CN109692334B - 具有靶向和响应缓释特性的抗骨髓瘤载药微球及制备方法 - Google Patents

具有靶向和响应缓释特性的抗骨髓瘤载药微球及制备方法 Download PDF

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CN109692334B
CN109692334B CN201811499560.0A CN201811499560A CN109692334B CN 109692334 B CN109692334 B CN 109692334B CN 201811499560 A CN201811499560 A CN 201811499560A CN 109692334 B CN109692334 B CN 109692334B
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王少会
温博
谈逸茗
王少民
谌芸
谢小丽
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Abstract

一种具有靶向和响应缓释特性的抗骨髓瘤载药微球及制备方法，所述方法以层状结构的蒙脱土为支撑载体，通过阳离子交换，在蒙脱土层间合成粒径可控的球状纳米碳酸钙，制备MMT‑NanoCaCO3为先驱模板；通过阴离子交换，将球状NanoCaCO3转变为纳米HAp，获得HAp‑MMT药物载体；同时在MMT表面通过静电吸附作用连接壳寡糖作为连接物；利用壳寡糖氨基端共价结合羧基端，引入对抗骨髓瘤细胞具有靶向特性的多肽A54，制备一种具有主动靶向和pH响应缓释功能的载药微球。本发明方法工艺简单，所使用的化学试剂均为常用试剂，所制备的载药微球既具有pH响应特性，又具有很强的药物负载能力，通过引入主动靶向特性分子，实现对肿瘤细胞的靶向作用。该载体有助于骨髓瘤治愈过程中的骨骼修复。

