CN115025240B - 一种蛋白聚糖修饰的纳米粒及其制备和应用 - Google Patents
一种蛋白聚糖修饰的纳米粒及其制备和应用 Download PDFInfo
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Abstract
本发明公开了一种蛋白聚糖修饰的纳米粒及其制备方法和应用，本发明的纳米粒包括纳米主体和修饰在所述的纳米主体表面的蛋白聚糖，纳米主体包括骨架和荷载在骨架上的药物成分，药物成分由阿霉素和ATO‑IR780结合形成，本发明制得的纳米粒在进入乳腺癌细胞后释放有效组成，破坏乳腺癌细胞内的线粒体，减少ATP生成，削弱P‑gp的药物外排能力，逆转肿瘤耐药，在乳腺癌的临床治疗中具备潜在的临床应用价值。
Description
技术领域
本发明涉及乳腺癌治疗技术领域，具体而言，涉及一种蛋白聚糖修饰的纳米粒及其制备和应用。
背景技术
2020年，乳腺癌以226万新发病例超越肺癌，成为发病率最高的恶性肿瘤，占所有新增癌症患者的11.7％。手术切除和放化疗是目前乳腺癌治疗的主要手段，但由于乳腺癌患者在长时间用药后，往往出现耐药的现象，限制了目前乳腺癌治疗的效果。肿瘤细胞的异质性是产生耐药的重要原因之一，因此基于单一机制的治疗策略往往会诱导耐药现象的产生。
阿霉素(doxorubicin，DOX)作为蒽环类的代表性药物之一，因其强效的抗癌作用而成为乳腺癌治疗中最常用的化疗药物之一。针对阿霉素递送的被动靶向递药系统(盐酸阿霉素脂质体注射液)在1995年被FDA 批准用于治疗恶性肿瘤。然而有文献报道，经DOXIL治疗的乳腺癌细胞可以通过高表达药物外排受体P-gp，从肿瘤细胞内排出DOX，从而产生耐药。P-gp 的排出药物功能高度依赖ATP的消耗产能，通过耗能完成主动运输。虽然纳米药物递送系统由于被动靶向作用在肿瘤部位聚集，但实际上进入肿瘤细胞内的药物浓度并不高，说明被动靶向的纳米药物制剂仍不足以达到有效的治疗效果。
发明内容
本发明的目的是提供一种硫酸软骨素修饰的纳米粒，其在进入乳腺癌细胞后释放有效组成，破坏乳腺癌细胞内的线粒体，减少ATP生成，削弱P-gp的药物外排能力，逆转肿瘤耐药。
为解决上述问题，本发明提供一种蛋白聚糖修饰的纳米粒，所述的纳米粒包括纳米主体和修饰在所述的纳米主体表面的蛋白聚糖，所述的纳米主体包括骨架和荷载在所述的骨架上的药物成分，所述的药物成分由阿霉素和ATO-IR780结合形成，所述的ATO-IR780的结构式为：
本发明的目的之二在于提供一种蛋白聚糖修饰的纳米粒的制备方法：将纳米主体分散于蛋白聚糖水溶液中，在冰浴条件下超声10-20min得到悬浊液，将悬浊液室温搅拌后离心，再将离心得到的沉淀经水洗和真空干燥后得蛋白聚糖修饰的纳米粒。
作为优选，所述的蛋白聚糖为硫酸软骨素，所述的骨架的材料为ZIF-8。金属有机框架材料(MOFs)是一类由金属簇或金属离子和有机配体通过配位作用生成的有机、无机杂化材料，具有较大的孔径体积、高比表面积和易于调节的骨架结构，可以实现高载药量。沸石咪唑酯骨架材料-8(ZIF-8) 是一种由锌离子和2-甲基咪唑构建的无毒且具有生物相容性的MOFS，在中性的生理条件下结构稳定，但是可以在肿瘤细胞内pH值较低的环境下降解。因此，ZIF-8可以被用作有潜力的抗肿瘤药物载体实现高载药量和肿瘤部位 pH响应性药物释放。
