CN111956610B - 一种用于动脉粥样硬化治疗的载药体系及其制备方法 - Google Patents
一种用于动脉粥样硬化治疗的载药体系及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于动脉粥样硬化诊疗的载药体系及其制备方法。该载药体系包括载药分子和将其包裹的两亲聚合物;载药分子由通过二羰基键连接的荧光分子和负载有药物的环糊精组成。本发明制备得到的载药分子是由具有双光子聚集诱导发光效应的荧光分子通过二羰基键与内腔负载抗炎药物的环糊精连接而成。制备得到的纳米药物具有活性氧响应性,而且二羰基键可敏感性断裂,释放的荧光分子可用于动脉粥样硬化的诊断。此外,游离的环糊精‑抗炎药复合物可在富脂质的环境中发生解离,药物发挥抗炎作用,空载的环糊精可移除病灶部位的脂质,对动脉粥样硬化具有良好的治疗效果。
Description
技术领域
本发明属于药物载体技术领域,具体涉及一种用于动脉粥样硬化治疗的载药体系及其制备方法。
背景技术
动脉粥样硬化主要是由体内高血脂环境以及血管内皮破损所引起,脂质在血管内壁堆积所引发的一种慢性炎症疾病。其本质上与冠心病引起的心绞痛或急性心肌梗死有关,由免疫细胞浸润和脂质沉积的进行性炎症过程引起。一般情况下,糖皮质激素和非甾体类抗炎药可用于动脉粥样硬化的抗炎治疗。然而,这些药物的各种副作用也令人担忧,如骨质疏松、消化道出血和慢性肾脏疾病。为了降低不良反应,提高治疗效果,近年来各种纳米药物载体如聚合物胶束、脂质体等被开发出来用于动脉粥样硬化的抗炎治疗。除此之外,动脉粥样硬化部位常伴有大量的脂质堆积,如何高效地移除堆积的脂质也成为动脉粥样硬化治疗的关键问题。
系统构建的纳米载药系统已被证明在动脉粥样硬化组织中有选择性的积累能力,其中破损的血管内皮为纳米颗粒提供了一个外渗途径。然而,富集后的纳米载体还需要进一步实现药物的智能准确释放。在动脉粥样硬化病变中,由于炎性反应可产生高浓度的活性氧,为药物的准确传递提供了靶点。因此,在纳米颗粒中引入一系列活性氧响应结构,以实现炎症治疗药物在动脉粥样硬化部位的准确、高效释放。除此之外,动脉粥样硬化部位堆积的脂质可使环糊精-药物复合物中的疏水性药物释放出来,同时脂质被环糊精负载,从病变部位移除,为动脉粥样硬化的治疗提供了新的释药方式和治疗策略。
此外,纳米颗粒在体内的可视性在炎症部位的整个循环、积累和分布过程中也应被准确地监测。近年来,荧光成像已被证明是一种高分辨率观察生物微观结构的有力工具。然而,传统的荧光团存在积累后的聚集猝灭效应、背景荧光干扰等严重缺陷。而一种具有聚集诱导发光效应的荧光团作为一类新型分子,在稀溶液中荧光发射较弱,而在聚集态下表现出强荧光。此外,与传统的单光子荧光成像相比,双光子激发荧光显微镜可以提供更清晰的空间分辨率,同时具有更少的自荧光,更深入的组织穿透。因此,具有双光子激发和聚集诱导发光效应的荧光分子将是解决动脉粥样硬化纳米医学追踪和空间荧光成像的合适策略
因此,开发用于动脉粥样硬化的诊疗纳米药物载体有着非常重要的临床意义。
发明内容
针对现有技术中的上述不足,本发明提供一种用于动脉粥样硬化治疗的载药体系及其制备方法,该药物载体具有对高活性氧、脂质堆积环境的敏感性以及双光子聚集诱导发光的荧光功能,可在动脉粥样硬化斑块部位准确高效给药,同时实现药物在体内及细胞内的精确追踪和定位。
