CN106668882A - 一种超声敏感脂质体及其应用 - Google Patents
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Abstract
本发明涉及超声敏感脂质体及其应用，可有效解决化疗毒副作用大、疗效低，治疗效率低，免疫毒性大的问题，其解决的技术方案是，称取2‑10mg胆固醇、2‑20mg 1,2‑棕榈酰磷脂酰甘油（DPPG）、5‑30mg二棕榈酰磷脂酰胆碱（DPPC）、0‑20mg二油酰磷脂酰乙醇胺（DOPE），溶于5‑30ml溶剂中，超声5‑60min充分溶解，先50℃下旋蒸除去溶剂，再在真空条件下旋蒸4h除去残余溶剂，然后加入1‑10ml含药物甘露醇溶液，甘露醇浓度为0.2M‑1M，迅速用热风吹瓶底以加速水化，超声5‑10min待溶液成均匀透明状后，冷冻、解冻3‑6次，即得；本发明使脂质体里包裹的药物定点释放，从而降低化学药物的毒副作用，增加疗效，可作为超声成像诊断剂，是化疗药物上的创新。
Description
技术领域
本发明涉及化学领域，特别是一种超声敏感脂质体及其应用。
背景技术
化学药物治疗现仍是多种疾病的主要治疗方式，如脑梗、心绞痛、癌症、消化系统疾病等，大大提高了人类的生活质量，是对抗疾病道路上不可取代的一种治疗方式。化学药物治疗方式简单，成本较低，危险系数低，所以应用极为广泛，但化疗仍存在多种弊端，如毒副作用大，治疗效率低，免疫毒性大，尤其随着耐药机制的出现，化学药物对多种疾病的治疗效率大大降低，显著降低了其应用。如何解决化疗的这些问题，是医学界致力研究的一个主要方向。化疗之所以会出现这么多问题，很重要的一个原因为：药物不能完全作用在病变部位的药物靶点上。若药物不能完全作用在病变部位，将会有一部分药物作用在非病变即正常器官，产生毒副作用，同时使病变部位的药物浓度降低，降低药物对病变部位的治疗效率。那么如何将药物靶向转运到病变部位且在病变部位靶向释放是克服化疗缺陷的一个关键问题。
为增加病变部位的药物浓度，各类药物递送系统应运而生，如胶束、脂质体、介孔类材料等。脂质体由脂质双分子构成，具有类似生物膜的结构，其生物相容性好，半衰期长，载药率高，且具有较强的靶向性，如可通过EPR效应富集在肿瘤组织内，通过被巨噬系统吞噬,从而激活机体的自身免疫功能，并改变被包封药物的体内分布，使药物主要在肝、脾、肺和骨髓等组织器官中积蓄，从而提高药物的治疗指数，减少药物的治疗剂量，降低药物的毒副作用以及延长药物在体内的循环时间。
将药物递送系统富集在病变部位的同时，将药物定点释放，以降低药物对正常组织的损伤，从而降低化疗毒副作用。目前，已有多种方式可实现对药物定点释放，大致可归为以下几类：1、物理响应型，如：激光照射、超声刺激等；2、自响应型，如缓释制剂；3、生理响应型，如利用肿瘤偏酸性环境、血栓氧含量低等病理特性。物理响应型即远程调控型，准确性高、操作性强、刺激性小，是定点释放药物的一种主要方式。
超声作为物理响应型定点释放药物的一种方式，其几乎无损伤性，且成本低，准确度高，被广泛应用。超声诊断成像更是当前应用最广泛的医学成像模式，在疾病诊断方面发挥了巨大作用，据统计全世界每年有近一亿次心血管系统、腹部脏器的超声检查。而超声造影剂,是应超声诊断成像技术的需要发展起来的。它是一类能够显著增强医学超声检测信号的诊断试剂。通过增强散射回声，明显提高超声诊断的分辨力、敏感性和特异性的技术。超声造影剂主要由成膜材料与成像气体两部分组成。