硫酸软骨素(CS)是一种广泛分布于细胞表面，可以与蛋白质共价连接的蛋白聚糖。由于其在肿瘤表面特异性高表达，可作为肿瘤主动靶向递送的包装材料，在ZIF-8外使用硫酸软骨素包装可以显著提升递送药物的主动靶向性。
作为优选，所述纳米主体的制备方法包括以下步骤：
S1、配制药物溶液：将ATO-IR780和阿霉素共溶于去离子水中得药物溶液；
S2、配制骨架溶液：将2-甲基咪唑溶解于水中得A溶液，将六水硝酸锌溶解于水中得B溶液；
S3、一锅法反应：控制搅拌速度为1000-1200rpm，将药物溶液逐滴滴加到B溶液后搅拌均匀得混合溶液，再将混合溶液逐滴滴加到A溶液中，搅拌得悬浊液；
S4、离心干燥：将步骤S3制得的悬浊液离心，将离心得到的沉淀经水洗和真空干燥后得到纳米主体。
本发明以6-氨基己酸、三乙胺活化IR780合成IR780-COOH后在一定条件下与ATO合成ATO-IR780小分子前药并采用硅胶柱色谱法提纯产物，通过一锅法(one-pot synthesis)原位合成荷载ATO-IR780和DOX的ZIF-8 纳米粒，再将硫酸软骨素(CS)修饰于ZIF-8@ATO-IR780/DOX表面进行制得肿瘤细胞主动靶向纳米粒。
作为优选，所述步骤S1中，ATO-IR780和阿霉素的质量比为(1-2)： 1。
作为优选，所述步骤S1中，ATO-IR780的制备方法包括以下步骤：
(1)合成IR780-COOH：将IR780超声溶解于无水DMF中得C溶液，将 6-氨基乙酸溶解于无水DMF中得D溶液，控制油浴温度为80-90℃，将D溶液和三乙胺溶液依次滴加到C溶液中反应4-5h，经后处理得IR780-COOH固体；
(2)配制原料溶液：将步骤(1)制得的IR780-COOH超声溶解于无水 DMF中得E溶液，将EDCI超声溶解于无水DMF中得F溶液，将DMAP溶解于无水DMF中得G溶液，将NHS超声溶解于无水DMF溶液中得H溶液，将ATO 超声溶解于无水DMF溶液中得I溶液；
(3)制备ATO-IR780：在0-5℃条件下，将E溶液、H溶液、F溶液和 G溶液依次滴加到容器中反应0.5-1h，然后在常温条件下，将I溶液加入到反应后的容器中继续反应24-48h，反应结束后经后处理得ATO-IR780。
阿托伐醌(ATO)是常见的抗寄生虫药物，通过与寄生虫线粒体中的辅酶Q竞争结合细胞色素C还原酶，破坏线粒体电子传递过程，从而起到杀伤作用。近年来，大量研究报道了ATO在肿瘤治疗中的应用。ATO可以通过靶向肿瘤的线粒体促进肿瘤细胞的死亡。并且可以通过破坏线粒体减少肿瘤细胞的ATP的产生，抑制肿瘤细胞药物外排，对于化疗药物耐药的肿瘤细胞也有较好的杀伤效果，通过偶联ATO与IR780可以协同增强ATO与IR780 的线粒体靶向能力与ROS积累，提高对肿瘤的杀伤作用。
作为优选，所述步骤(1)中，IR780、6-氨基乙酸和三乙胺的摩尔比为(1-2):2:4。
作为优选，所述步骤(1)和步骤(3)中，反应均在锡箔纸避光、氮气保护中进行。
作为优选，所述步骤(1)和步骤(3)中，后处理均包括以下步骤：先用旋转蒸发仪去除溶剂，经硅胶色谱柱分离提纯后，用体积比为100:1 的二氯甲烷和甲醇混合液进行梯度洗脱。
作为优选，所述步骤(2)中，IR780-COOH、NHS、EDCI和DMAP的摩尔比为(1-1.5):2:2:2。
本发明ATO-IR780的合成过程如下：
本发明的目的之三在于提供蛋白聚糖修饰的纳米粒在乳腺癌药物中的临床应用。
