CN113087929B - 一种氢键超分子聚合物纳米颗粒及其制备方法 - Google Patents
一种氢键超分子聚合物纳米颗粒及其制备方法 Download PDFInfo
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- CN113087929B CN113087929B CN202110249365.8A CN202110249365A CN113087929B CN 113087929 B CN113087929 B CN 113087929B CN 202110249365 A CN202110249365 A CN 202110249365A CN 113087929 B CN113087929 B CN 113087929B
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Abstract
本发明公开了一种氢键超分子聚合物纳米颗粒及其制备方法。所述纳米颗粒包括两亲性三嵌段聚合物链,两亲性三嵌段聚合物链规则排列使得所述纳米颗粒内核为第一疏水聚合物链,外壳为亲水聚合物链;第一疏水聚合物链的侧基含有酰胺基团,亲水聚合物链的侧基为具有亲水基团的丙烯酸酯类,第一疏水聚合物链的侧基能够与含有酰胺基团的药物形成多重氢键,实现通过非共价键作用负载药物的目标;和/或相邻的两个第一疏水聚合物链的侧基之间能够形成氢键。本发明利用氢键和亲疏水作用负载药物,由此解决纳米给药系统中药物负载量低,血液循环过程中易泄露的技术问题,并实现响应性释药,提高药物的生物利用度,达到提高治疗指数的目标。
Description
技术领域
本发明属于超分子聚合物领域,更具体地,涉及一种氢键超分子聚合物纳米颗粒及其制备方法。
背景技术
氢键是一种超分子相互作用力,广泛存在于人体内,是一种典型的非共价键作用力,其高度的取向性和对pH、温度等的响应性,在超分子化学及材料中发挥着重要作用。虽然一重氢键的键能较小,结合常数较低,但是多重氢键之间的相互叠加和协同却可以得到具有较强结合能的作用,因而多重氢键结合的超分子聚合物体系得到了广泛的应用和研究。
而随着纳米技术的发展,纳米材料越来越广泛地被应用于临床疾病的诊断、预防和治疗,并且在肿瘤的诊断和治疗上表现出巨大的潜力。纳米材料具有组成多样、形貌可控、表面易修饰、生物相容性好等优点,是良好的药物载体,能够有效调控药物的释放。然而针对含有酰胺基团的药物,传统的纳米给药系统载药量低,其载药原理是基于静电吸附包裹药物,在血液循环过程中易泄露,并且负载药物的方法较复杂,无法控制药物在特定的部位响应性释放。
发明内容
针对现有技术的以上缺陷或改进需求,本发明提供了一种氢键超分子聚合物纳米颗粒及其制备方法,其目的在于利用氢键和亲疏水作用负载药物,由此解决纳米给药系统中药物负载量低,血液循环过程中易泄露的技术问题,并实现响应性释药,提高药物的生物利用度,达到提高治疗指数的目标。
为实现上述目的,按照本发明的一个方面,提供了一种氢键超分子聚合物纳米颗粒,所述纳米颗粒包括两亲性三嵌段聚合物链,所述两亲性三嵌段聚合物链规则排列使得所述纳米颗粒内部为第一疏水聚合物链,外层为亲水聚合物链;所述第一疏水聚合物链的侧基含有酰胺基团,所述亲水聚合物链的侧基为具有亲水基团的丙烯酸酯类,所述第一疏水聚合物链的侧基能够与含有酰胺基团的药物形成氢键,和/或相邻的两个所述第一疏水聚合物链的侧基之间能够形成氢键。
优选地,所述亲水聚合物链为聚二乙二醇乙醚丙烯酸酯或聚乙二醇单甲醚丙烯酸酯。
优选地,所述第一疏水聚合物链的结构式如下所示:
其中,R1为所述第一疏水聚合物的主链,R1包括n个(-CH2-CH-)重复单元,n﹥1,R2为烷基链。示例性地,R2中碳的数量例如可以为1~10。
优选地,所述两亲性嵌段聚合物的亲疏水链段比为0.5~2;优选地,所述纳米颗粒的粒径为100~500nm。
