CN115364244B - 一种搭便车中性粒细胞的药物递送体系及其制备方法和应用 - Google Patents
一种搭便车中性粒细胞的药物递送体系及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种搭便车中性粒细胞的药物递送体系及其制备方法和应用，该制备方法包括将还原型谷胱甘肽溶液和牛血清白蛋白溶液进行混合并搅拌处理；向混合溶液中添加DAC进行反应，再添加无水乙醇，透析，得到DAC纳米颗粒，再负载N‑羟基琥珀酰亚胺修饰的近红外荧光试剂，得到负载近红外荧光试剂的DAC纳米颗粒；然后与巯基化的SMCC进行孵育，加入TCEP还原的CD11b抗体进行孵育；该制备方法通过IR820和CD11b修饰纳米粒，实现影像引导和中性粒搭便车靶向递送，达到精准递送目的；同时负载地西他滨，使其与IR820联用，实现药物联合光热疗法引发肿瘤细胞焦亡进而利用免疫细胞杀伤肿瘤的治疗；此外，该制备方法实现简单、效率高、效果好、达到了应用的要求。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种搭便车中性粒细胞的药物递送体系及其制备方法和应用。
背景技术
对于生长致密且免疫原性低的肿瘤来说，如何防止术后复发和转移是肿瘤治疗面临的巨大挑战之一。精准有效的递送系统的问题是药物的靶向递送和影像引导递送。
搭便车体内细胞的肿瘤靶向方法为主动靶向提供了一种新的可能。手术切除肿瘤后，肿瘤残余部位是一种急性炎症微环境，体内中性粒细胞能被炎症因子激活并趋向炎症部位。且人体内中性粒细胞是最丰富的循环白细胞，利用中性粒细胞特有的趋化特性靶向术后肿瘤急性炎症微环境为防止术后复发和转移提供了一种思路。中性粒细胞激活后表面抗原CD11b表达显著上调，利用CD11b抗体修饰纳米粒可以赋予纳米粒与中性粒细胞结合的能力，从而搭便车中性粒细胞靶向残余肿瘤。中性粒细胞到达残余肿瘤后可以通过释放细胞外陷阱或凋亡等方式将细胞内物质释放到肿瘤部位。IR820作为近红外光敏剂，在近红外区域显示出强荧光，并能够与生物自发荧光区分开，为药物精准递送提供了可视化导航功能。
有鉴于此，特提出本发明。
发明内容
本发明的目的在于提供一种搭便车中性粒细胞的药物递送体系及其制备方法和应用，该制备方法制得的药物递送体系采用CD11b抗体偶联的牛血清白蛋白作为载体，能够在体内被激活的中性粒细胞识别并通过搭便车中性粒细胞的方式主动靶向肿瘤，通过IR820影像引导，有效提高了药物对肿瘤的精准靶向效率，并通过近红外光热剂与去甲基化药物联合使肿瘤细胞发生焦亡达到激活全身免疫活性的目的。
为了实现本发明的上述目的，特采用以下技术方案：
本发明第一方面提供一种搭便车中性粒细胞的药物递送体系的制备方法，所述制备方法包括如下步骤：
(a)将还原型谷胱甘肽溶液和牛血清白蛋白溶液进行混合并搅拌处理，得到混合溶液；
(b)向混合溶液中添加地西他滨(DAC)进行反应，待反应结束，向反应液中添加无水乙醇，再进行透析，得到DAC纳米颗粒，再将DAC纳米颗粒与N-羟基琥珀酰亚胺修饰的近红外荧光试剂共孵育，得到负载近红外荧光试剂的DAC纳米颗粒；
(c)将负载近红外荧光试剂的DAC纳米颗粒与巯基化的SMCC进行孵育，待孵育结束后，加入TCEP还原的CD11b抗体进行孵育，即得所述搭便车中性粒细胞的药物递送体系。
地西他滨(DAC)是一种天然2′-脱氧胞苷酸的腺苷类似物，通过抑制DNA甲基转移酶，减少DNA的甲基化，是目前发现的最强的DNA去甲基化药物，最近的研究显示低剂量的DAC即可达到DNA去甲基化作用。4T1肿瘤细胞中低表达GSDME，GSDME可被caspase蛋白酶剪切为两部分：GSDME-N端和GSDME-C端，GSDME-N可以给细胞打孔，使得细胞外液流入，细胞肿胀，即造成细胞焦亡，同时，大量的细胞内容物流出能够充当抗原被微环境中的免疫细胞识别，进而激活免疫系统，产生抗肿瘤作用。本发明中，蛋白酶的表达是由光热剂的光热效应引发的，近红外光热剂IR820在低功率近红外光的照射下，在肿瘤局部发挥光热效应，诱导肿瘤细胞中caspase-3的高表达，低功率的激光照射产生较低温度(不超过45℃)不发挥消融肿瘤的作用。NHS修饰的IR820能在温和条件下与白蛋白纳米粒上的伯胺反应。
