CN106943603A - 一种以pH敏感胶束为模板的纳米金壳的制备方法 - Google Patents
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Abstract
本发明属于生物纳米医学技术领域,具体公开了一种以pH敏感胶束为模板的纳米金壳的制备方法,具体包括如下步骤:(1)PDPA+DDAT合成;(2)PDPA的合成;(3)BA‑PBLA的合成;(4)PBLA‑PDPA的合成;(5)PAsp(DAB)‑PDPA的合成;(6)胶束的制备;(7)纳米金种子的制备;(8)纳米金壳的制备。本发明制备的纳米金壳的粒径分布在40nm左右,并且比较均一,相对于现有的纳米金壳粒径较小,可防止治疗药物在中性条件下泄露,并且能更好的实现治疗药物的可控释放。
Description
技术领域
本发明涉及生物纳米医学技术领域,具体地,涉及一种以pH敏感胶束为模板的纳米金壳的制备方法。
背景技术
单一治疗的方法难以有效治疗恶性肿瘤。例如,化疗存在副作用大、靶向性差、容易产生耐药性等问题,热疗存在治疗持久性差等问题,组合化疗和热疗充分结合他们的优势是一种潜在有效的途经。因此,开发多功能的组合化疗和热疗的纳米药物载体变得尤为重要。这种载体要具备以下特征:1.能有效的包载药物,并且能靶向癌症组织后能有效释放;2.能作为热疗的对比剂具有有效的光热转换效果。纳米金壳具有上述特点,是一种理想的材料。传统的纳米金壳很多以介孔硅或者PLGA等非响应性材料作为模版,但是以介孔硅或者PLGA等非响应性材料作为模版的纳米金壳存在储存泄露,在非靶点位置释放或者靶点位置释放过慢等缺点。两亲性聚合物胶束可以在体内的特定环境下分解从而释放药物,可以实现药物在靶点释放的目的,但是,现有技术中公开的以两亲性聚合物胶束为模版的纳米金壳的粒径都比较大,造成在中性条件下容易泄露药物,并且不能很好的实现治疗药物的可控释放。
发明内容
本发明的目的是为了克服现有技术的不足,提供一种以pH敏感胶束为模板的纳米金壳的制备方法。
为了实现上述目的,本发明是通过以下技术方案予以实现的:
一种以pH敏感胶束为模板的纳米金壳的制备方法,包括如下步骤:(1)PDPA+DDAT合成;(2)PDPA的合成;(3)BA-PBLA的合成;(4)PBLA-PDPA的合成;(5)PAsp(DAB)-PDPA的合成;(6)胶束的制备:将聚合物PAsp(DAB)-PDPA和阿霉素按2:1~1:2的质量比溶于甲醇中,在超声作用下缓慢滴到中性水中,超声混匀后,在大量的水中透析,最后用水性过滤器过滤,得到包载阿霉素的胶束溶液;(7)纳米金种子的制备:向氯金酸和柠檬酸溶液中加入硼氢化钠溶液,混匀后用220nm的水性过滤器过滤,即得纳米金种子;(8)纳米金壳的制备:将纳米金种子加入到胶束溶液中,搅拌混匀,将pH值为7.0~8.0的氯金酸溶液加入上述溶液中,混匀加入羟胺溶液,混匀后再加入PEG5k-SH,搅拌混匀,最后用大量的水透析,浓缩即得。
优选地,所述胶束的制备具体为:将聚合物PAsp(DAB)-PDPA和阿霉素按2:1~1:2的质量比溶于2~5mL甲醇中,在超声作用下缓慢滴到10~20mL中性的水中,超声2~4min,然后在大量的水中透析6~10h,最后用450nm的水性过滤器过滤,得到包载阿霉素的胶束溶液。
优选地,所述纳米金种子的制备具体为:将100~250μL的20mM的氯金酸和柠檬酸溶液稀释到20~30mL,在搅拌的情况下加入30~60μL的1M的硼氢化钠溶液,搅拌混匀,然后用220nm的水性过滤器过滤。
