发明属于药物制剂领域,涉及一种癌细胞膜修饰的仿生纳米粒子及其制备和应用。
背景技术
恶性肿瘤作为现代医学领域的一大难题,造成了仅次于心血管疾病的极高死亡率,对全世界人民造成巨大的威胁。目前,传统的肿瘤治疗方法主要有手术切除、化学疗法以及放射疗法。这些疗法对早期肿瘤均显示出积极的治疗效果,但对晚期转移的肿瘤疗效十分有限。近年来,利用免疫系统对抗和清除肿瘤细胞的肿瘤免疫治疗已成为令人兴奋的医学突破,为肿瘤治疗带来新的希望。免疫疗法是一种刺激机体免疫系统,激活自身免疫细胞,特异性识别和消灭恶性肿瘤细胞的治疗方法,主要包括嵌合抗原受体T(CAR-T)细胞疗法、免疫检查点阻断疗法和肿瘤疫苗疗法等手段,可以通过增强免疫反应或逆转免疫抑制来抑制肿瘤的生长和转移。但是,仅依靠单一的免疫检查点阻断难以产生显著的抗肿瘤免疫,通常将免疫治疗与其他传统治疗手段联用可以有效杀伤肿瘤细胞,增强肿瘤的免疫原性,提高肿瘤的综合治疗效果。光热疗法(Photothermaltherapy,PTT)是把特定波长的激光照射肿瘤部位,光热剂将光能转化为热量来对实体瘤进行局部热消融的一种新手段。具有无创、时空可控性、对正常组织毒性低等优点。许多研究证明了PTT结合免疫疗法具有惊人的抗癌作用。
2011年,Che-MingJHu使用了一种自上而下的将纳米粒子功能化仿生方法,首先通过低渗处理得到天然红细胞膜(RBC),并挤压涂覆在带负电荷的聚合物纳米颗粒(NPs)上,制成可生物降解的聚合物纳米粒子。用这种方法能将RBC表面的膜脂和相关的膜蛋白完整地保留,使其在小鼠体内有一个更好地循环半衰期。现在细胞膜涂层技术已经扩展到包括有核细胞膜包裹的颗粒,细胞膜可以通过蔗糖梯度或差速离心法从核和线粒体成分中分离出来,这种方法对细胞膜的污染非常小。再使用共挤压法、超声法和微流控电穿孔法将细胞膜涂覆在纳米粒子表面。细胞膜修饰策略可以使得NPs具有高度可控的生物学功能,提高NPs的肿瘤靶向能力,而不同的细胞膜来源可赋予NPs多样的肿瘤治疗作用。
发明内容
本发明的第一个目的是针对现有技术的不足,提出一种癌细胞膜包裹的仿生纳米粒子的合成工艺。
步骤S1:制备疏水吲哚菁绿(ICG):
将吲哚菁绿ICG和碘化四丁胺分散在适量二氯甲烷中,室温下搅拌至溶液由浑浊变成澄清,得到疏水吲哚菁绿(ICG)。
作为优选,所述吲哚菁绿ICG和碘化四丁胺的质量比为1:5~10;
步骤S2:制备纳米颗粒(FIN):
冰浴下,两亲性聚合物F127在外力超声的作用下自组装形成胶束,进而将疏水吲哚菁绿ICG和免疫抑制剂(NLG919)包裹,从而得到F127包裹ICG和NLG919的胶束内核FIN;其中疏水吲哚菁绿ICG和免疫抑制剂(NLG919)的质量比为1:1;
作为优选,所述疏水吲哚菁绿ICG、免疫抑制剂NLG919、两亲性聚合物F127的质量比为1:1:5~10,更为优选1:1:7.5;
步骤S3:FIN纯化后与癌细胞膜共挤出得到仿生纳米复合物(CFIN)。
作为优选,所述癌细胞与FIN的质量比为1:(8~15)。
作为优选,所述免疫抑制剂(NLG919)的结构式如下:
作为优选,所述的纯化具体为将FIN溶液移入MWCO8000-10000Da的透析袋中,放置于去离子水中透析24h,除去未包载的游离药物、转疏水所产生的盐以及DMSO溶剂,冷冻干燥。
作为优选,所述癌细胞膜采用4T1CM癌细胞膜,是通过4T1细胞离心收集细胞,留细胞沉淀。然后加入低渗裂解缓冲液重悬。冰浴孵育10min后,置于液氮和37℃反复冻融。将混合物在4℃下以700g离心,收集上清液,再14000g,4℃离心30分钟,弃上清。加入少量含有PMSF的PBS,重悬。
