CN113633785B - 一种智能响应性壳-核式聚电解质纳米凝胶的制备方法与应用 - Google Patents
一种智能响应性壳-核式聚电解质纳米凝胶的制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种智能响应性壳‑核式聚电解质纳米凝胶的制备方法与应用,该纳米凝胶由透明质酸或其衍生物、类似物的壳层和由谷胱甘肽敏感或酸敏感的交联剂交联而成的配体修饰的超支化聚乙烯亚胺的核层构成,透明质酸外壳和超支化聚乙烯亚胺内核再由肿瘤微环境敏感的交联剂通过点击化学反应连接形成智能响应性壳‑核式纳米凝胶。该纳米凝胶由于其带电性可包载多种含电性的亲疏水药物或蛋白质,并且含有多种肿瘤微环境响应的交联剂,可在肿瘤部位响应并快速释放其包载的药物,达到高效的抗肿瘤效果。
Description
技术领域
本发明涉及高分子材料制备方法及用途,特别涉及一种智能响应性壳-核式聚电解质纳米凝胶的制备方法与应用。
背景技术
在过去的几十年里,为了解决化疗药物的精准治疗,人们研制了各种生物相容性的纳米给药系统如聚合物前药、纳米胶束、囊泡、脂质体等来提高药物的稳定性、溶解性和延长体内循环时间。如(聚乙二醇-聚乳酸负载紫杉醇的胶束药物),已被应用于非小细胞肺癌、乳腺癌、卵巢癌的临床治疗;/>(白蛋白结合型紫杉醇纳米药物)已被应用于转移性乳腺癌、非小细胞肺癌(与卡铂联用)、晚期胰腺癌(与吉西他滨联用)等的治疗。但随着人们的研究发现,纳米药物在临床治疗中仍然存在一些难以克服的问题,如药物早泄,细胞内吞效率低及在病灶部位不能迅速释放等。
随着人们对肿瘤微环境的研究,利用肿瘤组织较低pH、较高的活性氧水平和各种酶的过表达,多功能智能响应性的纳米药物被大量研发来达到药物的控制释放,提高药物的生物利用度。人们利用肿瘤微环境的特点,设计出可解体的纳米载体。该纳米载体在血液循环中,能够保持稳定的结构和合适的纳米尺寸(20-100nm),通过增强渗透和截留(EPR)效应从血管渗透到肿瘤组织,由于在肿瘤组织中环境的改变,纳米粒子的结构和尺寸发生不可逆的变化,从大尺寸变为小尺寸(<10nm),或表面电荷发生反转而有利于细胞对纳米药物的内吞。例如,Fukumura(Proc.Natl.Acad.Sci.U.S.A.2011,108(6),2426-2431.)等人报道了明胶纳米粒子在肿瘤微环境金属蛋白酶MMP-2作用下从表面降解释放10nm左右的纳米粒子,增强了在纤维肉瘤HT-1080肿瘤组织内部渗透扩散。Chen(Drug Deliv.2019,26(1),1125-1139.)等人报道了用具有线粒体靶向聚合物3,4-二羟基苯基丙酸-壳寡糖-二硫代二丙酸-小檗碱(DHPA-CDB)自组装形成阳离子胶束,作为唾液酸和CD44的配体,带负电荷的低聚透明质酸-3-羧基苯基硼酸(oHA-PBA)被进一步添加到预制的DHPA-CDB核心的表面,以屏蔽正电荷并延长血液持久性。弱酸性肿瘤环境导致硼酸酯键降解,实现阳离子胶束暴露,电荷由-19.47转至+12.01mV,促进细胞内化和线粒体定位。因此构建肿瘤微环境介导的智能性可分拆型纳米载体对进一步克服肿瘤治疗中遇到的问题具有重大的研究意义。
纳米凝胶是能够吸收大量水的纳米级交联网络状聚合物粒子。纳米凝胶是将水凝胶和纳米材料的性能相结合有很高的含水量、可调的化学和物理结构、良好的力学性能和生物相容性。在目前的研究中,纳米凝胶由于交联的网状结构而具有良好的稳定性,可以实现体内长循环,减少药物早释和改善药代动力学参数。在肿瘤/炎症微环境作用下,智能纳米凝胶可降解为尺寸更小的前药,增强药物在肿瘤组织内的渗透,同时纳米凝胶所包载的活性大分子可以在肿瘤微环境中发挥作用。目前具有多功能和新颖性能且生物相容性好的智能纳米凝胶已经被报道。在未来的研究中,可解离型的壳核纳米凝胶对肿瘤治疗将具有重大意义。