为实现上述目的,本发明解决其技术问题所采用的技术方案是:
一种用于动脉粥样硬化治疗的载药体系,包括载药分子和将其包裹的两亲聚合物;载药分子由通过二羰基键连接的荧光分子和负载有药物的环糊精组成,如式I所示;
载药分子是由具有双光子聚集诱导发光效应的荧光分子通过二羰基键与内腔负载抗炎药物的环糊精连接而成。制备得到的纳米药物具有活性氧响应性,而且二羰基键可敏感性断裂,释放的荧光分子可用于动脉粥样硬化的诊断。此外,游离的环糊精-抗炎药复合物可在富脂质的环境中发生解离,药物发挥抗炎作用,空载的环糊精可移除病灶部位的脂质,对动脉粥样硬化具有良好的治疗效果。
进一步地,荧光分子为具有双光子聚集诱导发光效应的荧光分子,其化学结构如式II所示:
其中,R为共轭结构,R’为烷基或芳基,R”为氢、甲基或甲氧基,X为卤素阴离子、双三氟甲磺酰亚胺阴离子、六氟磷酸阴离子、四氟硼酸阴离子或三氟甲磺酸阴离子。
进一步地,共轭结构为苯、炔基或噻吩。
进一步地,烷基为甲基。
进一步地,药物为抗炎药物。
进一步地,载药分子的制备方法为:
(1)将荧光分子溶解后加入至草酰氯溶液中,室温搅拌10~15h后,减压去除多余的草酰氯和溶剂;然后加入溶解后的羟乙基环糊精和三乙胺,室温反应20~30h后,用色谱纯化,得药物载体;其中,所述羟乙基环糊精、草酰氯、三乙胺和荧光分子的摩尔比为1~10:3~30:3~30:1~10;
(2)将步骤(1)所得药物载体溶解于1-5mL二甲基亚砜中并滴加到10-50mL去离子水中,搅拌1~4h后透析20~24h,再于20~30℃搅拌透析液的同时加入抗炎药物,继续搅拌1~5h后透析并冻干得到负载药物的载药分子;其中,药物载体和抗炎药物的摩尔比为1~20:1~10。
进一步地,两亲聚合物为由亲水物质和疏水物质聚合而成的双嵌段聚合物,如式III所示;
进一步地,亲水物质包括但不限于聚乙二醇、聚谷氨酸、聚赖氨酸、聚2-甲基丙烯酰氧基乙基磷酰胆碱。
进一步地,疏水物质包括但不限于聚乳酸、聚己内酯、聚谷氨酸苄酯、聚乙醇酸。
上述载药体系的制备方法,将两亲聚合物和载药分子溶解于四氢呋喃和二甲基亚砜的混合溶剂中,然后加入混合溶剂2~20倍体积的生理盐水或超纯水,搅拌1~4h后,除去溶剂即可;
或将两亲聚合物和载药分子溶解于四氢呋喃中,然后除去有机溶剂,再加入生理盐水或超纯水,振荡水化即可。
进一步地,四氢呋喃和二甲基亚砜的体积比为1~2:1~2,搅拌时间为2h。
本发明的有益效果为:
(1)本发明制备得到的诊载药体系中的二羰基键可在活性氧条件下发生敏感性断裂,释放的荧光分子可用于动脉粥样硬化的诊断。
(2)游离的环糊精-抗炎药复合物可在富脂质的环境中发生解离,药物发挥抗炎作用,空载的环糊精可移除病灶部位的脂质,对动脉粥样硬化具有良好的治疗效果
(3)本发明制备得到的载药胶束在体外细胞水平和体内动物水平上,与自由药物对比,在药效、生物安全性和循环时间均有明显提高,可以实现高效低毒的药物递送。
(4)本发明提供的载药胶束在用于动脉粥样硬化组织双光子成像效果以及优异的炎症治疗效果。
附图说明
图1为无药物诊疗复合物的核磁共振氢谱图谱;
图2为诊疗胶束的粒径分布图和透射电镜图;
图3为不同活性氧条件下胶束的粒径变化结果图;
