CN113599368A - 一种细胞膜拮抗联合纳米酶的仿生载药纳米系统、制备方法和用途 - Google Patents

一种细胞膜拮抗联合纳米酶的仿生载药纳米系统、制备方法和用途 Download PDF

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CN113599368A
CN113599368A CN202110847434.5A CN202110847434A CN113599368A CN 113599368 A CN113599368 A CN 113599368A CN 202110847434 A CN202110847434 A CN 202110847434A CN 113599368 A CN113599368 A CN 113599368A
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张宇
孔非
马明
顾宁
王建国
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Xuzhou Huaihai Life Science Industry Research Institute Co ltd
Southeast University
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Southeast University
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Abstract

本发明公开了一种细胞膜拮抗联合纳米酶的仿生载药纳米系统、制备方法和用途，该系统包括载化疗药物的细胞膜的外壳和纳米酶修饰的负载携氧体的高分子聚合物纳米微球的内核。该仿生纳米载体保持了细胞膜蛋白的生物活性，提高纳米粒子躲避免疫清除能力和生物相容性，并延长其血液循环时间，改善其体内生物分布。载药纳米微球形貌均匀，具有较长的血液循环时间，能够发生级联的催化反应产生大量的活性氧，杀伤白血病细胞，并可以有效地抑制白血病的复发与转移，为协同治疗白血病提供新的策略。该系统是结合纳米酶化学动力治疗与细胞膜的仿生治疗及药物化疗，可实现白血病骨髓靶向治疗，并有望解决其转移、复发、耐药等问题。

Description

一种细胞膜拮抗联合纳米酶的仿生载药纳米系统、制备方法 和用途
技术领域
本发明涉及药物制剂及其制备方法，特别涉及一种细胞膜拮抗联合纳米酶的仿生载药纳米系统、制备方法和用途。
背景技术
目前，许多纳米粒子作为药物递送系统已被开发研究，其中一些载药纳米系统已经被批准应用于各种癌症的诊断与治疗。白血病患者经化疗后，由于骨髓腔内的白血病细胞没有被药物完全清除，仍旧残留在患者体内，导致病情复发。基质细胞分泌的基质细胞衍生因子1(CXCL12，亦称为SDF-1)可以激活白血病细胞膜表面过表达的特异性受体CXCR4，从而促进白血病细胞的增殖和向内脏器官的迁移、浸润。CXCR4/CXCL12的相互作用也可以招募白血病细胞归巢至骨髓并获得耐药信号，为白血病的复发和耐药埋下安全隐患。拮抗CXCR4/CXCL12生物轴不仅可以阻断白血病细胞与基质细胞之间的相互作用，而且有效地抑制白血病细胞向CXCL12的迁移、粘附，因此应用CXCR4抑制剂可以有效地提高白血病的治疗效果。白血病的复发和耐药仍旧是现在有待攻克的医学难题，因此迫切需要开发能够有效清除骨髓内白血病细胞并可以避免副作用的新治疗系统。
细胞膜仿生技术是一种仿生复制细胞的方法，将天然细胞膜特性与人工内芯材料特性结合起来，从而大大提高生物相容性，同时在体内实现较长循环和靶向药物递送。细胞膜作为载体已广泛应用于各种疾病的诊断和治疗，可以实现有效的肿瘤治疗、诊断成像、免疫调节。细胞膜仿生载药系统可提高化疗药物在体内的生物相容性和特异性靶向性，已经被证实是非常理想的肿瘤治疗方案。