发明内容
发明目的:本发明的目的是提供一种智能响应性壳-核式聚电解质纳米凝胶的制备方法。
本发明的另一目的是提供所述智能响应性壳-核式聚电解质纳米凝胶的用途。
技术方案:本发明所述的智能响应性壳-核式聚电解质纳米凝胶的制备方法:
由透明质酸或其衍生物、类似物的壳层和由谷胱甘肽敏感或酸敏感的交联剂交联而成的超支化聚乙烯亚胺的核层构成,透明质酸外壳和超支化聚乙烯亚胺内核再通过肿瘤微环境敏感的交联剂连接形成智能响应性壳-核式纳米凝胶。
进一步地,所述透明质酸或其衍生物、类似物的分子量为7~100kDa;支状聚乙烯亚胺的分子量为0.6~70kDa。
进一步地,所述含谷胱甘肽敏感或酸敏感的交联剂选自如下所示结构的化合物:
其中,R1选自H或CH3。
进一步地,所述超支化聚乙烯亚胺通过以下方法合成:
将支状聚乙烯亚胺和谷胱甘肽敏感或酸敏感的交联剂以氨基∶双键=3∶1的摩尔比溶于甲醇中,加入三乙胺作为催化剂,反应后得到。
进一步地,所述配体修饰的超支化聚乙烯亚胺选自叠氮基修饰的超支化聚乙烯亚胺。
进一步地,所述肿瘤微环境敏感的交联剂,如:活性氧敏感的交联剂选自如下所示结构的化合物:
基质金属蛋白酶(MMP)敏感的交联剂选自双马来酰亚胺-MMP9多肽。
进一步地,所述的透明质酸或其衍生物、类似物选自叠氮基修饰的透明质酸。
进一步地,所述点击化学反应是将分别由叠氮基修饰的透明质酸和超支化聚乙烯亚胺与两端带有炔基的肿瘤微环境响应的交联剂在不需要催化剂的条件下进行叠氮和炔基的点击化学反应。
进一步,超支化聚乙烯亚胺与透明质酸的质量比为1∶(2~4)。
本发明的智能响应性壳-核式聚电解质纳米凝胶由超支化聚乙烯亚胺的核层和外层包被的透明质酸壳层构成,由于壳核之间是通过交联剂连接,且核层是交联的超支化聚乙烯亚胺并带有正电性,因此整个纳米粒子是一个带电性的具有网状空间结构的纳米凝胶。
制备上述智能响应性壳-核式聚电解质纳米凝胶的方法包括以下步骤:(1)将制备好的叠氮基修饰的超支化聚乙烯亚胺与两端带有炔基的肿瘤微环境响应的交联剂的一端连接,其中叠氮基与炔基的摩尔比优选为1∶2。
(2)将(1)步骤中得到的炔基修饰的超支化聚乙烯亚胺分散在水中,滴加到叠氮基修饰的透明质酸水溶液中,反应后得到智能响应性壳-核式聚电解质纳米凝胶。
本发明还提供了所述智能响应性壳-核式聚电解质纳米凝胶作为药物载体的应用。
所述智能响应性壳-核式聚电解质纳米凝胶的网状空间结构可以负载带电性的亲疏水药物或蛋白质,并通过交联增加载药纳米凝胶的稳定性。
有益效果:本发明与现有技术相比,具有如下优势:
本发明的纳米凝胶可通过交联的网状空间结构和物理作用负载带电性的亲疏水药物或蛋白质,并且交联增加了纳米凝胶的稳定性。多重响应性显著提高了其在肿瘤治疗方面的应用,使其在肿瘤部位快速释放药物,从而产生高效的治疗作用,在智能响应性和药物的控制释放领域具有很大的应用前景。
附图说明
图1为实施例2中活性氧敏感交联剂RBCN的氢核磁谱图;
图2为实施例3中叠氮化透明质酸(HA-N3)的氢核磁谱图;
图3为实施例4中智能响应性壳-核式聚电解质纳米凝胶(HA-D-PEI)的粒径图;
图4为实施例6所得纳米凝胶在100μM H2O2、10mM GSH(pH 7.4)条件下的粒径变化;
图5为实施例7所得纳米凝胶对小鼠乳腺癌4T1细胞的细胞毒性结果图。
具体实施方式
实施例1合成叠氮化超支化聚乙烯亚胺(D-PEI-N3)