Description

具有靶向和响应缓释特性的抗骨髓瘤载药微球及制备方法
技术领域
本发明涉及一种具有靶向和响应缓释特性的抗骨髓瘤载药微球及制备方法，属生物医药技术领域。
背景技术
多发性骨髓瘤( multiple myeloma，MM) 是一种起源于浆细胞的恶性增殖性疾病，骨髓瘤细胞产生并分泌的单克隆免疫球蛋白，浆细胞及骨髓间质细胞分泌的细胞因子，最终导致包括贫血、肾功能不全、高钙血症及骨痛在内的多发性骨髓瘤临床症状（CRAB）。MM是血液系统的第二大肿瘤，在北美洲、欧洲和亚洲每年MM新发率分别约为3.5～4.5/10万人、2.5～3.5/10万人和0.5～2.0/10万人。美国阿卡纳·斯瓦米博士在美国《国家科学院学报》上最新发表的研究论文表示：骨骼的微环境极为适宜癌细胞的生长，乳腺癌、前列腺癌以及血癌等癌症发生转移后，极易向骨骼转移。骨髓瘤的治疗应该重点关注两点：（1）有效重塑骨骼微环境，防止疾病进一步发展；（2）促进骨骼组织的恢复和生长。阿霉素(doxorubicin,DOX)属蔥环类抗肿瘤药物，临床上广泛用于治疗多种恶性肿瘤，且价格相对便宜。但是该药不能很好的区分癌细胞和正常细胞，经常使用会引起正常组织的毒副作用如心脏毒性、神经毒性、骨髓压制等，且局部药物浓度过高，也会造成不良反应，因而限制了该药物的使用。因此，将DOX负载在具有靶向特性的和缓释特性的药物载体上，可解决这一难题。常用药物载体材料主要有两大类，高分子材料和无机材料。药物载体高分子材料的研究开发虽得到大量的关注，但由于它伴随药物进入体内，有些暂时停留于体内，有些则在体内降解、吸收，因此有可能对人体产生毒副作用。而用作药物载体的无机材料一般具有良好的生物相容性、生物可降解性及生物安全性的无机化合物，同时具有形貌粒径可控、比表面积大、负载效率高等优势。
发明内容
本发明的目的是，为了将抗肿瘤药物负载在具有靶向特性的和缓释特性的药物载体上，实现灭杀肿瘤，公开一种具有靶向和响应缓释特性的抗骨髓瘤载药微球及制备方法。
本发明实现的技术方案如下，一种具有靶向和响应缓释特性的抗骨髓瘤载药微球，所述载药微球以层状蒙脱土为载体，CaCl2为钙源，Na2CO3为碳源，磷酸氢二钠或磷酸氢钠为磷源；制备成纳米羟基磷灰石层间柱撑蒙脱土的载药微球，并采用COS和多肽A54进行靶向修饰；所述载药微球具有超大负载容量、靶向性、pH响应控释特性，用于治疗多发性骨髓瘤。
一种具有靶向和响应缓释特性的抗骨髓瘤载药微球的制备方法，所述方法以层状结构的蒙脱土（MMT）为支撑载体，通过阳离子交换，在MMT层间合成粒径可控的球状纳米碳酸钙，制备MMT-NanoCaCO3为先驱模板，通过阴离子交换，将球状NanoCaCO3转变为纳米HAp，获得HAp-MMT药物载体；同时在MMT表面通过静电吸附作用连接壳寡糖（COS）作为连接物，利用COS氨基端共价结合羧基端，引入对抗骨髓瘤细胞具有靶向特性的多肽A54，制备一种具有主动靶向和pH响应缓释功能的载药微球。
具有靶向和响应缓释特性的抗骨髓瘤载药微球的制备方法，步骤如下：
（1）在室温条件下，将30ml一定浓度的氯化钙溶液匀速倒入到装有150 ml的MMT水悬浮液的三颈烧瓶中，机械搅拌4h，充分混合均匀；
（2）在步骤（1）的产物中缓慢滴加30ml Na2CO3水溶液，同时控制pH在7~8之间，滴加溶液结束后，继续搅拌2h后，静置陈化24h，抽滤洗涤，在烘箱80℃条件下干燥2h后，管式炉中焙烧1h；
（3）步骤（2）中产物研磨后，配置成质量浓度为5%的水悬浮液，将浓度为0.1mol/L的磷酸盐水溶液滴加到悬浮液中，机械搅拌0.5h，将混合溶液转移至聚四氟乙烯内衬的水热反应釜中，在120℃条件下反应1h，将水热反应釜中产物倒出，并用去离子水洗涤，60℃下干燥24h；
（4）将步骤（3）所得产物放置在球磨机中，将COS的无水乙醇溶液15ml分三次加入，球磨0.5h后，再将多肽A54的稀乙酸溶液15ml分三次加入，继续球磨0.5h；将球磨的样品放置在120℃的真空干燥箱中，干燥1h，去除所有溶剂至恒重，所得样品为载药微球。
所述氯化钙溶液质量浓度为1%～5%，MMT悬浮液浓度为2%～5%。
所述Na2CO3水溶液质量浓度为2%～8%。
所述磷酸盐为NaH2PO4和Na2HPO4的一种，用量为8～12ml。
所述COS乙醇溶液浓度为0.05mol/L～0.1mol/L，多肽A54的用量为5-10mg。
本发明的有益效果是，本发明方法工艺简单，所使用的化学试剂均为常用试剂、原料易得，所制备的载药微球既具有pH响应特性，能依据人体内的pH值的变化实现药物缓释，无生物毒性，且具有很强的药物负载能力，通过引入主动靶向特性分子，可实现对肿瘤细胞的靶向作用，同时该载体有助于骨髓瘤治愈过程中的骨骼修复。
附图说明
图1为本发明中载药微球制备的示意图；
图2为本发明所制备的载药微球的氮气吸附脱附曲线图（实施例1样品）；
图3为本发明所制备的载药微球红外光谱图（实施例1样品）；
图4 为本发明所制备的载药微球对阿莫西林吸附曲线（实施例1-4样品）；