纳米酶是具有优异的酶催化活性的纳米材料或纳米复合材料，极大促进了纳米材料在各领域的应用，是酶工程领域的重大突破。与天然酶相比，纳米酶具有成本低、稳定性高、易于生产、催化活性可控和循环利用等诸多优点。纳米酶具有多酶催化活性以及双向调控细胞内活性氧的功能，还具有丰富的光、电、磁、热以及载药、靶向、成像、治疗等多功能。纳米酶的独特性质使其能够代替天然酶，被广泛应用于环境保护、疾病诊断与治疗、食品安全和生物传感等领域，尤其在癌症的治疗中起关键作用。化学动力治疗(ChemodynamicTherapy，CDT)是通过化学反应在瘤内原位产生活性氧(ROS)，如羟基自由基，导致不可逆的线粒体破坏、DNA链断裂以及蛋白和膜的氧化，从而诱导细胞死亡。多数纳米酶具有氧化还原活性，能够在温和的生理条件下催化细胞内的一系列生化反应，从而在没有任何外部刺激的情况下产生活性氧，这种纳米酶催化导致的促氧化作用已经被广泛应用于肿瘤治疗研究。
发明内容
发明目的：本发明目的是提供具有较好生物相容性、生物活性等功能的细胞膜拮抗联合纳米酶的仿生载药纳米系统。
本发明李另一目的是提供所述细胞膜拮抗联合纳米酶的仿生载药纳米系统的制备方法及用途。
技术方案：本发明提供一种细胞膜拮抗联合纳米酶的仿生载药纳米系统，包括载化疗药物的细胞膜的外壳和纳米酶修饰的负载携氧体的高分子聚合物纳米微球的内核。
权利要求1所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统，其特征在于：所述负载携氧体的高分子聚合物纳米微球粒径为50～150nm，纳米酶的粒径为1～10nm。
权利要求1所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统的制备方法，包括如下步骤：
(1)制备负载携氧体的高分子聚合物纳米微球；
(2)制备聚乙二醇修饰的高分子聚合物纳米微球；
(3)制备超小纳米酶修饰高分子聚合物纳米微球；
(4)制备细胞膜；
(5)制备细胞膜包覆的高分子聚合物纳米微球。
进一步地，所述步骤(1)制备方法：将携氧体、高分子共聚物超声溶解于有机试剂中，并加入到乳化剂水溶液中，冰浴并超声破碎，搅拌，离心洗涤收集沉淀获得负载携氧体的高分子聚合物纳米微球；
所述步骤(2)制备方法：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、N-羟基琥珀酰亚胺(NHS)混合并溶解于含有负载携氧体的高分子聚合物纳米微球的水溶液中，置于恒温摇床活化微球表面的残留羧基，然后加入聚乙二醇，再次置于恒温摇床反应，聚乙二醇通过酰胺键偶联到高分子聚合物纳米微球表面；
所述步骤(3)制备方法：聚乙二醇修饰的高分子聚合物纳米微球与阳离子溶解于超纯水中，搅拌，利用高分子聚合物纳米微球外端暴露的巯基吸附阳离子，加入还原剂在高分子聚合物纳米微球表面原位还原阳离子形成超小纳米颗粒，再加入聚乙二醇进一步修饰超小纳米颗粒，除去游离的聚乙二醇，制得超小纳米酶修饰的高分子聚合物纳米微球；
所述步骤(5)制备方法：化疗药物溶解于有机试剂中，逐滴加入到含有细胞膜与超小纳米酶修饰的高分子聚合物纳米微球的混合液中，采用薄膜挤出法制备细胞膜包覆高分子聚合物纳米微球。
进一步地，所述高分子共聚物为聚乳酸-羟基乙酸、聚乳酸-乙醇酸、聚乳酸、白蛋白、聚谷氨酸中的一种或几种混合。
进一步地，所述乳化剂为聚乙烯醇、聚丙烯酸、聚氧乙烯醚中的一种或几种混合；携氧体为全氟溴辛烷、全氟溴庚烷、全氟溴己烷中的一种或几种混合；有机试剂为二氯甲烷或三氯甲烷。
进一步地，所述化疗药物为长春新碱、长春地辛、柔红霉素、去甲氧柔红霉素、阿霉素、紫杉醇、多西紫杉醇、米托蒽醌中的一种或几种。
进一步地，所述阳离子为Pt、Au或Pd阳离子。
进一步地，所述还原剂为硼氢化钠、柠檬酸钠或L-抗坏血酸。