(1)合成超支化聚乙烯亚胺(D-PEI)
取聚乙烯亚胺PEI(600mg,1mmol)和N,N’-双(丙烯酰)胱胺(CBA,260mg,1mmol)分别溶于5mL甲醇(MeOH)中,混合后再加入20μL三乙胺(TEA),于室温下搅拌反应。反应结束后将反应液用透析袋收集在MeOH中透析,再将透析介质换成高纯水透析,经冷冻真空干燥得到产物。
(2)合成叠氮化超支化聚乙烯亚胺(D-PEI-N3)
将叠氮乙酸(AATA,12mg,116μmol)溶于水中,加入4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(DMTMM,25mg,92.8μmol),室温搅拌均匀后,加入上述超支化聚乙烯亚胺(D-PEI,50mg,58μmol),调pH为中性,室温下搅拌过夜,反应结束后将反应液用透析袋收集在水中透析,经冷冻真空干燥得到产物。
实施例2合成活性氧敏感交联剂RBCN
将双环[6.1.0]壬-4-炔-9-基甲醇(BCN,100mg,0.67mmol)溶于DCM中,加入92μLTEA,氮气保护,在冰浴条件下缓慢滴加草酰氯(37μL,0.44mmol)的DCM溶液,于室温下搅拌反应。反应结束后将反应液减压浓缩,采用柱层析法分离出RBCN,收集产物后进行减压浓缩,真空干燥后得到白色固体RBCN。氢核磁图谱如图1所示。
实施例3合成叠氮化透明质酸(HA-N3)
将透明质酸(HA,1g,0.17μmol)溶于20mL水中,加入DMTMM(110mg,0.4mmol),室温下搅拌后,加入2-[2-(2-叠氮乙氧基)乙氧基]乙胺(NH2-PEG2-N3)(69mg,0.4mmol),调pH为中性,室温下搅拌2天,反应结束后将反应液用透析袋收集在水中透析,经冷冻真空干燥得到产物。氢核磁图谱如图2所示。
实施例4智能响应性壳-核式聚电解质纳米凝胶(HA-D-PEI)的制备
将D-PEI-N3(15mg,14μmol)溶于1.5mL DMSO中,加入RBCN(14.8mg,42μmol)室温下搅拌过夜,反应结束后将反应液用透析袋在DMSO中透析,再将透析介质换成高纯水透析,冷冻真空干燥得到产物。取D-PEI-RBCN 1mg溶于1mL DMSO中,在搅拌条件下,滴加到HA-N3的5mM PB溶液(pH 7.4,1mg/mL,1mL)中,滴加结束后继续搅拌5-8h,结束后,用透析袋收集在5mM PB溶液(pH 7.4)中透析4h除去有机溶剂。动态光散射仪测得胶束的平均粒径为188nm,粒径分布指数为0.16,如图4所示。
实施例5智能响应性壳-核式聚电解质纳米凝胶(HA-D-PEI)对葡萄糖氧化酶(Gox)和含羧基小分子药物UK-5099的包载
将0.5mg UK-5099加入D-PEI-RBCN的DMSO溶液(0.5mg/mL,50μL)中,涡旋溶解后静置。再将上述溶液在搅拌的条件下缓慢滴加入HA和Gox的混合pH 7.4水溶液(HA:1mg/mL,Gox:0.05mg/mL,1 mL)中,搅拌3-5h后,透析除去有机溶剂。
载药量(wt.%)=(纳米粒子中药物质量/纳米粒子中聚合物与药物的质量总和)×100%
包封率(%)=(纳米粒子中药物质量/投入的药物质量)×100%
表1.包载Gox和UK-5099的纳米凝胶的表征a
a胶束最终浓度为1mg/mL。
b平均粒径(nm)和粒径分布在25℃、pH 7.4条件下通过动态光散射仪测定。
实施例6智能响应性壳-核式聚电解质纳米凝胶(HA-D-PEI)在100μM H2O2、10mMGSH(pH 7.4)条件下粒径的变化
