CN115227671A - 一种药物递送系统及其制备方法和应用 - Google Patents
一种药物递送系统及其制备方法和应用 Download PDFInfo
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- CN115227671A CN115227671A CN202210823054.2A CN202210823054A CN115227671A CN 115227671 A CN115227671 A CN 115227671A CN 202210823054 A CN202210823054 A CN 202210823054A CN 115227671 A CN115227671 A CN 115227671A
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Abstract
本发明涉及生物技术领域,具体公开了一种药物递送系统及其制备方法和应用。所述药物递送系统包括壳‑核结构,红细胞膜作为壳层,树突状介孔二氧化硅作为内核,所述树突状介孔二氧化硅装载有麻醉药物和/或超声成像制剂。本发明将红细胞膜和树突状介孔二氧化硅联合,装载麻醉药物和超声成像制剂,通过液气相变技术提高麻醉药物的超声响应性,超声辐照激发液态氟碳发生液气相变,增强局麻药物在肿瘤局部的释放性能,同时产生的气体可在超声下观察到成像信号,为麻醉药物递送提供影像学信息,实现超声成像与局麻药物递送一体化。
Description
技术领域
本发明涉及生物技术领域,尤其是一种药物递送系统及其制备方法和应用。
背景技术
目前,术后10-50%的患者存在术后疼痛,持续的术后疼痛与延迟出院相关,从而严重降低了生活质量。因此,持续性术后疼痛的管理对于以患者为中心的临床诊疗至关重要。尽管多种麻醉药物(如局部麻醉剂、环氧合酶抑制剂和阿片类药物)可以在手术期间和术后不久控制疼痛,但即使在局限性疼痛情况下,阿片类药物仍然是术后疼痛管理的主要手段。但是阿片类药物副作用明显,包括恶心、皮肤瘙痒、便秘、成瘾、耐受性差、注意力无法集中等,过量服用甚至致命。尽管局部麻醉剂可用于缓解术后疼痛,但作用时间有限,过量使用会产生严重的心血管或神经疾病等副作用。此外,不能调整镇痛强度以满足患者的需求。尽管通过导管持续输注局部麻醉剂可以提供长期镇痛,但不建议抗凝患者使用。因此,有必要开发一种新型麻醉药物进行高效术后疼痛管理。
为了解决局麻药物可控释放的难题,已有学者利用激光辐照控制疼痛管理。但是近红外激光触发的按需镇痛系统存在穿透深度低的难题,因此只能用于浅表部分镇痛,临床价值受限。与近红外激光触发的按需镇痛系统相比,超声波在组织穿透深度方面具有优势,且超声设备和超声技术已广泛应用于各种临床和理疗场景中。但是现有超声响应体系存在三方面问题:第一,现有超声响应体系需要更高的超声刺激强度,这可能对机体造成一定程度的损伤。第二,纳米药物在体内会迅速被机体免疫系统清除,造成药物在体内无法长时间发挥作用。第三,纳米药物在体内缺乏影像学监控手段。为了解决以上难题,超声微泡在超声辐照下产生的空化效应可能增强局部麻醉药物的药物递送,增强药物对超声辐照的敏感性,从而降低临床上超声的应用强度,降低副损伤。改善药物输送的机制主要归因于惰性空化效应和间隙流体流量的增加。此外,然而,在生理条件下,这些微泡是不稳定的,单次注射的半衰期短,无法长期控制药物释放。虽然大多数研究都使用微泡来辅助疾病治疗,但目前尚不清楚如何将这些技术结合起来进行有效的疼痛管理。
发明内容