因此，构建一种靶向性好，且能在病变部位准确定点释放药物，并将诊断与治疗有效结合的药物递送系统，是解决化疗毒副作用大、疗效低的一个重要方向。因此，药物递送系统的改进是目前亟需解决的问题。
发明内容
针对上述情况，为解决现有技术之缺陷，本发明之目的就是提供一种超声敏感脂质体及其应用，可有效解决化疗毒副作用大、疗效低，治疗效率低，免疫毒性大的问题。
本发明解决的技术方案是，称取2-10mg胆固醇、2-20mg 1,2-棕榈酰磷脂酰甘油（DPPG）、5-30mg二棕榈酰磷脂酰胆碱（DPPC）、0-20mg二油酰磷脂酰乙醇胺（DOPE），溶于5-30ml溶剂中，超声5-60min充分溶解，先50℃下旋蒸除去溶剂，再在真空条件下旋蒸4h除去残余溶剂，然后加入1-10ml含药物甘露醇溶液，甘露醇浓度为0.2M-1M，迅速用热风吹瓶底以加速水化，超声5-10min待溶液成均匀透明状后，冷冻、解冻3-6次，即得超声敏感脂质体，4℃下保存备用；所述的溶剂为甲醇、氯仿、二氯甲烷、乙酸乙酯的一种或两种以上的混合物；所述的药物为心血管药物、泌尿系统药物、呼吸系统药物、消化系统药物、抗感染药物、抗癌药物的一种；所述的冷冻为干冰、液氮或降低温度。
所述的超声敏感脂质体，粒径在200nm-700nm之间。
本发明通过实验条件筛选与优化，制备出一种稳定性良好的超声敏感性脂质体。脂质体磷脂双分子层之间分布的气体，在超声作用下逐渐膨胀，爆破脂质层，使脂质体里包裹的药物定点释放，从而降低化学药物的毒副作用，增加疗效，并且脂质体磷脂双分子层间的空气层可增加超声成像的散射回声，可作为超声成像诊断剂，集成像与诊断于一体，是化疗药物上的创新。
附图说明
图1为本发明超声敏感脂质体透射电镜图（Tecnai G2 20,FEI）。
图2为本发明超声敏感脂质体超声成像信号强度图(Vevo2100)。
图3为本发明分别向核瘤小鼠尾静脉注射荧光成像剂IR783或超声敏感脂质体后，不同时间的活体成像图(Bruker MI)。
图4为本发明抗肿瘤长期药效实验结果。
具体实施方式
以下结合附图和实施例对本发明的具体实施方式作进一步详细说明。
实施例1
本发明在具体实施时，可称取3.8mg胆固醇、3.1mg 1,2-棕榈酰磷脂酰甘油（DPPG）、13.5mg二棕榈酰磷脂酰胆碱（DPPC）、13.6mg二油酰磷脂酰乙醇胺（DOPE）于茄型瓶中，缓慢加入4ml氯仿与1ml甲醇溶剂，超声30min充分溶解，先50℃下缓慢旋蒸除去溶剂，以在茄型瓶壁上形成一层均匀透明薄膜，再在真空条件下继续旋蒸4h除去残余溶剂，然后加入2ml5mg/ml的阿霉素水溶液，其中含甘露醇浓度为0.3M，迅速用热风吹瓶底以加速水化，超声5min待溶液成均匀透明状后，用干冰冷冻、解冻3次，即得超声敏感脂质体，4℃下保存备用。
实施例2