优选地,所述纳米颗粒还包括第二疏水聚合物链,该第二疏水聚合物链的侧基含有酯基和氟原子。
优选地,所述含有酰胺基团的药物具有下式结构:
其中,R3为H、-CO-NH-(CH2)5-CH3或烷基链。当R3为烷基链时,示例性地,R3中碳的数量例如可以为1~10。
按照本发明的另一个方面,提供了一种氢键超分子聚合物纳米颗粒的制备方法,所述方法包括下列步骤:
(1)通过可逆加成-断裂转移聚合方法合成两亲性嵌段共聚物:将具有亲水基团的丙烯酸酯类单体和链转移剂按照(30~60):1的摩尔比例混合,进行聚合反应,然后用液氮淬灭反应,透析、旋蒸除去溶剂后,得到亲水性均聚物;
(2)在所述亲水性均聚物中加入含酰胺基团的单体和含有氟的丙烯酸酯类单体,其中,所述亲水性聚合物的摩尔量:含酰胺基团的单体的摩尔量:含有氟的丙烯酸酯类单体的摩尔量=1:(15~30):(30~60);发生聚合反应,然后用液氮淬灭反应,沉淀、离心后真空干燥,得到两亲性三嵌段共聚物。
(3)将两亲性三嵌段共聚物溶解于有机溶剂中,搅拌至氢键形成,随后加入10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物乳液液滴;
(4)待所述聚合物乳液液滴中有机溶剂挥发完全后,离心、清洗、透析、冷冻干燥,即得到氢键超分子聚合物纳米颗粒。
按照本发明的另一方面,还提供了一种氢键超分子聚合物纳米颗粒的制备方法,所述方法包括下列步骤:
(1)通过可逆加成-断裂转移聚合方法合成两亲性嵌段聚合物链:将具有亲水基团的丙烯酸酯类单体和链转移剂按照(30~60):1的摩尔比例混合,进行聚合反应,然后用液氮淬灭反应,透析、旋蒸除去溶剂后,得到亲水性聚合物;
(2)在所述亲水性聚合物中加入含酰胺基团的单体和含有氟的丙烯酸酯类单体,其中,所述亲水性聚合物的摩尔量:含酰胺基团的单体的摩尔量:含有氟的丙烯酸酯类单体的摩尔量=1:(15~30):(30~60);发生聚合反应,然后用液氮淬灭反应,沉淀、离心后真空干燥,得到两亲性三嵌段聚合物;
(3)将两亲性三嵌段聚合物与含有酰胺基团的药物溶解于有机溶剂中,搅拌至氢键形成,随后加入2~10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物-药物乳液液滴;
(4)待所述聚合物-药物乳液液滴中有机溶剂挥发完全后,离心、清洗、透析、冷冻干燥,即得到通过三重氢键与含酰胺基团的药物连接的所述氢键超分子聚合物纳米颗粒。
优选地,所述有机溶剂为二氯甲烷或三氯甲烷,所述具有亲水基团的丙烯酸酯类单体为二乙二醇乙醚丙烯酸酯或乙二醇单甲醚丙烯酸酯,所述含有氟的丙烯酸酯类单体为2,2,2-丙烯酸三氟乙酯、丙烯酸2,2,3,3,3-五氟丙酯、2,2,3,3-四氟丙基丙烯酸酯、2,2,3,3,4,4,4-七氟丁基丙烯酸酯中的一种。需要说明的是,上述单体可以作为本发明的具体示例,但不应理解为对本发明的限制,现有技术中具有亲水基团的丙烯酸酯类单体均可作为本发明中所述的具有亲水基团的丙烯酸酯类单体,现有技术中含氟的丙烯酸酯类单体且溶解性好的均可作为本发明中所述的含有氟的丙烯酸酯类单体。
优选地,所述链转移剂为二苄基三硫代碳酸酯。
优选地,所述含酰胺基团的单体具有下式结构:
优选地,所述两亲性三嵌段聚合物的浓度为1~15mg/mL,所述聚乙烯醇水溶液的浓度为3~10mg/mL;优选地,所述氢键超分子聚合物纳米颗粒中含有酰胺基团的药物质量分数为10~20%;优选地,所述步骤(3)还包括:在所述有机溶剂中加入疏水型光热剂、疏水型光敏剂或疏水型荧光染料,通过亲疏水作用包裹疏水型光热剂、疏水型光敏剂或疏水型荧光染料。
其中,上述疏水型光热剂可为IR780、卟啉、花菁等;所述疏水型光敏剂可以为酞菁类光敏剂或叶绿素;上述疏水型荧光染料可以为苏丹红、二甲基黄、尼罗红等。
总体而言,通过本发明所构思的以上技术方案与现有技术相比,至少能够取得下列有益效果。