本发明的第二个目的是提供一种癌细胞膜包裹的仿生纳米粒子。
本发明的第三个目的是提供一种癌细胞膜包裹的仿生纳米粒子在制备肿瘤的免疫协同光热治疗制剂上的应用。
本发明的有益效果是:
本发明采用F127包裹ICG和NLG919的胶束内核FIN,促进免疫抑制剂NLG919与疏水吲哚菁绿(ICG)发挥协同作用,可以在近红外激光照射下,产生热量杀伤癌细胞诱导癌细胞免疫原性死亡,释放出损伤相关分子模式,从而增强NLG919介导的免疫疗法,实现抗肿瘤的效果。将CFIN应用在生物体上,通过细胞摄取、细胞毒性检测、光热诱导细胞损伤相关分子模式(DAMPs)的分泌(如钙网蛋白、高迁移率组蛋白和三磷酸腺苷)和激活树突细胞的成熟等实验验证光热协同免疫治疗的效果以及其在小鼠体内抗肿瘤效果。
附图说明
图1为本发明癌细胞膜包裹的仿生纳米颗粒准备图(这里以4T1癌细胞膜为例);
图2为实施例2中CFIN的DLS图;
图3为实施例2中CFIN的TEM图;
图4为实施例2中CFIN的zeta电位图;
图5为实施例2中CFIN的紫外吸收谱图;
图6为实施例3中CFIN的细胞摄取激光共聚焦成像图;
图7为实施例3中CFIN的同源靶向流式细胞术图;
图8为实施例3中CFIN暗毒性和光毒性的MTT统计图;
图9为实施例3中CFIN诱导细胞表达钙网蛋白(CRT)的荧光成像图;
图10为实施例3中CFIN诱导细胞外排高迁移率组蛋白(HMGB-1)的荧光成像图;
图11为实施例3中CFIN诱导细胞释放三磷酸腺苷(ATP)的统计图;
图12为实施例3中CFIN诱导树突细胞(DCs)成熟的流式细胞术图;
图13为实施例3中CFIN在小鼠体内治疗18天内原发性肿瘤体积变化趋势图。
具体实施方式
如前所述,鉴于现有技术的不足,本案发明人经长期研究和大量实践,提出了本发明的技术方案,其主要是依据至少包括:
本发明采用F127包裹ICG和NLG919的胶束内核FIN,促进免疫抑制剂NLG919与疏水吲哚菁绿(ICG)发挥协同作用,可以在近红外激光照射下,产生热量杀伤癌细胞诱导癌细胞免疫原性死亡,释放出损伤相关分子模式,从而增强NLG919介导的免疫疗法,实现抗肿瘤的效果。将CFIN应用在生物体上,通过细胞摄取、细胞毒性检测、光热诱导细胞损伤相关分子模式(DAMPs)的分泌(如钙网蛋白、高迁移率组蛋白和三磷酸腺苷)和激活树突细胞的成熟等实验验证光热协同免疫治疗的效果以及其在小鼠体内抗肿瘤效果。
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。
第一方面,提供一种癌细胞膜包裹的仿生纳米粒子的合成工艺,具体是:
步骤S1:制备疏水吲哚菁绿(ICG):
将吲哚菁绿ICG和碘化四丁胺分散在适量二氯甲烷中,室温下搅拌至溶液由浑浊变成澄清,得到疏水吲哚菁绿(ICG)。
作为优选,所述吲哚菁绿ICG和碘化四丁胺的质量比为1:5~10;
步骤S2:制备纳米颗粒(FIN):
冰浴下,两亲性聚合物F127在外力超声的作用下自组装形成胶束,进而将疏水吲哚菁绿ICG和免疫抑制剂(NLG919)包裹,从而得到F127包裹ICG和NLG919的胶束内核FIN;其中疏水吲哚菁绿ICG和免疫抑制剂(NLG919)的质量比为1:1;
作为优选,所述疏水吲哚菁绿ICG、免疫抑制剂NLG919、两亲性聚合物F127的质量比为1:1:5~10,更为优选1:1:7.5;
步骤S3:FIN纯化后与癌细胞膜共挤出得到仿生纳米复合物(CFIN)。