与现有技术相比，本发明制得的硫酸软骨素修饰的纳米粒进入肿瘤细胞后释放DOX和ATO-IR780，破坏细胞内的线粒体，减少ATP生成，削弱 P-gp的药物外排能力，逆转肿瘤耐药，从而具有良好的抗肿瘤活性与逆转阿霉素耐药的能力，因此，其在乳腺癌的临床治疗中具备潜在的临床应用价值。
附图说明
图1为本发明实施例制得的纳米粒的粒径检测图；
图2为本发明实施例制得的纳米粒的电镜图；
图3为本发明实施例制得的中间体IR780-COOH的核磁共振氢谱图；
图4为本发明实施例制得的中间体ATO-IR780的核磁共振氢谱图；
图5为经不同试剂处理后的MCF-7细胞中ROS的DCFH-DA探针荧光强度图；
图6为经不同试剂处理后的MCF-7细胞中JC-1染料的荧光强度；
图7为经不同试剂处理后的MCF-7细胞中的ATP的量；
图8为经小动物活体成像实验后，不同实验组的试剂在体内的分布情况图；
图9为经小动物活体成像实验后，不同实验组的试剂在各主要脏器中的富集情况；
图10为抑瘤试验中，不同实验组的小鼠体重变化曲线图；
图11为抑瘤试验中，不同实验组的乳腺瘤细胞体积变化曲线图；
图12为抑瘤试验中，不同实验组的乳腺瘤细胞重量变化柱形图；
图13为抑瘤试验结束后，小鼠体内取出的乳腺瘤细胞大小测量图。
具体实施方式
为使本发明的上述目的、特征和优点能够更为明显易懂，下面结合附图对本发明的具体实施例做详细的说明。
本发明提供一种蛋白聚糖修饰的纳米粒，包括纳米主体和修饰在纳米主体表面的蛋白聚糖，纳米主体包括骨架和荷载在骨架上的药物成分，药物成分由阿霉素和ATO-IR780结合形成，ATO-IR780的结构式为：
本发明实施例还提供上述蛋白聚糖修饰的纳米粒的制备方法：将纳米主体分散于蛋白聚糖水溶液中，在冰浴条件下超声10min得到悬浊液，将悬浊液室温搅拌后离心，再将离心得到的沉淀经水洗和真空干燥后得蛋白聚糖修饰的纳米粒，其中，蛋白聚糖为硫酸软骨素，骨架的材料为ZIF-8，对制备的硫酸软骨素修饰的纳米粒进行体外表征，如图1所示，DLS测定纳米粒水动力学粒径约为124.0nm(PDI＝0.082)，满足EPR效应要求，透射电镜下的电镜照片如图2所示。
上述实施例中，纳米主体的制备方法包括以下步骤：
S1、配制药物溶液：将质量比为1:1的ATO-IR780和阿霉素共溶于去离子水中得药物溶液；
S2、配制骨架溶液：将2-甲基咪唑溶解于水中得A溶液，将六水硝酸锌溶解于水中得B溶液；
S3、一锅法反应：控制搅拌速度为1000rpm，将药物溶液逐滴滴加到B 溶液后搅拌均匀得混合溶液，再将混合溶液逐滴滴加到A溶液中，搅拌得悬浊液；
S4、离心干燥：将步骤S3制得的悬浊液离心，将离心得到的沉淀经水洗和真空干燥后得到纳米主体。
在本实施例中，ATO-IR780的制备方法包括以下步骤：
合成IR780-COOH：将IR780超声溶解于无水DMF中得C溶液，将6-氨基乙酸溶解于无水DMF中得D溶液，控制油浴温度为80℃，将D溶液和三乙胺溶液依次滴加到C溶液中反应4h，经后处理得蓝色的IR780-COOH固体，通过对产物使用核磁共振氢谱法(图3)进行化学鉴定，可证明合成成功，将IR780-COOH固体置于零下20℃冰箱中避光保存；
配制原料溶液：将步骤(1)制得的IR780-COOH超声溶解于无水DMF 中得E溶液，将EDCI超声溶解于无水DMF中得F溶液，将DMAP溶解于无水DMF中得G溶液，将NHS超声溶解于无水DMF溶液中得H溶液，将ATO 超声溶解于无水DMF溶液中得I溶液；