本发明制备方法中使用还原型谷胱甘肽(GSH)还原牛血清白蛋白(BSA)的二硫键，改变BSA的构象，DAC通过亲疏水相互作用进入BSA空腔形成DAC纳米颗粒，再通过乙醇促进BSA在空气中再形成二硫键进而形成载药纳米粒。Sulfo-SMCC是巯基化的SMCC，能够溶于水使反应在温和条件下进行，SMCC是一种小分子两亲双功能交联剂，NHS酯能在中性偏碱性条件下先与白蛋白纳米粒上的伯胺反应形成酰胺键，而马来酰亚胺在中性偏酸性条件下后与CD11b抗体上的巯基发生反应形成稳定的硫醚键。抗体本身带有游离巯基，TCEP是一种巯基还原剂，能使抗体表面巯基稳定存在。
本发明制备方法制得的搭便车中性粒细胞药物递送体系能被活化的中性粒细胞特异性摄取，与不偶联抗体的纳米制剂相比，提高了细胞对药物的摄取效率；同时通过搭便车中性粒细胞的方式主动靶向到肿瘤，提高了药物对肿瘤的靶向效率，使药物更多的蓄积到肿瘤减少了全身副作用；利用光热效应引发的肿瘤细胞焦亡策略能够激活免疫系统，实现较好的预防术后肿瘤复发和转移的效果。
本发明上述制备方法实现简单，效率高，效果好，达到了应用的要求。
优选地，所述近红外荧光试剂为吲哚菁绿或新吲哚菁绿。
优选地，所述步骤(a)中，牛血清白蛋白溶液和还原型谷胱甘肽溶液的体积比为(0.8～1.2)∶1；还原型谷胱甘肽与牛血清白蛋白的摩尔比为(1～1.5)∶1；牛血清白蛋白溶液浓度为10～20mg/mL；还原型谷胱甘肽溶液的pH值为8～8.5；搅拌处理时间为20～40min。
优选地，所述步骤(b)中，反应温度为室温，反应时间为10～120min。
优选地，所述步骤(b)中，向混合溶液中添加DAC进行反应具体包括：
将含有DAC的二甲基亚砜溶液添加到混合溶液中进行反应，其中，含有DAC的二甲基亚砜溶液添和混合溶液的体积比为1∶(18～22)；含有DAC的二甲基亚砜溶液的浓度为1～5mg/mL。
优选地，所述步骤(b)中，向反应液中添加无水乙醇具体包括：
向反应液中以0.8～1.2mL/min的速度滴加无水乙醇，无水乙醇与反应液的体积比为(0.8～1.2)∶1。
优选地，所述N-羟基琥珀酰亚胺修饰的近红外荧光试剂与牛血清白蛋白的摩尔比为(0.8～1.2)∶1。
优选地，所述步骤(c)中，巯基化的SMCC与CD11b抗体的摩尔比为(1～1.5)∶1；
CD11b抗体与牛血清白蛋白质量比为1∶(60～80)。
优选地，所述步骤(c)中，孵育温度为35～39℃，时间为0.5～1h。
本发明第二方面提供一种上述制备方法制得的搭便车中性粒细胞的药物递送体系。
本发明第三方面提供一种上述制备方法制得的搭便车中性粒细胞的药物递送体系在制备免疫联合光热治疗肿瘤药物中的应用。
本发明第四方面提供一种免疫联合光热治疗肿瘤药物，包括上述制备方法制得的搭便车中性粒细胞的药物递送体系。
与现有技术相比，本发明的有益效果至少包括：
本发明制备方法制得的搭便车中性粒细胞药物递送体系能被激活的中性粒细胞特异性摄取，与不偶联抗体的纳米制剂相比，提高了细胞对药物的摄取效率；同时通过搭便车中性粒细胞的方式主动靶向到肿瘤，提高了药物对术后肿瘤急性炎症微环境的靶向效率，使药物更多的蓄积到了肿瘤并浸润了肿瘤的深部；牛血清白蛋白纳米粒上连接的近红外荧光试剂是一种光热剂，通过低能量激光照射可产生光热效应促进肿瘤细胞蛋白酶表达与去甲基化药物联用实现了靶向肿瘤部位的促焦亡效果，有效改善了肿瘤免疫微环境。