取制备好的的纳米凝胶(0.5mg/mL,1mL),用一定量的高浓度的H2O2和GSH混合溶液调至所需缓冲液环境。将样品置于37℃恒温摇床(200rpm)中。在指定时间点用动态光散射仪测定其粒径的变化。
图4为在100μM H2O2、10mM GSH(pH 7.4)条件下放置不同时间的粒径图。胶束的粒径在经历一天后也没有发生明显的变化。但是,在100μM H2O2、10mM GSH(pH 7.4)条件下经历6小时胶束粒径就会明显变大,达到300nm,说明纳米凝胶发生明显的溶胀;到16小时,粒径开始混乱,说明纳米凝胶发生解体。
实施例7智能响应性壳-核式聚电解质纳米凝胶(HA-D-PEI)对4T1细胞毒性测试(MTT)
纳米凝胶(HA-D-PEI)在4T1细胞中的毒性通过MTT法测定。首先将100μL细胞的DMEM悬浮液(DMEM培养基中含10%胎牛血清、100IU/mL青霉素和100μg/mL链霉素)铺于96孔培养板中,并置于37℃,5%二氧化碳条件下培养h使单层细胞的覆盖率达到70~80%。然后向每孔中加入10μL不同浓度的纳米凝胶(G/HA-D-PEI/U)的PB溶液。待继续培养24h后,向每孔中加入10μL 3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)的PBS溶液(5mg/mL),并放入培养箱继续培养4h以使MTT与活细胞作用。随后移除含有MTT的培养液,向每孔中加入150μL DMSO以溶解活细胞与MTT产生的紫色甲瓒结晶,并使用酶标仪(SpectraMax i3x)测定每个孔在570nm处的吸收。细胞相对存活率通过与只有空白细胞的对照孔在570nm处的吸收相比得到。实验数据均是平行三组进行的。
细胞存活率(%)=(OD570样品/OD570对照)×100%
图5为智能响应性壳-核式聚电解质纳米凝胶(HA-D-PEI)对4T1细胞的细胞毒性结果图。结果表明:游离的Gox和空白纳米凝胶在设置浓度下对细胞几乎没有毒性,而载有Gox的纳米凝胶则随着Gox浓度的升高其细胞毒性也随之增强,说明该纳米凝胶在一定程度上有助于4T1细胞对Gox的内吞从而产生细胞毒性。
Claims (6)
1.一种智能响应性壳-核式聚电解质纳米凝胶的制备方法,其特征在于:由透明质酸壳层和由谷胱甘肽敏感或酸敏感的交联剂交联而成的配体修饰的超支化聚乙烯亚胺的核层构成,透明质酸外壳和超支化聚乙烯亚胺内核再由肿瘤微环境敏感的交联剂通过点击化学反应连接形成智能响应性壳-核式纳米凝胶;所述的超支化聚乙烯亚胺的制备方法为:将支状聚乙烯亚胺和谷胱甘肽敏感或酸敏感的交联剂以氨基:双键=3:1的摩尔比溶于甲醇中,加入三乙胺作为催化剂,反应后得到;所述的肿瘤微环境敏感的交联剂为;所述的谷胱甘肽敏感或酸敏感的交联剂为/>,其中,R1选自H。
2.根据权利要求1所述的智能响应性壳-核式聚电解质纳米凝胶的制备方法,其特征在于:所述的透明质酸的分子量为 7~100 kDa;超支状聚乙烯亚胺的分子量为0.6~70 kDa。
3.根据权利要求1所述的智能响应性壳-核式聚电解质纳米凝胶的制备方法,其特征在于:所述的配体修饰的超支化聚乙烯亚胺选自叠氮基修饰的超支化聚乙烯亚胺。
4.根据权利要求1所述的智能响应性壳-核式聚电解质纳米凝胶的制备方法,其特征在于:所述的透明质酸选自叠氮基修饰的透明质酸。
5.权利要求1-4任一项制备得到的智能响应性壳-核式聚电解质纳米凝胶在制备药物载体中的应用。
6.权利要求1-4任一项制备得到的智能响应性壳-核式聚电解质纳米凝胶在制备抗肿瘤药物中的应用。
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