作为优选,所述癌细胞与FIN的质量比为1:(8~15)。
作为优选,所述的纯化具体为将FIN溶液移入MWCO8000-10000Da的透析袋中,放置于去离子水中透析24h,除去未包载的游离药物、转疏水所产生的盐以及DMSO溶剂,冷冻干燥。
作为优选,所述癌细胞膜采用4T1CM癌细胞膜,是通过4T1细胞离心收集细胞,留细胞沉淀。然后加入低渗裂解缓冲液重悬。冰浴孵育10min后,置于液氮和37℃反复冻融。将混合物在4℃下以700g离心,收集上清液,再14000g,4℃离心30分钟,弃上清。加入少量含有PMSF的PBS,重悬。
第二方面,提供一种癌细胞膜包裹的仿生纳米粒子。
第三方面,提供一种癌细胞膜包裹的仿生纳米粒子在制备肿瘤的免疫协同光热治疗制剂上的应用。
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。
实施例1
步骤1、FIN纳米颗粒的制备:
制备疏水吲哚菁绿(ICG):将20mg(25.8mmol)ICG和100mg(300mmol)碘化四丁胺分散在适量二氯甲烷中,在磁力搅拌器上以600rpm的速度在室温下搅拌48h至溶液由浑浊变成澄清,即转疏水成功。制得的疏水ICG通过旋转蒸发仪完全除去DCM的溶剂。
称取2mg转疏水ICG、2mgNLG919混合溶解于4mLDMSO溶液。称取15mg F127溶解于10mL水溶液中。将F127水溶液置于冰浴中,在26W功率的超声下,将ICG、NLG919混合溶液用1mL的注射器逐滴加入到F127水溶液中,得到均匀分散的胶束分散液。
将得到的胶束分散液移入MWCO8000-10000Da的透析袋中,放置于去离子水中透析24h,除去未包载的游离药物、转疏水所产生的盐以及DMSO溶剂,得到透析后的F127包裹ICG和NLG919的胶束内核FIN,冷冻干燥,称重备用。
步骤2、CFIN仿生纳米颗粒的制备:
4T1细胞,在补充有10%FBS、1%青霉素(50.0IUmL-1)和链霉素(50.0IUmL-1)的DMEM中孵育(温度:37℃,饱和湿度:5%CO2)。4T1细胞铺满培养皿时,去除上清液,PBS轻轻洗涤贴壁4T1细胞,再用细胞刮子将细胞刮下,离心收集细胞,去除上清,留细胞沉淀。用预冷的PBS重悬细胞沉淀,离心5分钟以收集纯沉淀物。然后加入低渗裂解缓冲液(膜蛋白裂解液和蛋白酶抑制剂PMSF)中重悬。冰浴孵育10-15min后,将4T1细胞在液氮和37℃反复冻融三次。将混合物在4℃下以700g离心10分钟,收集上清液,再14000g,4℃离心30分钟,弃上清。收集最终的4T1细胞膜(4T1CM)沉淀,用BCA蛋白含量检测试剂盒测定细胞膜的质量。
然后4T1CM与FIN的质量比为1:(8~15),通过400nm、200nm的聚碳酸酯多孔膜反复多次的机械挤出将细胞膜涂覆在FIN表面,形成细胞膜仿生修饰的纳米粒CFIN。
实施例2
步骤1、CFIN纳米材料粒径及形貌的表征:
实施例1制得的聚合物胶束CFIN分散液稀释至1mg/mL,取2mL聚合物胶束分散液用动态光散射(DLS)测其粒径大小和zeta电位。将测完粒径后的溶液取适量滴加在200目碳膜铜网上,室温下自然风干后,再滴加一滴磷钨酸溶液于铜网上染色10min,吸走铜网表面磷钨酸液体,待进一步晾干后,样品置于透射电镜(TEM)下选区观测纳米颗粒的形貌。
如图2-4所示:FIN的粒径大小约为83nm,CFIN的粒径大小为220nm,TEM中明显观察到CFIN表面2~3nm的细胞膜,CFIN的zeta电位为-23.8mV,接近于4T1CM。