本发明提供一种药物递送系统及其制备方法和应用,解决了以下三个技术问题:1)纳米药物在体内会迅速被机体免疫系统清除,造成药物在体内无法长时间发挥作用;2)现有超声响应体系需要较高的超声刺激强度,这可能对机体造成一定程度的损伤;3)麻醉药物在体内缺乏影像学监控手段。本发明提供的药物递送系统通过红细胞膜修饰提高了其在生物体内的稳定性,避免免疫系统快速清除,延长其在体内的存留时间。此外,本发明通过液气相变技术提高麻醉药物的超声响应性,超声辐照激发液态氟碳发生液气相变,增强局麻药物在肿瘤局部的释放性能,同时产生的气体可在超声下观察到成像信号,为麻醉药物递送提供影像学信息。
为实现上述目的,本发明采取的技术方案为:
本发明提供了一种药物递送系统,所述药物递送系统包括壳-核结构,红细胞膜作为壳层,树突状介孔二氧化硅作为内核,所述树突状介孔二氧化硅装载有麻醉药物和/或超声成像制剂。
红细胞膜工程化是一种仿生策略,可以延长血液滞留时间,减少非特异性巨噬细胞的摄取。红细胞膜保留了天然红细胞表面的多种组分(例如CD47、各种膜蛋白、酸性唾液酸和聚糖),可以有效地使其附属物或内部内容物具有延长的血液滞留时间和免疫逃避能力。这种细胞膜封装技术可以使内部纳米材料半衰期显著延长,尚未应用于疼痛管理领域。
树枝状介孔二氧化硅具有高载药量的特点,可作为药物载体装载麻醉药物和/或超声成像制剂,用于临床术后镇痛及解决疼痛管理相关需求。但是树枝状介孔二氧化硅在生物体内会激起免疫反应,而迅速被机体清除,不利于其在体内长时间停留,严重制约了镇痛疗效。本申请的发明人经过大量研究及试验发现,以红细胞膜作为壳层,旨在提高其在体内的存留时间,使得树突状介孔二氧化硅在体内可以长时间停留,促进镇痛疗效的实现;并且红细胞囊泡有利于防止装载药物的渗漏。现有超声响应性局麻药物递送系统虽然可发生超声响应性释药,但无法提供超声成像数据。此外,超声响应性释放过程依赖于高强度超声触发,非特异性超声辐照可能带来不必要的副损伤,限制其临床应用。本研究通过装载超声成像制剂,在超声辐照下发生液气相变,生成的气体既可以增强超声响应性释药的敏感性,又可以产生超声成像信号,实现超声成像与局麻药物递送一体化的药物递送系统。
作为本发明所述药物递送系统的优选实施方式,所述麻醉药物为水溶性或油溶性的局部麻醉药物,优选地,所述麻醉药物为所述麻醉药物为左旋布比卡因、利多卡因、普鲁卡因、丁卡因和罗哌卡因中的至少一种。麻醉药物不仅限于上述药物,还包括了本领域中常用的麻醉剂。
麻醉药物选择上述组分时,可针对多种疼痛场景进行疼痛管理。
作为本发明所述药物递送系统的优选实施方式,所述超声成像制剂为疏水性和疏油性的超声成像制剂,优选地,所述超声成像制剂为全氟戊烷,当超声成像制剂不是疏水性和疏油性时,其可能存在激发相变困难的问题,因此,全氟戊烷为最佳选择。全氟戊烷在药物递送系统中的浓度为20-200μL。
与传统的超声微泡相比,全氟戊烷(PFP)是一种在体内稳定的“液-气”相变材料。超声辐照可以引发相转变,并将液相PFP转化为气相,从而增强药物传递过程,并可为临床提供超声影像学信息。
作为本发明所述药物递送系统的优选实施方式,所述树突状介孔二氧化硅的表面积为500-700m2g-1,平均孔径为3-20nm;优选地,所述树突状介孔二氧化硅的表面积为553.449m2g-1,平均孔径为18nm。
树突状介孔二氧化硅是一类具有较大载药量的药物载体,可装载多种水溶性及油溶性局部麻醉药物,也适合装载兼具有疏水性和疏油性的超声成像制剂全氟戊烷。本发明将多种性质药物同时装载于树突状介孔二氧化硅中,可作为超声响应性制剂应用于临床实践中。
传统二氧化硅孔径小(2-3nm),树突状二氧化硅孔径更大,本研究所合成的树突状二氧化硅比表面积相对传统介孔二氧化硅孔径更大,载药量更多,进而使得更佳的发挥镇痛的效果。