制备ATO-IR780：在0℃条件下，将E溶液、H溶液、F溶液和G溶液依次滴加到容器中反应0.5h，然后在常温条件下，将I溶液加入到反应后的容器中继续反应24h，反应结束后经后处理得蓝色的ATO-IR780固体，通过对产物使用核磁共振氢谱法(图4)进行化学鉴定，可证明合成成功，将 ATO-IR780固体置于零下20℃冰箱中避光保存。
在本实施例的步骤(1)中，IR780、6-氨基乙酸和三乙胺的摩尔比为1： 2:4。
在本实施例的步骤(1)和步骤(3)中，反应均在锡箔纸避光、氮气保护中进行。
在本实施例的步骤(1)和步骤(3)中，后处理均包括以下步骤：先用旋转蒸发仪去除溶剂，经硅胶色谱柱分离提纯后，用体积比为100:1的二氯甲烷和甲醇混合液进行梯度洗脱。
在本实施例的步骤(2)中，IR780-COOH、NHS、EDCI和DMAP的摩尔比为1:2:2:2。
发明人用生理盐水(NC)、DOX、ATO-IR780(A780)、未用硫酸软骨素修饰的纳米粒(ZIF-8@A780/DOX)、本发明制得的硫酸软骨素修饰的纳米粒(CS/ZIF-8@A780/DOX)作为平行实验组，利用DCFH-DA探针对人乳腺癌细胞(MCF-7)内产生的ROS进行了标记，如图5所示，发现本发明制得的纳米粒(CS/ZIF-8@A780/DOX)能促进乳腺癌细胞内ROS的产生和积累。进一步采用JC-1染色检测线粒体膜电位发现，采用本发明制得的纳米粒 (CS/ZIF-8@A780/DOX)处理MCF-7细胞后，线粒体膜电位显著降低，提示经本发明制得的纳米粒(CS/ZIF-8@A780/DOX)处理后，细胞内的线粒体被显著损伤，见图6。MCF-7细胞经本发明制得的纳米粒(CS/ZIF-8@A780/DOX)处理后，由于线粒体破坏，其ATP生成显著减少，见图7。
发明人用小动物活体成像实验测定小鼠尾静脉注射IR780、ATO-IR780 (A780)、未用硫酸软骨素修饰的纳米粒(ZIF-8@A780/DOX)、本发明制得的硫酸软骨素修饰的纳米粒(CS/ZIF-8@A780/DOX)后，1h、2h、4h、6h、 8h、24h后，纳米制剂在体内的分布情况以及注射24h后在各主要脏器中的富集情况，结果见图8和图9，体内分布试验表明ZIF-8载体包裹CS后，在体内存留和肿瘤富集能力有显著提升，提示本发明制得的纳米粒(CS/ZIF-8@A780/DOX)可以显著提升DOX的富集和存留能力。
抑瘤试验：发明人用生理盐水(NC)、DOX、ATO-IR780(A780)、 ATO-IR780/DOX(A780/DOX)、未用硫酸软骨素修饰的纳米粒 (ZIF-8@A780/DOX)、本发明制得的硫酸软骨素修饰的纳米粒(CS/ZIF-8@A780/DOX)作为平行实验组，对MCF-7/Adr细胞进行处理，然后进行抑瘤效果试验。
具体步骤为：共设置6个实验组，每组实验组布置6只小鼠，在第一天对每只小鼠接种相同量的乳腺瘤细胞，当检测到小鼠中的瘤细胞达到100 立方毫米后开始注射含有处理后的MCF-7/Adr细胞的药物，每组共用药7 次，检测用药过程中和用药结束后小鼠体重、小鼠中乳腺瘤细胞的体积和重量，并计算出最终抑瘤率，图10为小鼠体重变化曲线图；图11为乳腺瘤细胞体积变化曲线图，图12为乳腺瘤细胞重量变化柱状图。在用药结束后将小鼠体内的乳腺瘤细胞取出并对其大小进行测量，测量结果如图13所示。经过计算，采用本发明制得的硫酸软骨素修饰的纳米粒(CS/ZIF-8@A780/DOX)处理的MCF-7/Adr细胞用于治疗乳腺癌，其抑瘤率为90.25％，说明本发明制得的纳米粒(CS/ZIF-8@A780/DOX)可以用于乳腺癌药物的临床应用中，且具有良好的效果。