本发明在具体实施时，可称取5mg胆固醇、5mg 1,2-棕榈酰磷脂酰甘油（DPPG）、13mg二棕榈酰磷脂酰胆碱（DPPC）、13mg二油酰磷脂酰乙醇胺（DOPE）于茄型瓶中，缓慢加入4ml氯仿与1ml甲醇溶剂，超声30min以充分溶解，先50℃下缓慢旋蒸除去溶剂，以在茄型瓶壁上形成一层均匀透明薄膜，再在真空条件下继续旋蒸4h以除去残余溶剂，然后加入2ml 5mg/ml的盐酸利多卡因水溶液，其中含甘露醇浓度为0.3M，迅速用热风吹瓶底以加速水化，超声5min待溶液成均匀透明状后，-20℃冷冻、解冻3次，即得超声敏感脂质体，4℃下保存备用。
实施例3
本发明在具体实施时，还可称取3.8mg胆固醇、3.1mg 1,2-棕榈酰磷脂酰甘油（DPPG）、30mg二棕榈酰磷脂酰胆碱（DPPC）于50ml茄型瓶中，缓慢加入4ml氯仿与2ml甲醇溶剂，超声40min以充分溶解，先50℃下缓慢旋蒸除去溶剂，以在茄型瓶壁上形成一层均匀透明薄膜，再在真空条件下继续旋蒸4h以除去残余溶剂，然后加入2ml 5mg/ml的呋塞米水溶液，其中含甘露醇浓度为0.3M，迅速用热风吹瓶底以加速水化，超声5min待溶液成均匀透明状后，用干冰冷冻、解冻3次，即得超声敏感脂质体，4℃下保存备用。
实施例4
本发明在具体实施时，还可称取7mg胆固醇、7mg 1,2-棕榈酰磷脂酰甘油（DPPG）、30mg二棕榈酰磷脂酰胆碱（DPPC）、30mg二油酰磷脂酰乙醇胺（DOPE）于50ml茄型瓶中，缓慢加入8ml氯仿与4ml甲醇溶剂，超声40min以充分溶解，先50℃下缓慢旋蒸除去溶剂，以在茄型瓶壁上形成一层均匀透明薄膜，再在真空条件下继续旋蒸4h以除去残余溶剂，然后加入4ml10mg/ml的盐酸四环素水溶液，其中含甘露醇浓度为0.3M，迅速用热风吹瓶底以加速水化，超声5min待溶液成均匀透明状后，-20℃冷冻、解冻3次，即得超声敏感脂质体，4℃下保存备用。
本申请的试验资料，由图给出，图1中，为本发明超声敏感脂质体透射电镜图，a为冷冻前脂质体，b为超声敏感脂质体，c为对超声敏感脂质体超声作用后。
图2为本发明超声敏感脂质体超声成像信号强度图，a为普通脂质体超声成像图，b为超声敏感脂质体成像图。
图3为本发明分别向核瘤小鼠尾静脉注射荧光成像剂IR783（上图）或超声敏感脂质体（下图）后，不同时间的活体成像图。由图可以说明超声敏感脂质体可明显增加药物在肿瘤部位的富集浓度及时间，降低药物在非病变部位的聚集，从而可以增加疗效降低毒副作用。
图4为本发明抗肿瘤长期药效实验结果。由结果可以看出，本发明制备的超声敏感脂质体包载上抗肿瘤药物阿霉素后，对肿瘤的生长有明显的抑制作用，且相比于原料药阿霉素组，对肿瘤的抑制作用更为明显，显著增加了抗肿瘤药物的疗效。
本发明制备的超声敏感脂质体，粒径在200nm-700nm之间，由多种两亲性嵌段共聚物组成，其磷脂双分子层之间充满气体，在超声作用下，气体层逐渐膨胀，爆破脂质体磷脂层，定点定位释放药物，且气体层能增加超声成像信号，可作为超声成像剂。本发明制备的超声敏感脂质体，准确调控药物释放，集成像与诊断于一体，具有实际的临床意义和很好的推广应用价值。
Claims (8)
1.一种超声敏感脂质体，其特征在于，称取2-10mg胆固醇、2-20mg 1,2-棕榈酰磷脂酰甘油、5-30mg二棕榈酰磷脂酰胆碱、0-20mg二油酰磷脂酰乙醇胺，溶于5-30ml溶剂中，超声5-60min充分溶解，先50℃下旋蒸除去溶剂，再在真空条件下旋蒸4h除去残余溶剂，然后加入1-10ml含药物甘露醇溶液，甘露醇浓度为0.2M-1M，迅速用热风吹瓶底以加速水化，超声5-10min待溶液成均匀透明状后，冷冻、解冻3-6次，即得超声敏感脂质体；所述的溶剂为甲醇、氯仿、二氯甲烷、乙酸乙酯的一种或两种以上的混合物；所述的药物为心血管药物、泌尿系统药物、呼吸系统药物、消化系统药物、抗感染药物、抗癌药物的一种；所述的冷冻为干冰、液氮或降低温度。