图4为胶束的荧光发射图谱;
图5为胶束在不同条件下的体外药物释放结果图;
图6为胶束对巨噬细胞的炎症因子抑制结果图;
图7为胶束对泡沫细胞形成的抑制结果图;
图8为动物试验中胶束对动脉粥样硬化成像及治疗的结果图。
具体实施方式
下面对本发明的具体实施方式进行描述,以便于本技术领域的技术人员理解本发明,但应该清楚,本发明不限于具体实施方式的范围,对本技术领域的普通技术人员来讲,只要各种变化在所附的权利要求限定和确定的本发明的精神和范围内,这些变化是显而易见的,一切利用本发明构思的发明创造均在保护之列。
实施例1
一种用于动脉粥样硬化的诊疗载药体系,该诊疗纳米药物载体体系通过两亲性聚合物包裹用于进行诊疗的载药复合分子构成。其中,用于诊疗的载药复合分子是由具有双光子聚集诱导发光效应的荧光分子通过二羰基键与内腔负载抗炎药物的环糊精连接而成。
上述用于动脉粥样硬化诊疗的载药分子的制备方法如下:
(1)将荧光分子(三苯胺基苯羟乙基吡啶,0.2g)溶解,再滴加到草酰氯(0.032mL)溶液中。在室温下搅拌12小时后,在减压下去除多余的草酰氯和溶剂。将药物(0.36g)和三乙胺(0.11mL)溶解,加入。室温下反应24 h后,用色谱纯化,得到无药物诊疗复合物。
(2)将(1)所得化合物(0.16g)溶解于2mL二甲基亚砜中并滴加到10mL去离子水中,搅拌4小时并在去离子水中透析24小时。将透析液于30℃条件下不断搅拌,加入抗炎药物(0.01g),搅拌3小时后在去离子水中透析并冻干得到负载药物的诊疗复合物,即载药分子。
上述两亲性聚合物为由聚乙二醇5000和聚乳酸聚合而成的双嵌段聚合物。
实施例2
一种用于动脉粥样硬化的诊疗纳米药物载体的制备方法,包括以下步骤:
称取实施例1制得的诊疗复合物10mg,两亲性聚合物20mg,溶解于4mL二甲基亚砜和甲醇以体积比为1:1混合的混合溶液中,然后再滴加到10mL超纯水中,搅拌4h,透析除去有机溶剂,制得聚合物胶束。
上述制得的无药物诊疗复合物的核磁共振氢谱图谱见图1,由其出峰位置以及积分比例可知无药物诊疗复合物已被成功合成(1H NMR:δ=3.49-3.84(m,77H),4.75-5.18(m,21H),7.02(m,8H),7.31(m,6H),7.95(d,2H),8.20(t,2H),8.58(s,2H),9.05(s,2H)ppm)。
胶束粒径图及透射电镜图见图2,图2中A为透射电镜图,B为胶束粒径图;由图可知此类聚合物载体可在水中包覆诊疗复合物,自组装形成核-壳结构的胶束,其大小均一,形态规整。
试验例1 胶束的稳定性和敏感性的研究
将实施例2制得的胶束置于37℃,不同浓度过氧化氢浓度(0,0.01,0.1,1,10mM)的条件下,每隔一段时间用动态光散射仪DLS测定其粒径变化,粒径变化结果见图3。
由图3可知,本发明制得的胶束在无过氧化氢条件下表现出很好的稳定性,而在1mM及以上浓度的过氧化氢条件下胶束迅速膨胀,其粒径最终稳定在280nm左右。
试验例2 胶束聚集诱导发光特性研究
将实施例2制得的胶束加入二甲基亚砜,过氧化氢水溶液或纯水中,于410nm下激发聚合物载药胶束,观察其荧光发射情况,其荧光发射图谱见图4。
由图4可知,胶束荧光强度随着双光子荧光团在二甲基亚砜中的溶解而消失,而将聚合物载药胶束溶于水或过氧化氢溶液中,因其聚集态较为致密,而具有较强的荧光。