图5为本发明所制备的载药微球（实例1中样品）在不同pH值下的PBS缓冲溶液中的DOX缓释曲线（37.4℃）。
具体实施方式
如图1所示，为本发明实施例载药微球制备流程图。
本实施例载药微球的整个制备流程包括：蒙脱土层间离子交换，超声分散，焙烧，CaCO3转变为Hap，连接COS，偶联靶向分子多肽A54，载药微球。
实施例1：在室温条件下，将30ml浓度为2.5%的氯化钙水溶液匀速倒入到装有150ml的MMT水悬浮液的三颈烧瓶中，机械搅拌4h，充分混合均匀。缓慢滴加30ml质量浓度为5%Na2CO3水溶液，同时控制pH在7，滴加溶液结束后，继续搅拌2h后，静置陈化24h，抽滤洗涤，在烘箱80℃条件下干燥2h后，管式炉中焙烧1h。将焙烧后产物研磨后，配置成质量浓度为5%的水悬浮液，将浓度为0.1mol/L的磷酸二氢钠水溶液10ml滴加到悬浮液中，机械搅拌0.5h，将混合溶液转移至聚四氟乙烯内衬的水热反应釜中，在120℃条件下反应1h，将水热反应釜中产物倒出，并用去离子水洗涤，60℃下干燥24h。将干燥后所得产物放置在球磨机中，将0.1mol/L的COS的无水乙醇溶液15ml分三次加入，球磨0.5h后，再将含有7.5mg的多肽分子A54的稀乙酸溶液15ml分三次加入，继续球磨0.5h。将球磨的样品放置在120℃的真空干燥箱中，干燥1h，去除所有溶剂至恒重，所得样品为载药微球。
本实施例所制备的载药微球的氮气吸附脱附曲线图如图2所示；本实施例制备的载药微球红外光谱表征如图3所示；本实施例所制备的载药微球对阿莫西林吸附曲如图4所示；本实施例所制备的载药微球在不同pH值下的PBS缓冲溶液中的DOX缓释曲线如图5所示。
实施例2：在室温条件下，将30ml浓度为1%的氯化钙水溶液匀速倒入到装有150 ml的MMT水悬浮液的三颈烧瓶中，机械搅拌4h，充分混合均匀。缓慢滴加30ml质量浓度为2%Na2CO3水溶液，同时控制pH在8，滴加溶液结束后，继续搅拌2h后，静置陈化24h，抽滤洗涤，在烘箱80℃条件下干燥2h后，管式炉中焙烧1h。将焙烧后产物研磨后，配置成质量浓度为5%的水悬浮液，将浓度为0.1mol/L的磷酸氢二钠水溶液10ml滴加到悬浮液中，机械搅拌0.5h，将混合溶液转移至聚四氟乙烯内衬的水热反应釜中，在120℃条件下反应1h，将水热反应釜中产物倒出，并用去离子水洗涤，60℃下干燥24h。将干燥后所得产物放置在球磨机中，将0.05mol/L的COS的无水乙醇溶液15ml分三次加入，球磨0.5h后，再将含有5mg的多肽分子A54的稀乙酸溶液15ml分三次加入，继续球磨0.5h。将球磨的样品放置在120℃的真空干燥箱中，干燥1h，去除所有溶剂至恒重，所得样品为载药微球。本实施例所制备的载药微球对阿莫西林吸附曲线如图4所示。
实施例3：在室温条件下，将30ml浓度为5%的氯化钙水溶液匀速倒入到装有150 ml的MMT水悬浮液的三颈烧瓶中，机械搅拌4h，充分混合均匀。缓慢滴加30ml质量浓度为8%Na2CO3水溶液，同时控制pH在7，滴加溶液结束后，继续搅拌2h后，静置陈化24h，抽滤洗涤，在烘箱80℃条件下干燥2h后，管式炉中焙烧1h。将焙烧后产物研磨后，配置成质量浓度为5%的水悬浮液，将浓度为0.1mol/L的磷酸氢二钠水溶液10ml滴加到悬浮液中，机械搅拌0.5h，将混合溶液转移至聚四氟乙烯内衬的水热反应釜中，在120℃条件下反应1h，将水热反应釜中产物倒出，并用去离子水洗涤，60℃下干燥24h。将干燥后所得产物放置在球磨机中，将0.1mol/L的COS的无水乙醇溶液15ml分三次加入，球磨0.5h后，再将含有10mg的多肽分子A54的稀乙酸溶液15ml分三次加入，继续球磨0.5h。将球磨的样品放置在120℃的真空干燥箱中，干燥1h，去除所有溶剂至恒重，所得样品为载药微球。本实施例所制备的载药微球对阿莫西林吸附曲线如图4所示。
实施例4：在室温条件下，将30ml浓度为2%的氯化钙水溶液匀速倒入到装有150 ml的MMT水悬浮液的三颈烧瓶中，机械搅拌4h，充分混合均匀。缓慢滴加30ml质量浓度为4%Na2CO3水溶液，同时控制pH在8，滴加溶液结束后，继续搅拌2h后，静置陈化24h，抽滤洗涤，在烘箱80℃条件下干燥2h后，管式炉中焙烧1h。将焙烧后产物研磨后，配置成质量浓度为5%的水悬浮液，将浓度为0.075mol/L的磷酸二氢钠水溶液8ml滴加到悬浮液中，机械搅拌0.5h，将混合溶液转移至聚四氟乙烯内衬的水热反应釜中，在120℃条件下反应1h，将水热反应釜中产物倒出，并用去离子水洗涤，60℃下干燥24h。将干燥后所得产物放置在球磨机中，将0.075mol/L的COS的无水乙醇溶液15ml分三次加入，球磨0.5h后，再将含有5mg的多肽分子A54的稀乙酸溶液15ml分三次加入，继续球磨0.5h。将球磨的样品放置在120℃的真空干燥箱中，干燥1h，去除所有溶剂至恒重，所得样品为载药微球。本实施例所制备的载药微球对阿莫西林吸附曲线如图4所示。

