CN110478496B - 一种粒径均匀、尺寸可控的高分子纳米药物载体油胺枝接聚琥珀酰亚胺的制备方法 - Google Patents
一种粒径均匀、尺寸可控的高分子纳米药物载体油胺枝接聚琥珀酰亚胺的制备方法 Download PDFInfo
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Abstract
本发明公开了一种粒径均匀、尺寸可控的高分子纳米药物载体油胺枝接聚琥珀酰亚胺的制备方法,将高分子枝接聚合物PSIOAm溶于能与水互溶的四氢呋喃作为油相,氢氧化钠溶液作为水相,将等体积的两相溶液高速注入混合器的密闭腔体中,生成的混合溶液从出口流出,用容器收集乳液,完成制备过程。该方法绿色低能耗,简单快速,所制备的纳米药物载体粒径均匀,尺寸可控,粒径分布在70~150nm。该发明为有望应用于癌症临床治疗的纳米药物载体PSIOAm提供了新的制备方案。
Description
技术领域
本发明属于纳米药物载体制备领域,具体涉及一种粒径均匀、尺寸可控的高分子纳米药物载体油胺枝接聚琥珀酰亚胺(PSIOAm)的制备方法。
背景技术
癌症是目前人类健康的重大杀手之一,根据癌症数据统计2018年全球新增癌症病例达到1810万,而死亡病例超过960万,癌症治疗刻不容缓。而目前癌症治疗主要以手术治疗、化学疗法和放射疗法为主,对正常细胞也会产生严重的副作用,手术切除肿瘤的风险和成本均较大,因此,发展高效又低毒的癌症治疗方法意义非凡。高分子纳米药物载体因其生物相容性及可降解性,在癌症治疗方面展现出广阔的应用前景。
高分子聚合物油胺枝接聚琥珀酰亚胺PSIOAm是一种新型pH响应的纳米药物载体,可有效避免无机材料、金属材料的生物降解性差的特点被广泛关注。PSIOAm由于其外壳具有亲水性,使其具有良好的生物相容性和可降解性;内核具有疏水性,药物通过疏水作用被包裹在该纳米球内定向运输至靶细胞。作为一种未来有望应用于癌症临床治疗的药物载体,其设计通常与粒径大小,形态,电荷和内在结构有关,所以制备尺寸均匀的纳米药物载体是该领域共同关心的话题。而现有方法制备的纳米粒子,在纯度、产率、粒径分布、均匀性及粒子的可控制性等方面的问题依然存在,而纳米材料的形貌以及粒径大小是否均匀对其物理、化学特性有着决定性的影响,尤其对于特定功能的纳米材料而言是致命的,是急需解决的关键问题。文献Huang,S.;Bai,M.;Wang,L.,General and facile surfacefunctionalization of hydrophobic nanocrystals with poly(amino acid)for cellluminescence imaging.Sci Rep 2013,3,2023.和Huang,S.;Peng,S.;Li,Y.;Cui,J.;Chen,H.;Wang,L.,Development of NIR-II fluorescence image-guided and pH-responsive nanocapsules for cocktail drug delivery.Nano Research 2015,8(6),1932-1943.报道的关于纳米药物载体PSIOAm的制备方法得到的PSIOAm都不具备制备颗粒的粒径大小均匀,尺寸大小可控制,形状规整的优点。目前尚没有一种方法是提供制备小尺寸粒径均匀可控大小纳米药物载体PSIOAm的。所以本发明提出一种快速制备小尺寸粒径均匀大小可控的纳米药物载体PSIOAm的方法,拟填补这一应用空白。
发明内容
为解决上述关键技术问题,本发明提供了一种粒径均匀、尺寸可控的高分子纳米药物载体油胺枝接聚琥珀酰亚胺(PSIOAm)的制备方法。通过快速纳米沉淀技术制备了粒径均匀、尺寸可控的纳米药物载体PSIOam,其粒径分布在 70~150nm,该方法简单快速,绿色低能耗。制备的粒径均匀、尺寸可控的纳米粒子具有以下优点:纳米粒子产出迅速、产率较高,制备粒径均匀,尺寸大小可控;所得产物纯度高,不需要过滤和透析除去较大粒径的纳米粒子,大幅度节省了生产时间。
本发明提供的一种粒径均匀、尺寸可控的高分子纳米药物载体PSIOAm的制备方法,包括以下步骤:将高分子接枝聚合物PSIOAm溶解于有机溶剂中作为油相,氢氧化钠水溶液作为水相,将两相流体快速同时注入混合器内在混合器腔体中进行湍流混合,生成的混合溶液即为粒径均匀的高分子纳米药物载体 PSIOAm的纳米溶液,依据调整不同的剂量和注入速度,可以得到可控尺寸的目标大小纳米粒子。