(1)本发明提供的纳米颗粒内核为第一疏水聚合物链,外层为亲水聚合物侧链,该第一疏水聚合物链侧基能够与含有酰胺基团的药物形成多重氢键。通过纳米颗粒与药物之间形成的三重氢键作用,使得纳米颗粒与药物之间具有较强的结合能,避免了血液循环过程中药物易泄露的问题。由于氢键本身对温度和pH敏感,当pH降低或温度升高时,氢键断裂,可以实现药物缓慢持续的从载体中释放出来,实现可控释放。
(2)本发明提供的氢键超分子聚合物纳米颗粒制备方法中,可以通过调节每个聚合物的分子量来调节最终三嵌段聚合物的亲疏水链段比,从而直接影响到聚合物纳米颗粒的尺寸,疏水链越长,尺寸越大。而第一疏水聚合物侧链中氢键单体的含量与药物负载量成正相关。但聚合物纳米颗粒的尺寸并不是越大越好,本发明中优选地控制三嵌段聚合物的亲疏水链段比为0.5~2,可以实现负载含有酰胺基团的药物时的载药量达到10-20%。
(3)本发明提供的氢键超分子聚合物纳米颗粒制备方法中,加入含有氟的丙烯酸酯类单体能够增加聚合物的溶解性。
(4)本发明提供的氢键超分子聚合物纳米颗粒不仅可以通过氢键负载有含有酰胺基团的药物,还可以通过亲疏水作用包裹疏水型光热剂、疏水型光敏剂或疏水型荧光染料。以实现同时负载多种有效成分,达到联合治疗的效果。
(5)本发明提供的氢键超分子聚合物纳米颗粒制备方法步骤简单、条件温和、无需大型仪器、温度适中、成本低廉,设计性强,普适性好。
附图说明
图1是实施例3制备得到的负载卡莫氟(HCFU)和吲哚绿荧光探针(IR780)的氢键超分子聚合物纳米颗粒的透射电子显微镜照片;
图2是实施例3制备得到的负载卡莫氟(HCFU)和吲哚绿荧光探针(IR780)的氢键超分子聚合物纳米颗粒在不同pH和不同温度下的HCFU累积释放曲线。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。此外,下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
实施例1
本实施例提供了一种氢键超分子聚合物纳米颗粒的制备方法,包括下列步骤:
(1)亲水段聚合物聚(二乙二醇乙醚丙烯酸酯)的合成:通过可逆加成-断裂转移(RAFT)活性聚合的方法合成聚合物,单体(二乙二醇乙醚丙烯酸酯)和链转移剂(二苄基三硫代碳酸酯)的摩尔量比例为30/1,在70℃下聚合3h后用液氮淬灭反应,随后在四氢呋喃中透析3h,旋蒸除去溶剂后即可得到数均分子量为4000g/mol的聚(二乙二醇乙醚丙烯酸酯)聚合物,记为POEGEA。
(2)两亲性氢键超分子聚合物的合成:将步骤(1)中得到的亲水段聚合物POEGEA作为大分子链转移剂,同时加入提前合成得到的DAPA(含酰胺键的单体)和TFEA(2,2,2-丙烯酸三氟乙酯)两种单体,其中POEGEA/DAPA/TFEA=1/30/60(摩尔量比),在70℃下聚合3h后用液氮淬灭反应,用甲醇和水的混合溶剂为沉淀剂,沉淀离心,随后真空干燥,即可得到数均分子量为12000g/mol、亲疏水链段比为1/2的两亲性氢键超分子三嵌段共聚物,记为POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA。
(3)将两亲性三嵌段共聚物溶解于有机溶剂中,搅拌至氢键形成,随后加入10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物乳液液滴;
(4)待所述聚合物乳液液滴中有机溶剂挥发完全后,离心、清洗、透析、冷冻干燥,即得到氢键超分子聚合物纳米颗粒。
该两亲性氢键超分子三嵌段共聚物的结构可以用下式进行表示:
其中,上文中DAPA的合成按照下列步骤进行:
(2-1)称取2,6-二氨基吡啶(10.9g,100mmol)和三乙胺(20.88mL,150mmol)溶于150mL无水二氯甲烷中,然后向该溶液中缓慢滴加丁酰氯(9.3mL,90mmol)并在室温下反应过夜。待反应进行完全后旋蒸除去二氯甲烷,将得到的黑红色固体溶解在100mL乙酸乙酯中并依次用饱和食盐水、饱和碳酸氢钠、0.1M盐酸和水萃取,收集得到有机相并用无水硫酸镁干燥,过滤旋蒸后得到粗产物。最后利用柱层析的方法提纯(洗脱剂为石油醚/乙酸乙酯=1/1,v/v),收集产物除去溶剂后真空干燥即可得到化合物1。