优选地,所述纳米金壳的制备具体为:取100~500μL的纳米金种子加入步骤(6)制备的胶束溶液中,搅拌4~10h,取0.5~1mL氯金酸溶液,用1M的氢氧化钠溶液调pH值到7.0~8.0,然后加入上述溶液中,搅拌10min,然后加入0.5~1mL的5%的羟胺溶液,搅拌10min,然后加入10~40mg的PEG5k-SH,搅拌24h,最后用大量的水透析4~8h,浓缩即得。
优选地,所述PDPA+DDAT合成为:将2.19g的DBA单体,0.31g DDAT,0.01gAIBN和30ml二氧六环,通氮气鼓泡30min,密封,70℃油浴锅中反应12h,在二氧六环中透析3天,水中透析2天,冻干,即得。
优选地,所述PDPA合成为将1g的PDPA+DDAT,0.31gAIBN和30ml二氧六环,通氮气鼓泡30min,80℃油浴锅中反应12h,在二氧六环中透析3天,水中透析2天,冻干,即得。
优选地,所述BA-PBLA合成为将19.5μL正丁胺,1g BLA-NCA和30mL氯仿,在35℃反应72h,乙醚沉淀,离心收集沉淀,抽干,即得。
优选地,所述PBLA-PDPA合成为将0.15g的PDPA,0.12g的PBLA,0.15g的EDC.HCl,0.09g的NHS和30mL的氯仿,反应48h,乙醚沉淀,离心收集沉淀,抽干即得。
优选地,所述PAsp(DAB)-PDPA的合成为将0.2g的PBLA-PDPA,0.12g的DBA和20mL的DMSO,35℃反应24h,甲醇透析,浓缩抽干,即得。
与现有技术相比,本发明具有如下有益效果:
本发明制备的纳米金壳的粒径分布在40nm左右,并且比较均一,相对于现有的纳米金壳粒径较小,可防止治疗药物在中性条件下泄露,并且能更好的实现治疗药物的可控释放。
另外,本发明的纳米金壳以两亲性pH响应性聚合物胶束为模板,同时将阿霉素包载在胶束的核内,然后通过静电作用将金种子吸附到胶束的亲水层上,最后形成一层非致密金壳,通过控制条件使纳米金壳的最大吸收波长移到近红外区。在近红外区组织的背景干扰最少。
附图说明
图1为PDPA及中间产物核磁图。
图2为PAsp(DAB)-PDPA及中间产物核磁图。
图3为胶束纳米粒子的粒径分布图。
图4为纳米金种子的粒径分布图。
图5为纳米金壳的粒径分布图。
图6胶束纳米粒子的TEM。
图7纳米金种子的TEM。
图8为纳米金壳的TEM。
图9为纳米金壳的紫外-可见光-近红外吸收光谱图。
图10为光热转换图。
具体实施方式
下面结合说明书附图和具体实施例对本发明作出进一步地详细阐述,所述实施例只用于解释本发明,并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
实施例1
一种以pH敏感胶束为模板的纳米金壳的制备方法,包括如下步骤:
(1)PDPA+DDAT的合成:向50mL的反应瓶中加入2.19g的DBA单体,0.31gDDAT,0.01gAIBN和30ml二氧六环,通氮气鼓泡30min,密封,放入到70℃的油浴锅中反应12h,在二氧六环中透析3天,水中透析2天,冻干,得到淡黄色粉末2.05g。产物经核磁检测后,结果如图1,由图1可以得知,主要的核磁峰都有一个很好的归属,表明PDPA+DDAT已经成功制备。
(2)PDPA的合成:向50mg反应瓶中加入1g的PDPA+DDAT,0.31gAIBN和30ml二氧六环,通氮气鼓泡30min,放入到80℃的油浴锅中反应12h,在二氧六环中透析3天,水中透析2天,冻干,得到淡白色粉末0.71g。
(3)BA-PBLA的合成:向50mL的反应瓶中加入19.5μL正丁胺,1g BLA-NCA和30mL氯仿,在35℃反应72h,用大量乙醚沉淀,离心收集沉淀,抽干,得白色固体0.72g。