作为本发明所述药物递送系统的优选实施方式,所述树突状介孔二氧化硅的制备方法包括以下步骤:
将十六烷基三甲基氯化铵和三乙醇胺溶解在水中形成混合物,在混合物中添加正硅酸乙酯和双[3-(三乙氧基硅)丙基]四硫化物,搅拌,洗涤,清除残余反应物,然后使用含有乙醇的盐酸溶液回流提取产物,获得树突状介孔二氧化硅。
其树突状介孔二氧化硅合成方法简便,红细胞容易从各种生物体内轻松获取,两者的生物相容性较高,成本较为低廉。
本发明还提供了一种上述的药物递送系统的制备方法,将树突状介孔二氧化硅分散在麻醉药物水溶液中搅拌,然后再添加超声成像制剂继续搅拌,离心,收集装载有麻醉药物和超声成像制剂的纳米颗粒,将红细胞膜包被装载有麻醉药物和超声成像制剂的纳米颗粒,透析,浸入PBS溶液中,获得药物递送系统。
优选地,麻醉药物在麻药药物水溶液中的浓度为2-10mg/ml。
优选地,超声成像制剂的浓度为20-200μL。
作为本发明所述药物递送系统的制备方法的优选实施方式,所述透析的截留分子量为3500-8000Da。
此外,本发明提供了上述药物递送系统在制备用于治疗疼痛的试剂中的用途。
本发明提供了一种药物组合物,所述药物组合物包括上述的药物递送系统。
本发明提供了上述药物组合物在制备用于治疗疼痛的试剂中的用途。
与现有技术相比,本发明具有以下有益效果:
本发明提供了一种装载局部麻醉药物和全氟戊烷的药物递送系统及其制备方法和应用,所述药物递送系统包括壳-核结构,红细胞膜作为壳层,树突状介孔二氧化硅作为内核,以红细胞膜作为壳层时,提高了其在生物体内的稳定性,避免免疫系统快速清除,延长其在体内的存留时间,使得树突状介孔二氧化硅在体内可以长时间停留,促进镇痛疗效的实现;并且红细胞有利于防止装载药物的渗漏。本发明将红细胞膜和树突状介孔二氧化硅联合,装载麻醉药物和超声成像制剂,通过液气相变技术提高麻醉药物的超声响应性,超声辐照激发液态氟碳发生液气相变,增强局麻药物在肿瘤局部的释放性能,同时产生的气体可在超声下观察到成像信号,为麻醉药物递送提供影像学信息,实现超声成像与局麻药物递送一体化。
附图说明
图1为树突状介孔二氧化硅透射电子显微镜图(200nm);
图2为树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电子显微镜图(200nm);
图3为红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电子显微镜图(200nm);
图4为红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的SDS-PAGE图;
图5为红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电镜元素成分分析图;
图6为药物递送系统RDBP和RDB的超声响应性释药图;
图7为药物递送系统RDBP和RDB的无超声释药图;
图8为药物递送系统RDBP和RDB的超声响应性释药定量图;
图9为药物递送系统RDBP在超声辐照后的超声基波和谐波成像图;
图10为药物递送系统RDBP的B-Mode基波超声定量图;
图11为药物递送系统RDBP的造影模式谐波超声定量图;
图12为药物递送系统RDBP的生物安全性评估图;
图13为药物递送系统RDBP的超声辐照安全性评估图;
图14为实施例4中PBS处理组、RDBP处理组、DBP处理组和左旋布比卡因处理组测试小鼠抬脚的阈值刺激强度图;
图15为实施例4中RDBP处理组、RDBP+超声辐照处理组和DBP+超声辐照处理组测试小鼠抬脚的阈值刺激强度图;