进一步地，所述步骤(3)中超声破碎时间为2～5s，超声间隔时间为2～5s，功率为100～250W，超声次数为60～100；机械搅拌时间为2～5h，搅拌速度为300～500rpm。所述的恒温摇床温度为25～30℃，转速为100～150r/min，活化时间为20～30min，偶联时间为2～4h。所述的超滤离心管分子量为30～100KDa，离心速度为4000～5000rpm，离心时间为5～8min，离心次数为3～5次。所用聚乙二醇的分子量为2000、3500或者5000。所述的细胞膜为骨髓基质细胞、骨髓造血干细胞或者骨髓间充质干细胞；液氮冷冻时间为8～10s，反复冻融的次数至少为6～12次；收集细胞膜首先1500～3000rpm低速离心5～10min，取上清，其次以12000～14000rpm高速离心5～10min，弃上清，取沉淀；高渗蔗糖溶液浓度为20％～40％。利用Avanti挤出机，所用的聚碳酸酯多孔膜分子量为200～600nm，至少对混合液挤压8～12次；化疗药物为长春新碱、长春地辛、柔红霉素、去甲氧柔红霉素、阿霉素、紫杉醇、多西紫杉醇、米托蒽醌中的一种或几种。所述的仿生载药纳米微球具有核壳机构，形貌均匀，其水动力尺寸在60～200nm之间，表面电位为-10～-40mV之间。
本方法首先采用双乳剂溶剂挥发法制备包裹携氧体的高分子聚合物纳米微球作为供氧内核；其次聚乙二醇修饰高分子聚合物纳米微球；然后利用高分子聚合物纳米微球表面末端基团吸附阳离子并进行原位还原形成超小纳米酶，进一步用聚乙二醇修饰形成的纳米酶；最后采用薄膜挤出法，在纳米酶修饰的高分子聚合物纳米微球表面包覆细胞膜，并采用吸附法在细胞膜双层脂质结构内负载化疗药物，制备出细胞膜联合纳米酶的仿生载药纳米系统。所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统在制备治疗白血病药物中的用途。细胞膜仿生纳米微球发生级联的催化反应产生大量的活性氧，杀伤白血病细胞，并可以有效地抑制白血病的复发与转移。本发明仿生载药纳米酶系统通过主动靶向和骨髓归巢解决体内骨髓中白血病细胞的残留问题，同时阻断CXCR4/CXCL12生物轴，使仿生载药纳米酶系统精准靶向白血病细胞，级联催化产生活性氧来有效杀伤白血病细胞，同时抑制白血病细胞浸润和转移。
有益效果：与现有技术相比，具有如下优势：
该仿生纳米载体保持了细胞膜蛋白的生物活性，提高纳米粒子躲避免疫清除能力和生物相容性，并延长其血液循环时间，改善其体内生物分布。该载药纳米系统是结合纳米酶化学动力治疗与细胞膜的仿生治疗及药物化疗，可以实现白血病骨髓靶向治疗，并有望解决其转移、复发、耐药等问题。
附图说明
图1为PFOB@PLGA(a)、PFOB@PLGA@Pt(b)、PFOB@PLGA@Pt@DOX-CM(c)纳米微球的透射电镜图；
图2为PFOB@PLGA@Pt、PFOB@PLGA@Pt@DOX-CM纳米微球的粒径分布图；
图3为PFOB@PLGA@Pt、PFOB@PLGA@Pt@DOX-CM纳米微球的Zeta电位图；
图4为SO@PLGA、PFOB@PLGA、PFOB@PLGA@Pt纳米微球的超声成像图；
图5为PFOB@PLGA、PLGA@Pt、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CM纳米微球的电子自旋共振检测结果；
图6为PFOB@PLGA、PLGA@Pt、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CM纳米微球的过氧化物酶活性动力学曲线；
图7为PFOB@PLGA@Pt@DOX-CM纳米微球的DOX和铂离子的累积释放曲线；
图8为PFOB@PLGA@Pt@DOX-CM纳米微球与细胞共孵育12h后的生物透射电镜图；
图9为DOX、PFOB@PLGA、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CMPFOB@PLGA@Pt@DOX-CM对细胞的毒性研究；
图10为骨髓中DOX、PFOB@PLGA、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CMPFOB@PLGA@Pt@DOX-CM的治疗效果；