Claims (5)

1.一种具有靶向和响应缓释特性的抗骨髓瘤载药微球的制备方法，所述方法以层状结构的蒙脱土为支撑载体，通过阳离子交换，在蒙脱土层间合成粒径可控的球状纳米碳酸钙，制备MMT-NanoCaCO3为先驱模板；通过阴离子交换，将球状NanoCaCO3转变为纳米HAp，获得HAp-MMT药物载体；同时在MMT表面通过静电吸附作用连接壳寡糖COS 作为连接物；利用壳寡糖氨基端共价结合羧基端，引入对抗骨髓瘤细胞具有靶向特性的多肽A54，制备一种具有主动靶向和pH响应缓释功能的载药微球；
所述方法的步骤如下：
（1）在室温条件下，将30ml一定浓度的氯化钙溶液匀速倒入到装有150 ml的MMT水悬浮液的三颈烧瓶中，机械搅拌4h，充分混合均匀；
（2）在步骤（1）的产物中缓慢滴加30ml Na2CO3水溶液，同时控制pH在7~8之间，滴加溶液结束后，继续搅拌2h后，静置陈化24h，抽滤洗涤，在烘箱80℃条件下干燥2h后，管式炉中焙烧1h；
（3）步骤（2）中产物研磨后，配置成质量浓度为5%的水悬浮液，将浓度为0.1mol/L的磷酸盐水溶液滴加到悬浮液中，机械搅拌0.5h，将混合溶液转移至聚四氟乙烯内衬的水热反应釜中，在120℃条件下反应1h，将水热反应釜中产物倒出，并用去离子水洗涤，60℃下干燥24h；
（4）将步骤（3）所得产物放置在球磨机中，将COS的无水乙醇溶液15ml分三次加入，球磨0.5h后，再将多肽A54的稀乙酸溶液15ml分三次加入，继续球磨0.5h；将球磨的样品放置在120℃的真空干燥箱中，干燥1h，去除所有溶剂至恒重，所得样品为载药微球。
2.根据权利要求1所述的具有靶向和响应缓释特性的抗骨髓瘤载药微球的制备方法，其特征在于，所述氯化钙溶液质量浓度为1%～5%，MMT悬浮液浓度为2%～5%。
3.根据权利要求1所述的具有靶向和响应缓释特性的抗骨髓瘤载药微球的制备方法，其特征在于，所述Na2CO3水溶液质量浓度为2%～8%。
4.根据权利要求1所述的具有靶向和响应缓释特性的抗骨髓瘤载药微球的制备方法，其特征在于，所述磷酸盐为NaH2PO4和Na2HPO4的一种，用量为8～12ml。
5.根据权利要求1所述的具有靶向和响应缓释特性的抗骨髓瘤载药微球的制备方法，其特征在于，所述COS乙醇溶液浓度为0.05mol/L～0.1mol/L，多肽A54的用量为5-10mg。
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