图16为实施例4中PBS处理组、PBS+超声辐照组和RDP组测试小鼠抬脚的阈值刺激强度图;
图17为普通介孔二氧化硅与树突状二氧化硅比较载PFP成像比较图;
图18为实施例5中RDBP+US处理组、RDBP处理组、PBS处理组的超声成像观察液气相变图。
具体实施方式
为更好的说明本发明的目的、技术方案和优点,下面将结合附图和具体实施例对本发明作进一步说明。
在以下实施例中,所使用的实验方法如无特殊说明,均为常规方法,所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
缩写:
全氟戊烷(PFP);红细胞膜(red blood cell membrane,RBCM);树突状介孔二氧化硅纳米颗粒(DMSN);左旋布比卡因(bupi)。
红细胞膜包被的DMSN-bupi-PFP(简称RDBP);红细胞膜包被的DMSN-bupi(简称RDB);装载全氟戊烷的树突状介孔二氧化硅纳米颗粒(DMSN-PFP)、装载左旋布比卡因的树突状介孔二氧化硅纳米颗粒(DMSN bupi,简称DB)。、红细胞裂解液的配方为:10ml原液1号+10ml原液2号,加双蒸水定容至100ml。
原液1号:10g葡萄糖+0.6g磷酸二氢钾+3.58g磷酸氢二钠(7H2O)+20ml5g/L酚红溶液,加双蒸水定容至1 000ml。
原液2号:1.86g氯化钙(2H2O)+4.0g氯化钾+80g氯化钠+1.04g氯化镁+2.0g硫酸镁(7H2O),加双蒸水定容至1 000ml。
实施例1、一种装载左旋布比卡因和全氟戊烷的药物递送系统及其制备方法
1、树突状介孔二氧化硅的合成:在95℃下搅拌,并将2g十六烷基三甲基氯化铵和三乙醇胺溶解在20毫升水中。20分钟后,逐滴添加1g正硅酸乙酯和1.3g双[3-(三乙氧基硅)丙基]四硫化物并将混合物再搅拌4小时。将产物离心并用乙醇和水洗涤多次,以清除残余反应物。在78℃条件下,使用乙醇的盐酸溶液(10%v/v)回流提取产物两次,持续12小时,以去除十六烷基三甲基氯化铵。上述制备的树突状介孔二氧化硅透射电子显微镜图像如图1所示。氮气吸附实验表面树突状二氧化硅比表面积为553.449m2g-1,采用BJH理论分析,其平均孔径约为18nm。
2、红细胞膜囊泡的合成:从小鼠的眶后丛中采集小鼠全血,并收集在EDTA抗凝管中以避免凝血。然后用预冷的PBS溶液(pH=7.4)稀释全血,离心以收集红细胞(800g,4℃,20min)。用1倍PBS(pH=7.4)洗涤红细胞3次,将获得的红细胞在冰浴条件下使用红细胞裂解液处理5min,15000rpm离心30min收集红细胞膜。将红细胞膜超声处理2min,得到红细胞膜囊泡,将所得的红细胞膜囊泡储存在4℃中以备进一步使用。
3、一种药物递送系统的制备方法,包括以下步骤:
将树突状介孔二氧化硅(10mg)分散在5mL左旋布比卡因水溶液(2-10mg/mL,优选为10mg/mL)中,并在室温下搅拌12小时,然后添加20-200μL(优选为200μL)全氟戊烷,并在冰浴中再搅拌12小时。将溶液在12000rpm下离心10分钟,以收集装载全氟戊烷和左旋布比卡因的纳米颗粒(DMSN-bupi-PFP,简称DBP)。收集上清液以确定左旋布比卡因的确切装载剂量。
以下方程式用于计算载药效率:载药效率=1-左旋布比卡因上清液量/左旋布比卡因总量。树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电子显微镜图像如图2所示。