虽然本公开披露如上，但本公开的保护范围并非仅限于此。本领域技术人员，在不脱离本公开的精神和范围的前提下，可进行各种变更与修改，这些变更与修改均将落入本发明的保护范围。
Claims (5)
1.一种蛋白聚糖修饰的纳米粒的制备方法，其特征在于：所述的纳米粒包括纳米主体和修饰在所述的纳米主体表面的蛋白聚糖，所述的纳米主体包括骨架和荷载在所述的骨架上的药物成分，所述的药物成分由阿霉素和ATO-IR780结合形成，所述的蛋白聚糖为硫酸软骨素，所述的骨架的材料为沸石咪唑酯骨架材料-8即ZIF-8，所述的ATO-IR780的结构式为：
；
所述蛋白聚糖修饰的纳米粒的制备方法如下：将纳米主体分散于蛋白聚糖水溶液中，在冰浴条件下超声10-20min得到悬浊液，将悬浊液室温搅拌后离心，再将离心得到的沉淀经水洗和真空干燥后得蛋白聚糖修饰的纳米粒；
所述纳米主体的制备方法包括以下步骤：
S1、配制药物溶液：将ATO-IR780和阿霉素共溶于去离子水中得药物溶液；
S2、配制骨架溶液：将2-甲基咪唑溶解于水中得A溶液，将六水硝酸锌溶解于水中得B溶液；
S3、一锅法反应：控制搅拌速度为1000-1200rpm，将药物溶液逐滴滴加到B溶液后搅拌均匀得混合溶液，再将混合溶液逐滴滴加到A溶液中，搅拌得悬浊液；
S4、离心干燥：将步骤S3制得的悬浊液离心，将离心得到的沉淀经水洗和真空干燥后得到纳米主体；
所述ATO-IR780的制备方法包括以下步骤：
（1）合成IR780-COOH：将IR780超声溶解于无水DMF中得C溶液，将6-氨基乙酸溶解于无水DMF中得D溶液，控制油浴温度为80-90℃，将D溶液和三乙胺溶液依次滴加到C溶液中反应4-5h，经后处理得IR780-COOH固体；
（2）配制原料溶液：将步骤（1）制得的IR780-COOH超声溶解于无水DMF中得E溶液，将EDCI超声溶解于无水DMF中得F溶液，将DMAP溶解于无水DMF中得G溶液，将NHS超声溶解于无水DMF溶液中得H溶液，将阿托伐醌即ATO超声溶解于无水DMF溶液中得I溶液；
（3）制备ATO-IR780：在0-5℃条件下，将E溶液、H溶液、F溶液和G溶液依次滴加到容器中反应0.5-1h，然后在常温条件下，将I溶液加入到反应后的容器中继续反应24-48h，反应结束后经后处理得ATO-IR780；
所述步骤（1）和步骤（3）中，后处理均包括以下步骤：先用旋转蒸发仪去除溶剂，经硅胶色谱柱分离提纯后，用体积比为100:1的二氯甲烷和甲醇混合液进行梯度洗脱。
2.如权利要求1所述的蛋白聚糖修饰的纳米粒的制备方法，其特征在于，所述步骤S1中，ATO-IR780和阿霉素的质量比为1-2：1。
3.如权利要求1所述的蛋白聚糖修饰的纳米粒的制备方法，其特征在于，所述步骤（1）中，IR780、6-氨基乙酸和三乙胺的摩尔比为1-2:2:4。
4.如权利要求1所述的蛋白聚糖修饰的纳米粒的制备方法，其特征在于，所述步骤（2）中，IR780-COOH、NHS、EDCI和DMAP的摩尔比为1-1.5:2:2:2。
5.一种如权利要求1所述的蛋白聚糖修饰的纳米粒的制备方法制备得到的蛋白聚糖修饰的纳米粒在制备乳腺癌药物中的应用。
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