图11为脾脏中DOX、PFOB@PLGA、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CMPFOB@PLGA@Pt@DOX-CM的治疗效果；
图12为外周血中DOX、PFOB@PLGA、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CMPFOB@PLGA@Pt@DOX-CM的治疗效果。
具体实施方式
实施例1
本实施例的细胞膜包被的载药仿生纳米酶系统及其制备方法与应用，包括如下步骤：
(1)PFOB@PLGA纳米微球的制备
将50mg聚乳酸-羟基乙酸(PLGA)和2mg全氟溴辛烷(PFOB)超声溶解于2mL二氯甲烷溶液中，并加入到10mL 30％聚乙烯醇(PVA)水溶液中，冰浴并超声破碎(时间为2s，超声间隔时间为3s，功率为120W，超声次数为80)。再转移入50mL三颈瓶内，400rpm机械搅拌4h，以挥发二氯甲烷。8000rpm离心洗涤3次，收集沉淀获得负载PFOB的PLGA纳米微球(PFOB@PLGA)。最后，去离子水离心超滤(超滤管分子量30KDa，离心速度为4500rpm，离心时间为5min，离心次数为3次)除去反应中多余的PLGA、PVA等杂志，得到白色的PFOB@PLGA纳米微球。
(2)PFOB@PLGA@PEG纳米微球的制备
10mg 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、5mg N-羟基琥珀酰亚胺(NHS)混合并溶解于含有50mg PFOB@PLGA纳米微球的水溶液中，置于25℃恒温摇床120r/min活化(20min)微球表面的残留羧基。然后加入20mg聚乙二醇(NH2-PEG2000-SH)，再次置于25℃恒温摇床120r/min反应4h，聚乙二醇通过酰胺键偶联到PFOB@PLGA纳米微球表面。反应结束后，将产物转移入15mL超滤管(超滤管分子量100KDa，离心速度为5000rpm，离心时间为6min)，去离子水反复超滤离心洗涤3次去除游离的聚乙二醇等杂质，最终获得PFOB@PLGA@PEG纳米微球。
(3)PFOB@PLGA@Pt@PEG纳米微球的制备
50mg PFOB@PLGA@PEG纳米微球与20mg H2PtCl4溶解于10mL超纯水中，室温下200rpm机械搅拌12h，利用PFOB@PLGA@PEG微球表面外端暴露的巯基吸附pt4+，然后5500rpm超滤(超滤管分子量30KDa，离心时间为5min)离心3次除去未吸附的pt4+，加入2mg的硼氢化钠在微球表面原位还原pt4+形成超小铂纳米颗粒。再次加入聚乙二醇(COOH-PEG2000-SH)修饰超小铂纳米颗粒，进一步超滤(超滤管分子量30KDa，离心速度为5500rpm，离心时间为5min，超滤离心次数为3次)离心除去游离的聚乙二醇，制得黑色超小PFOB@PLGA@Pt@PEG纳米微球。
(4)小鼠骨髓基质细胞膜的制备
小鼠骨髓基质细胞膜的制备是通过低渗溶胀法和液氮反复冻融法来实现，收集小鼠骨髓基质细胞溶于低浓度的2mM PBS溶液中，分装于1.5mL EP管里，在低渗溶液里，细胞会慢慢涨破，然后每管依次放入液氮冷冻8s，随后室温下融化至液体，再放入液氮里冷冻，这种反复快速冻融会破坏细胞膜的完整性。如此反复冻融8次后，加入1mL 30％高渗蔗糖溶液，使细胞膜漂浮起来，首先2000rpm低速离心5min，取上清，然后再12000rpm高速离心10min，弃上清，小的细胞器和细胞内含物被弃掉，收集细胞膜碎片。在EP管里再加入1mL无菌水，移液枪吹打重悬，并置于低温(-20℃或-80℃)中待用。
(5)PFOB@PLGA@Pt@DOX-CM纳米微球的制备