将红细胞膜包被的DMSN-bupi-PFP(简称RDBP)与红细胞膜包被的DMSN-bupi(简称RDB)包裹在透析袋(截留分子量3500Da)中,并浸入PBS溶液(20mL)中,最终获得装载左旋布比卡因和全氟戊烷的药物递送系统及装载左旋布比卡因的药物递送系统。红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电子显微镜图像如图3所示。
采用SDS-PAGE证实红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷后保留了红细胞膜,结果如图4所示。
红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电镜元素成分分析(参考图5),数据显示所合成的药物递送系统含有介孔二氧化硅(Si、O元素),左旋布比卡因(C、O、N元素)和全氟戊烷(C、F元素)的特征性元素。
实施例2、药物递送系统的超声响应性体外释药研究
将上述获得的药物递送系统(RDBP和RDB)研究左旋布比卡因的体外释放。在本研究中,超声辐照强度为0.6W cm-2,未使用超声辐照作为对照。在超声触发药物释放实验选择的时间内,在涂有超声偶联剂(医用超声耦合剂,广工牌,0.25L装)后对试管进行超声处理(0.6W cm-2,1MHz,15min),在37℃孵育下摇动所有试管。在指定时间,收集释放的样品(5mL)测定紫外-可见光吸收光谱,确定释放的左旋布比卡因的量。
当有超声辐照时,药物递送系统RDBP和RDB的超声响应性释药图如图6所示,箭头代表超声辐照时间点。
当未使用超声辐照时,药物递送系统RDBP和RDB的释药图如图7所示。
药物递送系统RDBP和RDB的超声响应性释药定量图(*p<0.05认为有统计学差异)如图8所示。
药物递送系统RDBP在超声辐照后的超声基波和谐波成像如图9所示。
药物递送系统RDBP的B-Mode基波超声定量图和造影模式谐波超声定量图分别如图10-11所示。
实施例3、药物递送系统的细胞毒性评估
采用标准CCK-8法评估RDBP的细胞毒性。在96孔板中种植处于对数生长期的HUVEC细胞,并于37℃下在5%CO2环境中培养。在HUVEC细胞培养基中添加不同浓度(0、50、100、200、400、600、800和1000μg mL-1)的RDBP。然后移除HUVEC细胞培养基,培养24或48h后,用CCK-8检测试剂盒(日本Dojindo,100μL,10%)替换培养基,并将细胞再培养2小时。最后,使用微孔板阅读器在450nm处测量HUVEC细胞的存活率。为了评估超声触发左旋布比卡因释放的安全性,在HUVEC细胞中添加不同浓度(0、50、100、200、300、400、500和600μg mL-1)的RDBP,并与HUVEC细胞一起培养4小时。之后,用PBS洗涤细胞三次,以去除孔板中游离的RDBP,将细胞暴露于超声辐照(0.6W cm-2,1MHz,2min,占空比50%)后。使用CCK-8检测试剂盒替换培养基并孵育2小时,并使用微孔板读取器测定HUVEC细胞的活性。
药物递送系统RDBP的生物安全性评估和超声辐照安全性评估如图12-13所示。
实施例4、构建小鼠切口疼痛模型
建立小鼠切口疼痛模型的步骤:按照文献所报道(G.J.Bennett,Y.K.Xie,Pain1988,33,87.)的方案创建小鼠切口疼痛模型。用2%异氟醚麻醉小鼠,在用10%聚维酮碘溶液清洁左臀部区域后,从臀部的近端边缘进行纵向切口(2mm)。做纵向切口后将底部肌肉提起,暴露坐骨神经,在切口中心用4-0尼龙线缝合皮肤后涂抹抗生素软膏预防感染。
体内机械性痛觉超敏的测量:为了测量小鼠对非伤害性机械刺激的反应,使用足底触觉计)进行了体内机械性痛觉超敏试验。小鼠在带有丝网地板的塑料笼中适应试验环境30分钟。随后,将探针压在小鼠后爪的鞋底上,力逐渐增加,直到小鼠缩回爪子。对两个后肢进行三次测试,并自动采用爪机械阈值,将平均值用于确定机械阈值(g)。