所述有机溶剂为四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜中的任意一种或多种,优选为四氢呋喃。
所述高分子接枝聚合物PSIOAm是通过将分子量为6000的聚琥珀酰亚胺和油胺在N,N-二甲基甲酰胺溶剂中加热后,经甲醇沉淀、离心、干燥制备得到;聚琥珀酰亚胺的分子量越大,油胺链越长,得到高分子接枝聚合物的粒径越大;本发明选用分子量为6000的聚琥珀酰亚胺作为原料,这样得到高分子接枝聚合物PSIOAm经快速沉淀后才能得到粒径分布在70~150nm的高分子纳米药物载体 PSIOAm。
所述高分子高分子接枝聚合物PSIOAm在有机溶剂中的浓度为4~10mg/mL,浓度过低,其达不到形成纳米粒子的过饱和度;浓度过高,形成的纳米粒子粒径偏大,且粒径分布不均匀,因此本发明控制PSIOAm浓度为4~10mg/mL。
所述氢氧化钠水溶液的浓度为0.5mmol/L。
所述有机溶剂与氢氧化钠水溶液的体积之比为1:1。
所述湍流混合的时间为2~3s。
所述湍流混合的雷诺数Re为5800,溶剂和反溶剂的充分和快速湍流混合是形成纳米颗粒的先决条件,雷诺数Re对纳米粒子尺寸的影响显著,当Re大于 4000时,流体为湍流状态,本发明将湍流混合的雷诺数Re控制在5800,此条件下能够形成粒径较小的纳米粒子。
所述的混合器为具有混合腔体的CIJ-D密闭混合器,具有至少两个流体注入口和一个流出口。
根据上述制备方法制备得到的粒径均匀、尺寸可控的高分子纳米药物载体PSIOAm,其粒径范围在70~150nm。
本发明提供的粒径均匀的高分子纳米药物载体PSIOAm的制备方法中,选用分子量为6000的聚琥珀酰亚胺和油胺为原料来制备高分子接枝聚合物 PSIOAm,这为快速沉淀法制备粒径为70-150nm的高分子纳米药物载体PSIOAm提供了前提条件;并在湍流混合时控制高分子接枝聚合物PSIOAm在有机溶剂中的浓度、湍流混合的时间及雷诺数,以进一步保证得到粒径为70-150nm且分布均匀的高分子纳米药物载体PSIOAm。
与现有技术相比,本发明具有如下优点:
1.通过快速纳米沉淀制备纳米药物载体PSIOAm,相比于常规超声法制备 PSIOAm,所制备的纳米粒子粒径更加均匀,分布在70-150nm,纳米药物载体粒径可调控,具有纳米材料独特的性质和特点。
2.快速纳米沉淀制备纳米药物载体PSIOAm,简单快速,绿色低能耗,未来可应用于量化生产。
3.该发明为有望应用于癌症临床治疗的纳米药物载体PSIOAm提供了新的制备方案。
附图说明
图1为实施例1制备得到的PSIOAm纳米溶液的SEM图
图2为实施例1制备得到的PSIOAm纳米溶液的TEM图(a)和粒径分布图 (b);
图3为实施例2制备得到的PSIOAm纳米溶液的TEM图(a),SEM图(b) 和粒径分布图(c);
图4为实施例3制备得到的PSIOAm纳米溶液的TEM图(a),SEM图(b) 和粒径分布图(c);
图5为实施例4制备得到的PSIOAm纳米溶液的TEM图(a),SEM图(b) 和粒径分布图(c);
图6为比较例1中的传统超声法制备的PSIOAm纳米粒子的TEM图(a) 和粒径分布图(b)。
具体实施方式
下面结合实施例对本发明进行详细说明。
本发明所使用的高分子接枝聚合物PSIOAm(PSIOAm前驱体)的制备方法为:量取32mLN,N-二甲基甲酰胺加热至90℃,加入1.6g聚琥珀酰亚胺(PSI)及 2.17mL油胺(OAm),保持100℃加热搅拌5小时,最后加入360mL甲醇使其沉淀,离心分离,干燥取沉淀即可得到高分子接枝聚合物PSIOAm。
本发明所用的混合器的型号为CIJ-D型瞬时涡流混合器,厂家为扬州大学化学化工学院朱正曦教授实验室提供。聚琥珀酰亚胺(PSI)的平均相对分子量为 6000,购买自石家庄德赛化工有限公司,油胺购买自阿拉丁公司。
实施例1
一种粒径均匀、尺寸可控的高分子纳米药物载体PSIOAm的制备方法,包括以下步骤:在常温下,首先称取14mg高分子接枝聚合物PSIOAm与3mL四氢呋喃充分混合,并置于100W超声机超声1min,使用注射器针头将溶液吸入 5mL塑料注射器中并清除所有气泡。将3mL的氢氧化钠水溶液吸入到另一同样尺寸的注射器中,以相同速度注射两液体进入混合器。两相液体在混合器腔体中充分湍流混合,所得乳液从混合器出口流出,混合共耗时2秒。用容器收集乳液,并用TEM、SEM和动态光散射法对乳液形貌和粒径大小进行表征,结果如图1、2所示,平均直径dv=83nm。
实施例2