步骤2、CFIN纳米材料载药测定:
称取一定体积CFIN纳米药物溶解于一定体积的去离子水中,用紫外分光光度计测其吸光度。
如图5所示:CFIN同时具有属于ICG的最大吸收峰(780nm)和NLG919的最大吸收峰(263nm),证明两种药物成功负载在CFIN内。
实施例3
测试例1、CFIN的细胞摄取:
4T1细胞,在补充有10%FBS、青霉素(50.0IUmL-1)和链霉素(50.0IUmL-1)的DMEM中培养24h(温度:37℃,饱和湿度:5%CO2)。将细胞接种于8孔小皿中,培养24h。然后将原始培养基替换为DMEM中的游离ICG、FIN或CFIN溶液,其中ICG浓度相同。孵育4h后,PBS洗两次除去游离的材料,4%(w/v)多聚甲醛室温下固定15min。PBS洗两次。Hoechst33342(蓝色)染色10min,PBS洗涤两次后加入新鲜的DMEM,并通过CLSM观察。
如图6所示:细胞内观察到ICG的红色荧光,证明FIN,CFIN均可以被细胞摄取且CFIN在细胞中的积累更多。
测试例2、CFIN的同源靶向性:
B16-F10、U87和4T1细胞在24孔板中分别培养24小时。然后将培养基替换为CFIN。孵育4h后,PBS洗三次除去游离的材料,最后使用FACS定量分析细胞摄取。
如图7所示:CFIN在4T1细胞中的荧光强度最强,证明CFIN具有同源靶向地能力。
测试例3、CFIN的细胞毒性检测
将4T1细胞接种于96孔板上,培养24h。将培养基更换为含有游离ICG、NLG、FIN、CFIN(ICG浓度为0、2.5、5、7.5、10μg/mL)的新鲜培养基。孵育4小时后,然后用或不用808nmNIR激光照射1分钟。将细胞进一步孵育18小时,并用MTT溶液替换培养基并再孵育4小时。随后,去除培养基并在每孔中加入DMSO裂解甲臢晶体15min。待甲臢晶体完全溶解后,置于酶标仪上测570nm处的吸收值(OD)。按下式计算细胞存活率,并绘制细胞生长抑制曲线。
如图8所示:CFIN在没有激光照射的时候具有良好地生物相容性,在808nm的激光照射下显示出优异的光热特性,有效杀死癌细胞。
测试例4、CFIN诱导细胞表面钙网蛋白(CRT)的表达
将4T1细胞在24孔板中培养24小时。将ICG、NLG、FIN、CFIN加入4T1细胞并孵育4小时。然后用或不用808nm激光照射。接下来,收获4T细胞,用冷PBS洗涤3次后,在多聚甲醛中固定5分钟。在冷PBS中洗涤,将细胞与CRT一抗一起孵育。30分钟后再次洗涤细胞,并与AlexaFluor488偶联的单克隆二抗孵育30分钟。最后,细胞用DAPI染色并通过荧光显微镜观察。
如图9所示:CFIN+Laser(激光照射)处理的细胞中观察到明显地绿色荧光,证明在激光的照射下CFIN能诱导癌细胞表达CRT。
测试例5、CFIN诱导细胞高迁移率组蛋白(HMGB-1)的外排
将4T1细胞种在置于24孔板中的盖玻片上,并孵育24小时。将ICG、NLG、FIN、CFIN加入4T1细胞并孵育4小时。然后用或不用808nm激光照射。接下来,细胞内HMGB-1用抗体染色。细胞用多聚甲醛固定20分钟,然后用TritonX-100透化。通过用PBS中的5%胎牛血清预温育30分钟来封闭非特异性结合位点,然后与HMGB-1一抗温育1小时,然后与AlexaFluor488偶联的二抗温育30分钟,PBS洗涤。最后,细胞用DAPI染色并通过荧光显微镜观察。
如图10所示:CFIN+Laser处理的细胞质中观察到明显地绿色荧光,证明在激光的照射下CFIN能诱导癌细胞将细胞核上的HMGB-1外排至细胞质中。