(2-2)向250mL重蒸四氢呋喃中加入化合物1(7.6g,42mmol)和三乙胺(17.55mL,127mmol),待溶解完全后向溶液中缓慢滴加丙烯酰氯(10.3mL,127mmol),随后在室温下反应过夜。反应进行完全后旋蒸除去溶剂并将所得的固体溶解于二氯甲烷中,依次用饱和食盐水、饱和碳酸氢钠和水萃取,随即将有机相用无水硫酸镁干燥后过滤,得到的粗产物通过柱层析方法(洗脱剂为二氯甲烷/甲醇,100:3)提纯,收集产物旋蒸除去溶剂,真空干燥后即得DAPA单体。
实施例2
本实施例提供了一种氢键超分子聚合物纳米颗粒的制备方法,包括下列步骤:
(1)亲水段聚合物聚(二乙二醇乙醚丙烯酸酯)的合成:通过可逆加成-断裂转移(RAFT)活性聚合的方法合成聚合物,单体(二乙二醇乙醚丙烯酸酯)和链转移剂(二苄基三硫代碳酸酯)的摩尔量比例为60/1,在70℃下聚合3h后用液氮淬灭反应,随后在四氢呋喃中透析3h,旋蒸除去溶剂后即可得到数均分子量为8000g/mol的聚合物,记为POEGEA。
(2)两亲性氢键超分子聚合物的合成:将步骤(1)中得到的亲水段聚合物POEGEA作为大分子链转移剂,同时加入DAPA和TFEA两种单体,其中POEGEA/DAPA/TFEA=1/15/30(摩尔量比),在70℃下聚合3h后用液氮淬灭反应,用甲醇和水的混合溶剂为沉淀剂,沉淀离心,随后真空干燥,即可得到数均分子量为12000g/mol、亲疏水链段比为2/1的两亲性氢键超分子三嵌段共聚物,记为POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA。
(3)将两亲性三嵌段共聚物溶解于有机溶剂中,搅拌至氢键形成,随后加入10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物乳液液滴;
(4)待所述聚合物乳液液滴中有机溶剂挥发完全后,离心、清洗、透析、冷冻干燥,即得到氢键超分子聚合物纳米颗粒。
该两亲性氢键超分子三嵌段共聚物的结构式以及DAPA的制备方法与实施例1中相同。
实施例3
本实施例提供一种负载有卡莫氟、IR780的氢键超分子聚合物纳米颗粒的制备方法,具体包含以下步骤:
(1)POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒的制备:将通过实施例1制备得到的聚合物溶解于1.5mL三氯甲烷中,同时加入6mg HCFU、2.25mg IR780,搅拌过夜,然后加入10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物乳液液滴,静置于30℃恒温环境中。
(2)POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒的后处理:待上述溶液中三氯甲烷挥发完全后,离心,并将所得的纳米颗粒放入透析袋中透析,一段时间后,将透析袋中的溶液冷冻干燥,即可得到POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒,其粒径约400nm,HCFU的负载量为18%。
实施例4
本实施例提供一种负载有卡莫氟、IR780的氢键超分子聚合物纳米颗粒的制备方法,具体包含以下步骤:
(1)POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒的制备:将通过实施例1制备得到的聚合物溶解于5mL三氯甲烷中,同时加入6mg HCFU、2.25mg IR780,搅拌过夜,然后加入10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物乳液液滴,静置于30℃恒温环境中,挥发三氯甲烷。