一种粒径均匀、尺寸可控的高分子纳米药物载体PSIOAm的制备方法,包括以下步骤:
在常温下,称取18mg PSIOAm前驱体与3mL四氢呋喃充分混合,并置于 100W超声机超声1min,使用注射器针头将溶液吸入5mL塑料注射器中并清除所有气泡。将3mL氢氧化钠水溶液吸入到另一同样尺寸的注射器中,同时以相同速度注射两液体进入混合器。所得乳液从混合器出口流出,混合共耗时2秒。用容器收集乳液,分别用去离子水和四氢呋喃冲洗混合器,让滞留量排出容器。并用TEM、SEM和动态光散射法对乳液粒径大小和分布进行表征,结果如图3 所示,平均直径dv=95nm。
实施例3
一种粒径均匀、尺寸可控的高分子纳米药物载体PSIOAm的制备方法,包括以下步骤:
在常温下,称取24mg PSIOAm前驱体与3mL四氢呋喃充分混合,并置于 100W超声机超声1min,使用注射器针头将溶液吸入5mL塑料注射器中并清除所有气泡。将3mL氢氧化钠溶液吸入到另一同样尺寸的注射器中,同时以相同速度注射两液体进入混合器,所得乳液从混合器出口流出,混合共耗时2秒。用容器收集乳液,分别用去离子水和四氢呋喃冲洗混合器。并用TEM、SEM和动态光散射法对乳液粒径大小和分布进行表征,结果如图4所示,平均直径dv =96nm。
实施例4
一种粒径均匀、尺寸可控的高分子纳米药物载体PSIOAm的制备方法,包括以下步骤:在常温下,称取28mg PSIOAm前驱体与3mL四氢呋喃充分混合,并置于100W超声机超声1min,使用注射器针头将溶液吸入5mL塑料注射器中并清除所有气泡。将3mL氢氧化钠溶液吸入到另一同样尺寸的注射器中,同时以相同速度注射两液体进入混合器。两相液体在混合器腔体中充分湍流混合,混合共耗时2秒,用容器收集乳液,分别用去离子水和四氢呋喃冲洗混合器,让滞留量排出容器。并用TEM、SEM和动态光散射法对乳液粒径大小和分布进行表征,结果如图5所示,平均直径dv=105nm。
比较例1
一种PSIOAm纳米粒子的制备方法,具体步骤为:称取60mg高分子接枝聚合物PSIOAm溶于1mL氯仿中,该溶液分散在10mL 0.5mmol/L NaOH中, 200W功率下超声5min,得到的乳状溶液在58℃下去除氯仿,离心取沉淀部分分散在10mL pH=7.4的PBS中,得到PSIOAm纳米粒子,对产物进行TEM和粒径分布表征。
从图6可以看出,此超声法制备PSIOAm纳米粒子耗时长,高能量输出,粒径较大,粒径范围在200-700nm,粒径分布不均匀,限制了纳米粒子的应用与发展。
上述参照实施例对一种粒径均匀、尺寸可控的高分子纳米药物载体油胺枝接聚琥珀酰亚胺(PSIOAm)的制备方法进行的详细描述,是说明性的而不是限定性的,可按照所限定范围列举出若干个实施例,因此在不脱离本发明总体构思下的变化和修改,应属本发明的保护范围之内。
Claims (4)
1.一种粒径均匀、尺寸可控的高分子纳米药物载体PSIOAm的制备方法,其特征在于,所述制备方法包括以下步骤:将高分子接枝聚合物PSIOAm溶解于有机溶剂中作为油相,氢氧化钠水溶液作为水相,将两相流体快速同时注入混合器内在混合器腔体中进行湍流混合,生成的混合溶液即为粒径均匀的高分子纳米药物载体PSIOAm的纳米溶液;
所述高分子接枝聚合物PSIOAm是通过将分子量为6000的聚琥珀酰亚胺和油胺在N,N-二甲基甲酰胺溶剂中加热后,经甲醇沉淀、离心、干燥制备得到;
所述高分子接枝聚合物PSIOAm在有机溶剂中的浓度为4~10mg/mL;
所述有机溶剂与氢氧化钠水溶液的体积之比为1:1;
所述湍流混合的雷诺数Re为5800;所述湍流混合的时间为2~3s;
所述的混合器为具有混合腔体的CIJ-D型密闭混合器,具有至少两个流体注入口和一个流出口;
所述粒径均匀、尺寸可控的高分子纳米药物载体PSIOAm的粒径范围在70~150nm。
2.根据权利要求1所述的制备方法,其特征在于,所述有机溶剂为四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜中的任意一种或多种。
3.根据权利要求1或2所述的制备方法,其特征在于,所述氢氧化钠水溶液的浓度为0.5mmol/L。
4.根据权利要求1-3任意一项所述的制备方法制备得到的粒径均匀、尺寸可控的高分子纳米药物载体PSIOAm,其特征在于,所述粒径均匀的高分子纳米药物载体PSIOAm的平均粒径在70~150nm。
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