本发明上述制备方法通过IR820和CD11b修饰纳米粒，实现影像引导和中性粒搭便车靶向递送，达到精准递送目的；同时负载地西他滨，使其与IR820联用，实现药物联合光热疗法引发肿瘤细胞焦亡进而利用免疫细胞杀伤肿瘤的治疗；此外，该制备方法实现简单，效率高，效果好，达到了应用的要求。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍。在所有附图中，类似的元件或部分一般由类似的附图标记标识。附图中，各元件或部分并不一定按照实际的比例绘制。
图1为本发明实验例中BNP和ANP的粒径检测结果；
图2为本发明实验例中BNP和ANP的Zata电位检测结果；
图3为本发明实验例中CD11b抗体偶联效率的检测结果；
图4为本发明实验例中用PE-Ly-6G染色中性粒细胞并通过激光共聚焦显微镜观察拍照图；
图5为本发明实验例中小鼠不同脏器和肿瘤组织利用小动物活体成像系统在ICG通道进行荧光成像图；
图6为本发明实验例中小鼠不同脏器和肿瘤组织中BNP和ANP含量；
图7为本发明实验例中治疗后小鼠肿瘤及瘤重结果。
具体实施方式
下面将结合实施例对本发明技术方案的实施例进行详细的描述。以下实施例仅用于更加清楚地说明本发明的技术方案，因此只作为示例，而不能以此来限制本发明的保护范围。
需要注意的是，除非另有说明，本申请使用的技术术语或者科学术语应当为本发明所属领域技术人员所理解的通常意义。
实施例
本实施例为一种搭便车中性粒细胞的药物递送体系的制备方法，该制备方法包括如下步骤：
(a)采用1M标准NaOH溶液调节还原型谷胱甘肽溶液pH值至8.2，再按照牛血清白蛋白溶液和还原型谷胱甘肽溶液的体积比为1∶1，将还原型谷胱甘肽溶液和浓度为20mg/mL的牛血清白蛋白溶液进行混合并搅拌处理30min，得到混合溶液，其中，还原型谷胱甘肽与牛血清白蛋白的摩尔比为1.2∶1；
(b)将含有DAC的二甲基亚砜溶液添加到混合溶液中并在室温下反应40min，待反应结束，向反应液中以1mL/min的速度滴加无水乙醇并搅拌2h，再进行透析，得到DAC纳米颗粒，再按照N-羟基琥珀酰亚胺修饰的近红外荧光试剂与牛血清白蛋白的摩尔比为1∶1，将DAC纳米颗粒与N-羟基琥珀酰亚胺修饰的近红外荧光试剂在37℃下共孵育0.5h，得到负载IR820的DAC纳米颗粒(记为BNP)，其中，含有DAC的二甲基亚砜溶液添和混合溶液的体积比为1∶20；含有DAC的二甲基亚砜溶液的浓度为1mg/mL；无水乙醇与反应液的体积比为1∶1；
(c)将sulfo-SMCC用100uL纯水溶解后与1mL BNP(BSA含量1.2mg)37℃孵箱共孵育0.5h，立即加入用TCEP还原的20ug CD11b抗体，37℃孵箱共孵育30min，得到CD11b抗体偶联的IR820-DAC纳米颗粒，即搭便车中性粒细胞的药物递送体系(记为ANP)，其中，巯基化的SMCC与CD11b抗体的摩尔比为1.2∶1。
实验例
1、通过动态光散射粒度分析仪检测实施例1中BNP和ANP的粒径和Zata电位，其粒度检测结果如图1所示；Zata电位分析结果如图2所示；
由图1、图2可知，ANP的水合粒径比BNP增长了大约20nm；两种纳米粒子的Zeta电位均为-22左右。
2、CD11b抗体偶联效率的检测：
利用PE荧光染料偶联的CD11b抗体与BNP偶联，进行流式分析，使用FlowJo软件计算CD11b抗体偶联效率；流式细胞分析和计算结果如图3所示；
由图3可知，在CD11b抗体与BSA质量比为1：60的情况下，95％的纳米粒子都能与抗体偶联。
3、体外细胞摄取实验
为了在体外比较中性粒细胞对BNP和ANP的摄取效率，从小鼠骨髓中提取分离出中性粒细胞，并用脂多糖(LPS)活化中性粒细胞。将激活后的中性粒细胞与BNP、ANP(IR820:10ug/mL,DAC:1.9ug/mL)共孵育12h，用PE-Ly-6G染色中性粒细胞并通过激光共聚焦显微镜观察拍照；拍照结果如图4所示；