(2)POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒的后处理:待上述溶液中三氯甲烷挥发完全后,离心,并将所得的纳米颗粒放入透析袋中透析,一段时间后,将透析袋中的溶液冷冻干燥,即可得到POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒,其粒径约200nm,HCFU的负载量为12%。
实施例5
本实施例提供一种负载有卡莫氟、IR780的氢键超分子聚合物纳米颗粒的制备方法,具体包含以下步骤:
(1)POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒的制备:将通过实施例2制备得到的聚合物溶解于1.5mL三氯甲烷中,同时加入6mg HCFU、2.25mg IR780,搅拌过夜,然后加入10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物乳液液滴,静置于30℃恒温环境中。
(2)POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒的后处理:透析完成后,将透析袋中的溶液取出,冷冻干燥,即可得到POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒,其粒径约200nm,HCFU的负载量为15%。
实施例6
本实施例提供一种负载有卡莫氟、IR780的氢键超分子聚合物纳米颗粒的制备方法,具体包含以下步骤:
(1)POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒的制备:将通过实施例2制备得到的聚合物溶解于5mL三氯甲烷中,同时加入6mg HCFU、2.25mg IR780,搅拌过夜,然后加入10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物乳液液滴,静置于30℃恒温环境中。
(2)POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒的后处理:透析完成后,将透析袋中的溶液取出,冷冻干燥,即可得到POEGEA-b-P(DAPA-co-TFEA)-b-POEGEA@HCFU/IR780纳米颗粒,其粒径约150nm,HCFU的负载量为10%。
结果与分析:
图1为实施例3制备得到的负载卡莫氟(HCFU)和吲哚绿荧光探针(IR780)的氢键超分子聚合物纳米颗粒的透射电子显微镜照片。可以看出,其为规则球形。
图2为实施例3制备得到的负载卡莫氟(HCFU)和吲哚绿荧光探针(IR780)的氢键超分子聚合物纳米颗粒在不同pH和不同温度下的HCFU累积释放曲线。该曲线示出了纳米粒子在不同pH下的释放,以及在释放过程中给与了两次光照,光照时,纳米粒子中负载的光热剂可以将光能转化成热量使温度升高,从而加速氢键的断裂,促进HCFU的释放。
本领域的技术人员容易理解,以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (7)
1.一种氢键超分子聚合物纳米颗粒,其特征在于,所述纳米颗粒包括两亲性三嵌段聚合物,所述两亲性三嵌段聚合物规则排列使得所述纳米颗粒内核为第一疏水聚合物链,外层为亲水聚合物链;所述第一疏水聚合物链的侧基含有酰胺基团,所述亲水聚合物链的侧基为含有亲水基团的丙烯酸酯类聚合物链段;所述第一疏水聚合物链的侧基能够与含有酰胺基团的药物形成多重氢键作用,和/或相邻的两个所述第一疏水聚合物链的侧基之间能够形成氢键;所述亲水聚合物链为聚二乙二醇乙醚丙烯酸酯或聚乙二醇单甲醚丙烯酸酯;
所述第一疏水聚合物链的结构式如下所示:
其中,R1为所述第一疏水聚合物的主链,R1包括n个(-CH2-CH-)重复单元,n﹥1,R2为烷基链;
所述两亲性嵌段聚合物的亲疏水链段比为0.5~2;所述纳米颗粒的粒径为50~500nm;所述纳米颗粒还包括第二疏水聚合物链,该第二疏水聚合物链的侧基含有酯基和氟原子。
3.一种氢键超分子聚合物纳米颗粒的制备方法,其特征在于,所述方法包括下列步骤:
(1)通过可逆加成-断裂转移聚合方法合成两亲性嵌段聚合物链:将具有亲水基团的丙烯酸酯类单体和链转移剂按照(30~60):1的摩尔比例混合,进行聚合反应,然后用液氮淬灭反应,透析、旋蒸除去溶剂后,得到亲水性聚合物;
(2)在所述亲水性聚合物中加入含酰胺基团的单体和含有氟的丙烯酸酯类单体,其中,所述亲水性聚合物的摩尔量:含酰胺基团的单体的摩尔量:含有氟的丙烯酸酯类单体的摩尔量=1:(15~30):(30~60);发生聚合反应,然后用液氮淬灭反应,沉淀、离心后真空干燥,得到两亲性三嵌段聚合物;
(3)将两亲性三嵌段聚合物溶解于有机溶剂中,搅拌至氢键形成,随后加入2~10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物乳液液滴;
(4)待所述聚合物乳液液滴中有机溶剂挥发完全后,离心、清洗、透析、冷冻干燥,即得到氢键超分子聚合物纳米颗粒;
其中,所述有机溶剂为二氯甲烷或三氯甲烷,所述具有亲水基团的丙烯酸酯类单体为二乙二醇乙醚丙烯酸酯或乙二醇单甲醚丙烯酸酯,所述含有氟的丙烯酸酯类单体为2,2,2-丙烯酸三氟乙酯、丙烯酸2,2,3,3,3-五氟丙酯、2,2,3,3-四氟丙基丙烯酸酯、2,2,3,3,4,4,4-七氟丁基丙烯酸酯中的一种;所述链转移剂为二苄基三硫代碳酸酯;所述含酰胺基团的单体具有下式结构:
4.一种氢键超分子聚合物纳米颗粒的制备方法,其特征在于,所述方法包括下列步骤:
(1)通过可逆加成-断裂转移聚合方法合成两亲性嵌段聚合物链:将具有亲水基团的丙烯酸酯类单体和链转移剂按照(30~60):1的摩尔比例混合,进行聚合反应,然后用液氮淬灭反应,透析、旋蒸除去溶剂后,得到亲水性聚合物;
(2)在所述亲水性聚合物中加入含酰胺基团的单体和含有氟的丙烯酸酯类单体,其中,所述亲水性聚合物的摩尔量:含酰胺基团的单体的摩尔量:含有氟的丙烯酸酯类单体的摩尔量=1:(15~30):(30~60);发生聚合反应,然后用液氮淬灭反应,沉淀、离心后真空干燥,得到两亲性三嵌段聚合物;
(3)将两亲性三嵌段聚合物与含有酰胺基团的药物溶解于有机溶剂中,搅拌至氢键形成,随后加入2~10倍体积的聚乙烯醇水溶液,利用超声波细胞粉碎仪或者过膜乳化的方法制备得到聚合物-药物乳液液滴;
(4)待所述聚合物-药物乳液液滴中有机溶剂挥发完全后,离心、清洗、透析、冷冻干燥,即得到通过三重氢键与含酰胺基团的药物连接的所述氢键超分子聚合物纳米颗粒;
其中,所述有机溶剂为二氯甲烷或三氯甲烷,所述具有亲水基团的丙烯酸酯类单体为二乙二醇乙醚丙烯酸酯或乙二醇单甲醚丙烯酸酯,所述含有氟的丙烯酸酯类单体为2,2,2-丙烯酸三氟乙酯、丙烯酸2,2,3,3,3-五氟丙酯、2,2,3,3-四氟丙基丙烯酸酯、2,2,3,3,4,4,4-七氟丁基丙烯酸酯中的一种;所述链转移剂为二苄基三硫代碳酸酯;所述含酰胺基团的单体具有下式结构:
5.根据权利要求3或4所述的制备方法,其特征在于,所述两亲性三嵌段聚合物的浓度为1~15mg/mL,所述聚乙烯醇水溶液的浓度为1~10mg/mL。
6.根据权利要求4所述的制备方法,其特征在于,所述氢键超分子聚合物纳米颗粒中含有酰胺基团的药物质量分数为10~20%。
7.根据权利要求4所述的制备方法,其特征在于,所述步骤(3)还包括:在所述有机溶剂中加入疏水型光热剂、疏水型光敏剂或疏水型荧光染料,通过亲疏水作用包裹疏水型光热剂、疏水型光敏剂或疏水型荧光染料。
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