试验例3 胶束体外药物释放行为
将实施例2制得的胶束制成浓度为1mg/mL的溶液,然后取2mL转移到截留分子量为3500的透析袋中,将透析袋密封后置于100mL PBS,1mM过氧化氢溶液,1mM过氧化氢和6mM胆固醇溶液中,于37℃避光条件下持续震荡,在固定时间内取出2mL,用高效液相色谱仪测药物释放量,其结果如图5所示。
由图5可知,胶束在活性氧环境下会实现药物的释放,而胆固醇(脂质)的引入可以加速药物的释放过程。
试验例4 胶束对巨噬细胞的抗炎作用
将实施例2制得的胶束,或自由药物与被脂多糖激活的巨噬细胞共培养48h,取上清液检测炎性分子(TNF-α,IL-1β,MPO)的含量。
由图6(图6中每组数据的柱状图由左至右依次表示TNF-α,IL-1β,MPO)可知,与自由药物相比,本发明制得的胶束能够实现细胞层面的高效抗炎。
试验例5 胶束对泡沫细胞形成的抑制作用
将实施例2制得的胶束,或自由药物与被脂多糖激活并加入氧化低密度脂蛋白的巨噬细胞共培养24h,对细胞进行油红O染色并用光学显微镜观察。
由图7可知,与自由药物相比,本发明制得的胶束能够实现对泡沫细胞形成的有效抑制作用。
试验例6 动物试验验证胶束对炎症组织的成像能力及抗炎效果
将已知载药量的胶束冷冻干燥,再用生理盐水复溶,配置成一定浓度的储存液,并配置相同药物浓度的自由药物储存液。建立动脉粥样硬化小鼠模型。由尾静脉分别注射自由药物、胶束或等体积的生理盐水。药物的药量为10mg/kg老鼠。用双光子激光共聚焦显微镜观察胶束的成像能力,检测各项炎症指标,实验结果见图8。
由图8可知,胶束具有优良的双光子成像能力,可在动脉粥样硬化病灶处明显看到胶束的富集所发出的强荧光(图8A-8C)。此外,按照图8D的治疗方案对小鼠进行给药治疗,与自由药物相比,胶束具有更好的抑制动脉粥样硬化形成效果(图8E-8H)。
Claims (4)
2.根据权利要求1所述的用于动脉粥样硬化治疗的载药体系,其特征在于,所述载药分子的制备方法为:
(1)将荧光分子溶解后加入至草酰氯溶液中,室温搅拌10~15h后,除去草酰氯和溶剂;然后加入溶解后的羟乙基环糊精和三乙胺,室温反应20~30h后,纯化,得药物载体;其中,所述羟乙基环糊精、草酰氯、三乙胺和荧光分子的摩尔比为1~10:3~30:3~30:1~10;
(2)将步骤(1)所得药物载体溶解于二甲基亚砜中,然后加入至去离子水中,搅拌1~4h后透析20~24h,再于20~30℃搅拌透析液的同时加入抗炎药物,继续搅拌1~5h后透析并冻干得到负载药物的载药分子;其中,药物载体和抗炎药物的摩尔比为1~20:1~10。
3.权利要求1或2所述的载药体系的制备方法,其特征在于,将两亲聚合物和载药分子溶解于四氢呋喃和二甲基亚砜的混合溶剂中,然后加入混合溶剂2~20倍体积的生理盐水或超纯水,搅拌1~4h后,除去溶剂即可;
或将两亲聚合物和载药分子溶解于四氢呋喃中,然后除去有机溶剂,再加入生理盐水或超纯水,振荡水化即可。
4.根据权利要求3所述的制备方法,其特征在于,所述四氢呋喃和二甲基亚砜的体积比为1~2:1~2,搅拌时间为2h。
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