分组为PBS处理组、RDBP处理组、DBP处理组和左旋布比卡因处理组,切口部位局部注射,100μL,0.05mg左旋布比卡因或相同剂量其他组/每只小鼠,每组5只评估,测试小鼠抬脚的阈值刺激强度,结果如图14所示。
分组为RDBP处理组、RDBP+超声辐照处理组和DBP+超声辐照处理组,切口部位局部注射,100μL,0.05mg左旋布比卡因或相同剂量其他组/每只小鼠,每组5只评估,评估测试小鼠抬脚的阈值刺激强度,结果如图15所示。
分组为PBS处理组、PBS+超声辐照组和RDP组,切口部位局部注射,100μL,0.05mg左旋布比卡因或相同剂量其他组/每只小鼠,每组5只评估,评估测试小鼠抬脚的阈值刺激强度,结果如图16所示。
实施例5、体外给药和超声成像测试
超声成像测试:将DMSN-PFP溶液、RDBP溶液、DMSN bupi(DB)溶液、PBS溶液或左旋布比卡因溶液注射到小鼠体内。固定小鼠,暴露后腿进行超声波触发。然后,使用强度低的温和超声强度(0.6W cm-2,1MHz,2min,占空比50%)将药物在超声引导下直接输送到注射位置。在辐照后不同时间点分别对药物注射部位进行超声辐照,超声基波成像观察神经位置,谐波成像观察药物相变情况,如图18所示(画圈部位为坐骨神经),CEUS图像变亮说明已发生相变。
如图17所示,普通介孔二氧化硅与本研究的树突状二氧化硅比较载PFP成像比较图。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
Claims (10)
1.一种药物递送系统,其特征在于,所述药物递送系统包括壳-核结构,红细胞膜作为壳层,树突状介孔二氧化硅作为内核,所述树突状介孔二氧化硅装载有麻醉药物和/或超声成像制剂。
2.如权利要求1所述的药物递送系统,其特征在于,所述麻醉药物为水溶性或油溶性的局部麻醉药物,优选地,所述麻醉药物为左旋布比卡因、利多卡因、普鲁卡因、丁卡因和罗哌卡因中的至少一种。
3.如权利要求1所述的药物递送系统,其特征在于,所述超声成像制剂为疏水性和疏油性的超声成像制剂,优选地,所述超声成像制剂为全氟戊烷。
4.如权利要求1所述的药物递送系统,其特征在于,所述树突状介孔二氧化硅的表面积为500-700m2g-1,平均孔径为3-20nm。
5.如权利要求1所述的药物递送系统,其特征在于,所述树突状介孔二氧化硅的制备方法包括以下步骤:
将十六烷基三甲基氯化铵和三乙醇胺溶解在水中形成混合物,在混合物中添加正硅酸乙酯和双[3-(三乙氧基硅)丙基]四硫化物,搅拌,洗涤,清除残余反应物,然后使用含有乙醇的盐酸溶液回流提取产物,获得树突状介孔二氧化硅。
6.一种如权利要求1所述的药物递送系统的制备方法,其特征在于,将树突状介孔二氧化硅分散在麻醉药物水溶液中搅拌,然后再添加超声成像制剂继续搅拌,离心,收集装载有麻醉药物和超声成像制剂的纳米颗粒,将红细胞膜包被装载有麻醉药物和超声成像制剂的纳米颗粒,透析,浸入PBS溶液中,获得药物递送系统。
7.如权利要求6所述的药物递送系统的制备方法,其特征在于,所述透析的截留分子量为3500-8000Da。
8.如权利要求1-7任一项所述的药物递送系统在制备用于治疗疼痛的试剂中的用途。
9.一种药物组合物,其特征在于,所述药物组合物包括如权利要求1-7任一项所述的药物递送系统。
10.如权利要求9所述的药物组合物在制备用于治疗疼痛的试剂中的用途。
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