2.根据权利要求1所述的超声敏感脂质体，其特征在于，称取3.8mg胆固醇、3.1mg 1,2-棕榈酰磷脂酰甘油、13.5mg二棕榈酰磷脂酰胆碱、13.6mg二油酰磷脂酰乙醇胺于茄型瓶中，缓慢加入4ml氯仿与1ml甲醇溶剂，超声30min充分溶解，先50℃下缓慢旋蒸除去溶剂，以在茄型瓶壁上形成一层均匀透明薄膜，再在真空条件下继续旋蒸4h除去残余溶剂，然后加入2ml 5mg/ml的阿霉素水溶液，其中含甘露醇浓度为0.3M，迅速用热风吹瓶底以加速水化，超声5min待溶液成均匀透明状后，用干冰冷冻、解冻3次，即得超声敏感脂质体，4℃下保存备用。
3.根据权利要求1所述的超声敏感脂质体，其特征在于，称取5mg胆固醇、5mg 1,2-棕榈酰磷脂酰甘油、13mg二棕榈酰磷脂酰胆碱、13mg二油酰磷脂酰乙醇胺于茄型瓶中，缓慢加入4ml氯仿与1ml甲醇溶剂，超声30min以充分溶解，先50℃下缓慢旋蒸除去溶剂，以在茄型瓶壁上形成一层均匀透明薄膜，再在真空条件下继续旋蒸4h以除去残余溶剂，然后加入2ml5mg/ml的盐酸利多卡因水溶液，其中含甘露醇浓度为0.3M，迅速用热风吹瓶底以加速水化，超声5min待溶液成均匀透明状后，-20℃冷冻、解冻3次，即得超声敏感脂质体，4℃下保存备用。
4.根据权利要求1所述的超声敏感脂质体，其特征在于，称取3.8mg胆固醇、3.1mg 1,2-棕榈酰磷脂酰甘油、30mg二棕榈酰磷脂酰胆碱于50ml茄型瓶中，缓慢加入4ml氯仿与2ml甲醇溶剂，超声40min以充分溶解，先50℃下缓慢旋蒸除去溶剂，以在茄型瓶壁上形成一层均匀透明薄膜，再在真空条件下继续旋蒸4h以除去残余溶剂，然后加入2ml 5mg/ml的呋塞米水溶液，其中含甘露醇浓度为0.3M，迅速用热风吹瓶底以加速水化，超声5min待溶液成均匀透明状后，用干冰冷冻、解冻3次，即得超声敏感脂质体，4℃下保存备用。
5.根据权利要求1所述的超声敏感脂质体，其特征在于，称取7mg胆固醇、7mg 1,2-棕榈酰磷脂酰甘油、30mg二棕榈酰磷脂酰胆碱、30mg二油酰磷脂酰乙醇胺于50ml茄型瓶中，缓慢加入8ml氯仿与4ml甲醇溶剂，超声40min以充分溶解，先50℃下缓慢旋蒸除去溶剂，以在茄型瓶壁上形成一层均匀透明薄膜，再在真空条件下继续旋蒸4h以除去残余溶剂，然后加入4ml 10mg/ml的盐酸四环素水溶液，其中含甘露醇浓度为0.3M，迅速用热风吹瓶底以加速水化，超声5min待溶液成均匀透明状后，-20℃冷冻、解冻3次，即得超声敏感脂质体，4℃下保存备用。
6.权利要求1或2-5任一项所述的超声敏感脂质体，粒径在200nm-700nm之间。
7.权利要求1或2-5任一项所述的超声敏感脂质体在制备抗肿瘤药物中的应用。
8.权利要求1或2-5任一项所述的超声敏感脂质体在作为超声成像剂中的应用。
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