(4)PBLA-PDPA的合成:向50mL的反应瓶中加入0.15g的PDPA,0.12g的PBLA,0.15g的EDC.HCl,0.09g的NHS和30mL的氯仿,反应48h,然后用大量的乙醚沉淀2次,离心收集沉淀,抽干得淡黄色固体0.23g。
(5)PAsp(DBA)-PDPA:向50mL的反应瓶中加入0.2g的PBLA-PDPA,0.12g的DBA和20mL的DMSO,35℃反应24h。在大量甲醇中透析,浓缩抽干,得淡黄色固体0.12g。产物经核磁检测后,结果如图2,由图2可以得知,主要的核磁峰都有一个很好的归属,表明PAsp(DAB)-PDPA已经成功制备。
(6)胶束的制备:将10mg聚合物PAsp(DAB)-PDPA和1.5mg的阿霉素溶于2mL甲醇中,在超声作用下缓慢滴到10mL,超声4min,然后在大量的水中透析6h,最后用450nm的水性过滤器过滤,得到包载阿霉素的胶束溶液。
(7)纳米金种子的制备:向小烧杯中加入250μL的20mM的氯金酸和柠檬酸溶液,稀释到20mL,在搅拌的情况下加入30μL的1M的硼氢化钠溶液,搅拌10min,然后用220nm的水性过滤器过滤。
(8)纳米金壳的制备:取100μL的纳米金种子加入步骤(6)制备的胶束溶液中,搅拌4h,取1mL氯金酸溶液,用1M的氢氧化钠溶液调pH值到8.0,然后加入上述溶液中,搅拌10min,然后加入1mL的5%的羟胺溶液,搅拌10min,然后加入40mg的PEG5k-SH,搅24h,最后用大量的水透析8h,浓缩。
载体结构的证明:用动态光散射仪对胶束、纳米金种子、纳米金壳进行水化粒径测量,结果见图3~5。从图3中的粒径分布图,可以看出,胶束的粒径大致分布在20nm左右,并且比较均一,从图4中的粒径分布图,可以看出,纳米金种子的粒径大致分布在3nm左右,并且比较均一。从图5中的粒径分布图,可以看出,纳米金壳的粒径大致分布在40nm左右,并且比较均一。以透射电子显微镜(TEM)表征聚合物胶束的形貌,以PhihPsCM120电子显微镜表征,激发电压为60KV。样品的制备方法如下:将10μL(浓度为1mg/mL)的样品溶液滴于铜网上,静置1min后,以滤纸吸干。风干,以醋酸铀(质量浓度为2%)对胶束样品进行染色,静置1min后,用滤纸吸干(纳米金种子和纳米金壳不需要染色)。将铜网置于干燥器继续室温干燥。用紫外-可见光-近红外光谱仪测试纳米金壳的光谱吸收。
光热效应的评价:取1mL的PBS或者纳米金壳放入5mL的小水杯中,用2W的激光照射5min,测不同时间的温度。
实施例2
一种以pH敏感胶束为模板的纳米金壳的制备方法,包括如下步骤:
步骤(1)至(7)同实施例1;
(8)纳米金壳的制备:取100μL的纳米金种子加入步骤(6)制备的胶束溶液中,搅拌4h,取0.6mL氯金酸溶液,用1M的氢氧化钠溶液调pH值到7.0~8.0,然后加入上述溶液中,搅拌10min,然后加入0.6mL的5%的羟胺溶液,搅拌10min,然后加入40mg的PEG5k-SH,搅24h,最后用大量的水透析8h,浓缩。
实施例3
一种以pH敏感胶束为模板的纳米金壳的制备方法,包括如下步骤:
步骤(1)至(7)同实施例1;
(8)纳米金壳的制备:取500μL的纳米金种子加入步骤(6)制备的胶束溶液中,搅拌4h,取1mL氯金酸溶液,用1M的氢氧化钠溶液调pH值到7.0~8.0,然后加入上述溶液中,搅拌10min,然后加入1mL的5%的羟胺溶液,搅拌10min,然后加入40mg的PEG5k-SH,搅24h,最后用大量的水透析8h,浓缩。
实施例4
一种以pH敏感胶束为模板的纳米金壳的制备方法,包括如下步骤:
步骤(1)至(7)同实施例1;