30mg阿霉素溶解于2mL二甲基亚砜溶液中，逐滴加入到含有16.5mg细胞膜与50mgPFOB@PLGA@Pt@PEG纳米微球的混合液(细胞膜与PFOB@PLGA@Pt@PEG纳米微球的质量比为1∶3)，采用薄膜挤出法，利用Avanti挤出机，在400nm聚碳酸酯多孔膜挤压12次，对混合液进行挤压，然后6500rpm离心3次去除多余的细胞膜或未被包裹的阿霉素，新制备的PFOB@PLGA@Pt@DOX-CM纳米微球置于低温(-20℃或-80℃)保存备用。
实施例2
取少量上述步骤制得的PFOB@PLGA、PFOB@PLGA@Pt和PFOB@PLGA@Pt@CM纳米微球，涂在铜网上，利用透射电镜观察纳米微球形貌和粒径。如图1所示，可以观察到PFOB@PLGA纳米微球呈球状，粒径分布均匀(60～120nm)，无团聚现象，稳定性好，EDS能谱结果表明其主要含有C、N、O、F、Br元素，含有预期的基本元素；从PFOB@PLGA@Pt纳米微球图中可以明显的看到黑色的Pt纳米颗粒簇，EDS能谱结果表明其主要含有C、N、O、S、F、Br、Pt元素；从PFOB@PLGA@Pt@CM纳米微球图中可以明显的看到细胞膜，进一步证实了细胞膜成功包覆PFOB@PLGA@Pt纳米微球。
如图2和3所示，采用马尔文粒度仪分别测定PFOB@PLGA@Pt、PFOB@PLGA@Pt@DOX-CM纳米微球的水动力尺寸和Zeta电位。未包膜PFOB@PLGA@Pt纳米微球的平均粒径约为100nm，包膜PFOB@PLGA@Pt@DOX-CM纳米微球的平均尺寸约为120nm，证明包裹细胞膜之后会增大微球的粒径。PFOB@PLGA@Pt纳米微球的Zeta电位约为-25±5mV，仿生载药纳米粒的电位约为-19±5mV，说明细胞膜己经包被在PFOB@PLGA@Pt纳米微球表面。
实施例3
PLGA@SO、PFOB@PLGA、PFOB@PLGA@Pt纳米微球的超声成像：
将0.2mg/mL PLGA@SO、PFOB@PLGA、PFOB@PLGA@Pt纳米微球水溶液分别注入凝胶体膜内，分别0、5、10分钟采集超声图片，氧气的多少与超声图片的亮度相关。
如图4所示，以PLGA纳米微球负载大豆油(PLGA@SO)作为对照组，PFOB@PLGA纳米微球的超声图像亮度较强，其中PFOB@PLGA@Pt纳米微球的超声图像最强，至少可以维持超声显影效果10分钟，说明PFOB@PLGA@Pt纳米微球具有较强的载氧功能。
实施例4
电子自旋共振(ESR)检测纳米微球形成的·OH：
使用Bruker EMX ESR光谱仪在室温下检测纳米微球形成的·OH。在H2O2条件下，5，5-二甲基-1-吡咯啉-N-氧化物(DMPO)被用来直接捕获短命自由基形成的DMPO/·OH加合物。50mL样品溶液包含1×10-3M H2O2、0.05M DMPO、2×10-3mg/mL的PFOB@PLGA、PLGA@Pt、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CM纳米微球置于玻璃毛细管中并密封，1min后记录光谱特征线。
如图5所示，当PFOB@PLGA纳米微球存在时，DMPO/·OH的ESR特征信号可以忽略不计。相比之下，加入PLGA@Pt、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CM纳米微球之后，ESR谱线特征为1∶2∶2∶1。此外，PFOB@PLGA@Pt的ESR信号强度要强于PLGA@Pt的ESR信号强度。由此可见，PFOB@PLGA@Pt的类过氧化物酶活性的体外机制已被证实，是由PFOB@PLGA@Pt催化分解H2O2生成·OH的结果，并且PFOB促进PFOB@PLGA@Pt产生的·OH比PLGA@Pt产生的·OH高。
实施例5
PFOB@PLGA、PLGA@Pt、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CM纳米微球的酶活性研究：
在H2O2存在下，通过催化3，3′，5，5′-四甲基联苯胺(TMB)底物，在653nm波长处测量PLGA@Pt、PFOB@PLGA、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CM纳米微球催化不同浓度(1～6mM)的H2O2形成蓝色产物的吸光度来研究过氧化物酶的活性。