测试例6、CFIN诱导细胞三磷酸腺苷(ATP)的释放
将4T1细胞接种于24孔板中,并孵育24小时。将ICG、NLG、FIN、CFIN加入4T1并孵育4小时。然后用或不用808nm激光照射并孵育4小时。使用ATP生物发光测定试剂盒通过多功能酶标仪,测量从处理细胞分泌到培养基中细胞外的ATP的含量。
如图11所示:CFIN+Laser组中ATP的释放量最高,证明在激光的照射下CFIN能释放出ATP。
测试例7、CFIN诱导树突细胞(DCs)的成熟
将细胞用ICG、NLG、FIN、CFIN预处理4小时,并用或不用808nm激光照射。然后将BMDCs与上述4T1细胞上清液共孵育24小时。最后收获BMDCs并用抗CD11c-FITC、抗CD86-PE、抗CD80-APC染色,通过FACS分析成熟的DC。
如图12所示:CFIN+Laser组处理的细胞诱导DCs的成熟率最高。
测试例8、CFIN在小鼠体内的抗肿瘤疗效
给Balb/c小鼠皮下植入4T1癌细胞,七天后开始给药,每隔一天给药一次,总共给药6次。在给药4h后每只小鼠的原发肿瘤用808nm激光照射10分钟。从给药开始每隔两天测量荷瘤小鼠肿瘤的最大径及最小径记录肿瘤大小。
如图13所示:在激光照射下,CFIN治疗的小鼠肿瘤生长受到了明显的抑制。
Claims (10)
1.一种癌细胞膜包裹的仿生纳米粒子的合成工艺,其特征在于包括以下步骤:
步骤S1:制备疏水吲哚菁绿ICG:
将吲哚菁绿ICG和碘化四丁胺分散在适量二氯甲烷中,室温下搅拌至溶液由浑浊变成澄清,得到疏水吲哚菁绿ICG;
步骤S2:制备纳米颗粒FIN:
冰浴下,两亲性聚合物F127在外力超声的作用下自组装形成胶束,进而将疏水吲哚菁绿ICG和免疫抑制剂NLG919包裹,从而得到F127包裹ICG和NLG919的胶束内核FIN;其中疏水吲哚菁绿ICG和免疫抑制剂NLG919的质量比为1:1;
步骤S3:FIN纯化后与癌细胞膜共挤出得到仿生纳米复合物CFIN。
2.根据权利要求1所述方法,其特征在于步骤S1所述吲哚菁绿ICG和碘化四丁胺的质量比为1:5~10。
3.根据权利要求1所述方法,其特征在于步骤S2所述疏水吲哚菁绿ICG、免疫抑制剂NLG919、两亲性聚合物F127的质量比为1:1:5~10。
4.根据权利要求3所述方法,其特征在于步骤S2所述疏水吲哚菁绿ICG、免疫抑制剂NLG919、两亲性聚合物F127的质量比为1:1:7.5。
5.根据权利要求1所述方法,其特征在于步骤S3所述癌细胞与FIN的质量比为1:(8~15)。
7.根据权利要求1所述方法,其特征在于步骤S3所述的纯化具体为将FIN溶液移入MWCO8000-10000Da的透析袋中,放置于去离子水中透析24h,除去未包载的游离药物、转疏水所产生的盐以及DMSO溶剂,冷冻干燥。
8.根据权利要求1所述方法,其特征在于所述癌细胞膜采用4T1 CM癌细胞膜,是通过4T1细胞离心收集细胞,留细胞沉淀;然后加入低渗裂解缓冲液重悬;冰浴孵育10min后,置于液氮和37℃反复冻融;将混合物在4℃下以700g离心,收集上清液,再14000g,4℃离心30分钟,弃上清;加入少量含有PMSF的PBS,重悬。
9.一种癌细胞膜包裹的仿生纳米粒子,采用权利要求1-8任一项所述方法制备。
10.权利要求9所述一种癌细胞膜包裹的仿生纳米粒子在制备肿瘤的免疫协同光热治疗制剂上的应用。
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