(8)取200μL的纳米金种子加入步骤(6)制备的胶束溶液中,搅拌4h,取0.8mL氯金酸溶液,用1M的氢氧化钠溶液调pH值到7.0~8.0,然后加入上述溶液中,搅拌10min,然后加入0.6mL的5%的羟胺溶液,搅拌10min,然后加入40mg的PEG5k-SH,搅24h,最后用大量的水透析8h,浓缩。
Claims (9)
1.一种以pH敏感胶束为模板的纳米金壳的制备方法,其特征在于,包括如下步骤:(1)PDPA+DDAT合成;(2)PDPA的合成;(3)BA-PBLA的合成;(4)PBLA-PDPA的合成;(5)PAsp(DAB)-PDPA的合成;(6)胶束的制备:将聚合物PAsp(DAB)-PDPA和阿霉素按2:1~1:2的质量比溶于甲醇中,在超声作用下缓慢滴到中性水中,超声混匀后,在大量的水中透析,最后用水性过滤器过滤,得到包载阿霉素的胶束溶液;(7)纳米金种子的制备:向氯金酸和柠檬酸溶液中加入硼氢化钠溶液,混匀后用220nm的水性过滤器过滤,即得纳米金种子;(8)纳米金壳的制备:将纳米金种子加入到胶束溶液中,搅拌混匀,将pH值为7.0~8.0的氯金酸溶液加入上述溶液中,混匀加入羟胺溶液,混匀后再加入PEG5k-SH,搅拌混匀,最后用大量的水透析,浓缩即得。
2.根据权利要求1所述的制备方法,其特征在于,所述胶束的制备具体为:将聚合物PAsp(DAB)-PDPA和阿霉素按2:1~1:2的质量比溶于2~5mL甲醇中,在超声作用下缓慢滴到10~20mL中性的水中,超声2~4min,然后在大量的水中透析6~10h,最后用450nm的水性过滤器过滤,得到包载阿霉素的胶束溶液。
3.根据权利要求1所述的制备方法,其特征在于,所述纳米金种子的制备具体为:将100~250µL的20mM的氯金酸和柠檬酸溶液稀释到20~30mL,在搅拌的情况下加入30~60µL的1M的硼氢化钠溶液,搅拌混匀,然后用220nm的水性过滤器过滤。
4.根据权利要求1所述的制备方法,其特征在于,所述纳米金壳的制备具体为:取100~500µL的纳米金种子加入步骤(6)制备的胶束溶液中,搅拌4~10h,取0.5~1mL氯金酸溶液,用1M的氢氧化钠溶液调pH值到7.0~8.0,然后加入上述溶液中,搅拌10min,然后加入0.5~1mL的5%的羟胺溶液,搅拌10min,然后加入10~40mg的PEG5k-SH,搅拌24h,最后用大量的水透析4~8h,浓缩即得。
5.根据权利要求1所述的制备方法,其特征在于,所述PDPA+DDAT合成为:将2.19g的DBA单体,0.31g DDAT,0.01g AIBN和30ml二氧六环,通氮气鼓泡30min,密封,70℃油浴锅中反应12h,在二氧六环中透析3天,水中透析2天,冻干,即得。
6.根据权利要求1所述的制备方法,其特征在于,所述PDPA合成为将1g的PDPA+DDAT,0.31g AIBN和30ml二氧六环,通氮气鼓泡30min,80℃油浴锅中反应12h,在二氧六环中透析3天,水中透析2天,冻干,即得。
7.根据权利要求1所述的制备方法,其特征在于,所述BA-PBLA合成为将19.5µL正丁胺,1g BLA-NCA和30mL氯仿,在35℃反应72h,乙醚沉淀,离心收集沉淀,抽干,即得。
8.根据权利要求1所述的制备方法,其特征在于,所述PBLA-PDPA合成为将0.15g的PDPA,0.12g的PBLA,0.15g的EDC.HCl,0.09g的NHS和30mL的氯仿,反应48h,乙醚沉淀,离心收集沉淀,抽干即得。
9.根据权利要求1所述的制备方法,其特征在于,所述PAsp(DAB)-PDPA的合成为将0.2g的PBLA-PDPA,0.12g的DBA和20mL的DMSO,35℃反应24h,甲醇透析,浓缩抽干,即得。
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