如图6所示，PFOB@PLGA@Pt纳米微球展现出与天然酶相似的过氧化物酶催化效率。与PLGA@Pt和PFOB@PLGA相比，PFOB@PLGA@Pt纳米微球具有最高的过氧化物酶催化活性。
实施例6
PFOB@PLGA@Pt@DOX-CM纳米微球的DOX、铂离子累积释放行为
取50mg PFOB@PLGA@Pt@DOX-CM纳米微球分散于30mL PBS中，置于分子量为3500的透析袋内，两端用夹子夹紧，将透析袋置于500mL PBS透析液中(PH＝7.4)，在37℃的摇床震荡(100rpm)4天。在规定的时间间隔点(2h、4h、6h、8h、12h、24h、36h、48h、72h、96h、120h)从透析液中取出1mL介质溶液，立即补充等量的透析液，通过紫外分光光度计、电感耦合等离子体质谱分别测量阿霉素、铂离子的累积释放量。
如图7所示，阿霉素缓慢地从PFOB@PLGA@Pt@DOX-CM纳米微球中释放，120h后阿霉素累积释放达到80％，显著增加了阿霉素在体内的循环时间，而铂离子在体内的累积释放量很少，更有利于铂纳米颗粒在体内发挥酶催化活性，说明PFOB@PLGA@Pt@DOX-CM纳米微球具有良好的药物释放性能。
实施例7
PFOB@PLGA@Pt@DOX-CM纳米微球在白血病细胞内的摄取情况
将白血病细胞接种于12孔板(1×106/孔)中，并与PFOB@PLGA@Pt@DOX-CM(Pt浓度为4.8μg/mL)纳米微球在37℃、5％CO2下孵育6h。随后，用PBS彻底清洗细胞，收集细胞固定后用生物透射电镜观察进入细胞内的纳米微球。
如图8所示，白血病细胞可以摄取大量的PFOB@PLGA@Pt@DOX-CM纳米微球到溶酶体内，这有利于发挥纳米微球的促氧化并诱导细胞凋亡能力。
实施例8
PFOB@PLGA@Pt@DOX-CM纳米微球的体外细胞毒性测定
体外细胞毒性实验是采用CCK8试剂盒检测纳米微球对白血病细胞活性的影响。将密度为1×105个/孔的白血病细胞与不同浓度DOX、PFOB@PLGA、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CM PFOB@PLGA@Pt@DOX-CM纳米微球(DOX浓度为0.3，0.6，1.2，2.4μg/mL Pt浓度为0.6，1.2，2.4，4.8μg/mL)在96孔板中孵育12h、24h。孵育结束后，每孔加入10μL CCK-8，置于恒温(37℃，5％C02)培养箱继续孵育4h，然后在酶标仪上于450nm处检测吸光度。进行6次独立实验，计算细胞平均存活率(％)。
如图9所示，随着纳米微球浓度的增加与培养时间的延长，细胞活力明显下降，PFOB@PLGA@Pt@DOX-CM纳米微球在体外能显著地降低白血病细胞活性。
实施例9
PFOB@PLGA@Pt@DOX-CM纳米微球对白血病小鼠的治疗效果
白血病小鼠模型构建成功后，小鼠被随机分为六组(n＝5)。分别尾静脉注射生理盐水、DOX、PLGA@Pt、PFOB@PLGA@Pt、PFOB@PLGA@Pt@CM、PFOB@PLGA@Pt@DOX-CM，注射剂量DOX、铂的浓度分别是1.5mg/kg、3mg/kg，每周治疗两次，共治疗3周，每天记录小鼠的体重。治疗21天结束后，收集小鼠骨髓、脾脏和外周血细胞，通过流式细胞术监测骨髓、脾脏和外周血细胞中白血病细胞的变化来评价纳米微球的治疗效果。
如图10、11、12所示，与生理盐水组相比，PFOB@PLGA@Pt@DOX-CM纳米微球组的骨髓、脾脏和外周血中白血病细胞比例下降最显著。骨髓内白血病细胞的比例大约由70.5％下降至13.2％，脾脏中白血病细胞的比例由52.2％降至3.4％，外周血中白血病细胞比例由58.3％降至2.3％。

Claims (10)

1.一种细胞膜拮抗联合纳米酶的仿生载药纳米系统，其特征在于：包括载化疗药物的细胞膜的外壳和纳米酶修饰的负载携氧体的高分子聚合物纳米微球的内核。