由图4可知，与不偶联抗体的纳米粒相比，偶联抗体的纳米粒能被更多的激活的中性粒细胞吞噬。
4、靶向荧光成像研究
手术切除部分肿瘤组织2h后，将BNP和ANP分别通过尾静脉的方式注射到小鼠体内。24h后，处死小鼠并取不同脏器和肿瘤组织利用小动物活体成像系统在ICG通道进行荧光成像，结果如图5所示；以IR820-NHS的荧光计算，不同脏器BNP和ANP含量如图6所示；
由图5、图6可知，与BNP组相比，ANP组小鼠的肝脏富集的纳米粒子较少，残余肿瘤部位富集的纳米粒子较多。
5、体内抗肿瘤效果
对于术后抗肿瘤复发效果的评价，BALB/c小鼠在右侧皮下接种1×1064T1细胞；4T1荷瘤BALB/c小鼠在肿瘤体积约200mm3时，手术切除肿瘤使残余肿瘤体积保持在30-80mm3，手术切除后2小时，将不同的药物通过尾静脉注射到小鼠体内，包括PBS、DAC、IR820纳米粒、BNP以及ANP，其中，IR820纳米粒、BNP以及ANP三组在药物注射后24小时时进行低能量的激光照射5分钟(808nm，0.5W/cm2)。这些注射和照射治疗重复一次，间隔一周。治疗后小鼠肿瘤及瘤重如图7所示；
由图7可知，BNP组和ANP组与PBS组相比，术后肿瘤体积得到了有效遏制。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围，其均应涵盖在本发明的权利要求和说明书的范围当中。
Claims (9)
1.一种搭便车中性粒细胞的药物递送体系的制备方法，其特征在于，包括如下步骤：
(a)将还原型谷胱甘肽溶液和牛血清白蛋白溶液进行混合并搅拌处理，得到混合溶液；
(b)向混合溶液中添加地西他滨进行反应，待反应结束，向反应液中添加无水乙醇，再进行透析，得到地西他滨纳米颗粒，再将地西他滨纳米颗粒与N-羟基琥珀酰亚胺修饰的近红外荧光试剂共孵育，得到负载近红外荧光试剂的地西他滨纳米颗粒；
(c)将负载近红外荧光试剂的地西他滨纳米颗粒与巯基化的SMCC进行孵育，待孵育结束后，加入TCEP还原的CD11b抗体进行孵育，即得所述搭便车中性粒细胞的药物递送体系。
2.根据权利要求1所述的制备方法，其特征在于，所述步骤(a)中，牛血清白蛋白溶液和还原型谷胱甘肽溶液的体积比为(0.8～1.2)∶1；还原型谷胱甘肽与牛血清白蛋白的摩尔比为(1～1.5)∶1；牛血清白蛋白溶液浓度为10～20mg/mL；还原型谷胱甘肽溶液的pH值为8～8.5。
3.根据权利要求1所述的制备方法，其特征在于，所述步骤(b)中，反应温度为室温，反应时间为10～120min。
4.根据权利要求1所述的制备方法，其特征在于，所述步骤(b)中，向混合溶液中添加地西他滨进行反应具体包括：
将含有地西他滨的二甲基亚砜溶液添加到混合溶液中进行反应，其中，含有地西他滨的二甲基亚砜溶液添和混合溶液的体积比为1∶(18～22)；含有地西他滨的二甲基亚砜溶液的浓度为1-5mg/mL。
5.根据权利要求1所述的制备方法，其特征在于，所述N-羟基琥珀酰亚胺修饰的近红外荧光试剂与牛血清白蛋白的摩尔比为(0.8～1.2)∶1。
6.根据权利要求1所述的制备方法，其特征在于，所述步骤(c)中，巯基化的SMCC与CD11b抗体的摩尔比为(1～1.5)∶1；
CD11b抗体与牛血清白蛋白质量比为1∶(60～80)。
7.权利要求1～6任一所述的制备方法制得的搭便车中性粒细胞的药物递送体系。
8.权利要求1～6任一所述的制备方法制得的搭便车中性粒细胞的药物递送体系在制备免疫联合光热治疗乳腺癌药物中的应用。
9.一种免疫联合光热治疗乳腺癌药物，其特征在于，包括权利要求1～6任一所述的制备方法制得的搭便车中性粒细胞的药物递送体系。
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