2.根据权利要求1所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统，其特征在于：所述负载携氧体的高分子聚合物纳米微球粒径为50～150nm，纳米酶的粒径为1～10nm。
3.根据权利要求1所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统的制备方法，其特征在于：包括如下步骤：
(1)制备负载携氧体的高分子聚合物纳米微球；
(2)制备聚乙二醇修饰的高分子聚合物纳米微球；
(3)制备超小纳米酶修饰高分子聚合物纳米微球；
(4)制备细胞膜；
(5)制备细胞膜包覆的高分子聚合物纳米微球。
4.根据权利要求3所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统的制备方法，其特征在于：
所述步骤(1)制备方法：将携氧体、高分子共聚物超声溶解于有机试剂中，并加入到乳化剂水溶液中，冰浴并超声破碎，搅拌，离心洗涤收集沉淀获得负载携氧体的高分子聚合物纳米微球；
所述步骤(2)制备方法：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、N-羟基琥珀酰亚胺(NHS)混合并溶解于含有负载携氧体的高分子聚合物纳米微球的水溶液中，置于恒温摇床活化微球表面的残留羧基，然后加入聚乙二醇，再次置于恒温摇床反应，聚乙二醇通过酰胺键偶联到高分子聚合物纳米微球表面；
所述步骤(3)制备方法：聚乙二醇修饰的高分子聚合物纳米微球与阳离子溶解于超纯水中，搅拌，利用高分子聚合物纳米微球外端暴露的巯基吸附阳离子，加入还原剂在高分子聚合物纳米微球表面原位还原阳离子形成超小纳米颗粒，再加入聚乙二醇进一步修饰超小纳米颗粒，除去游离的聚乙二醇，制得超小纳米酶修饰的高分子聚合物纳米微球；
所述步骤(5)制备方法：化疗药物溶解于有机试剂中，逐滴加入到含有细胞膜与超小纳米酶修饰的高分子聚合物纳米微球的混合液中，采用薄膜挤出法制备细胞膜包覆高分子聚合物纳米微球。
5.根据权利要求3所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统的制备方法，其特征在于：所述高分子共聚物为聚乳酸-羟基乙酸、聚乳酸-乙醇酸、聚乳酸、白蛋白、聚谷氨酸中的一种或几种混合。
6.根据权利要求4所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统的制备方法，其特征在于：所述乳化剂为聚乙烯醇、聚丙烯酸、聚氧乙烯醚中的一种或几种混合；携氧体为全氟溴辛烷、全氟溴庚烷、全氟溴己烷中的一种或几种混合；有机试剂为二氯甲烷或三氯甲烷。
7.根据权利要求4所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统的制备方法，其特征在于：所述化疗药物为长春新碱、长春地辛、柔红霉素、去甲氧柔红霉素、阿霉素、紫杉醇、多西紫杉醇、米托蒽醌中的一种或几种。
8.根据权利要求4所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统的制备方法，其特征在于：所述阳离子为Pt、Au或Pd阳离子。
9.根据权利要求4所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统的制备方法，其特征在于：所述还原剂为硼氢化钠、柠檬酸钠或L-抗坏血酸。
10.权利要求1所述的细胞膜拮抗联合纳米酶的仿生载药纳米系统在制备治疗白血病药物中的用途。
CN202110847434.5A 2021-07-27 2021-07-27 一种细胞膜拮抗联合纳米酶的仿生载药纳米系统、制备方法和用途 Pending CN113599368A (zh)

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