CN110115763A - 一种近红外光激活的多功能脂质体及其制备方法与应用 - Google Patents
一种近红外光激活的多功能脂质体及其制备方法与应用 Download PDFInfo
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Abstract
本发明揭示了一种近红外光激活的多功能脂质体及其制备方法与应用，首先将已有的光敏剂小分子Ce6通过PEG共轭和延长碳链得到两亲性的Ce6聚合物，然后将Ce6聚合物、环装RGD功能化的脂质体与吲哚菁绿、替拉扎明混合，通过薄膜水合法和自组装的方式得到一种两亲性的脂质体，最后将顺磁性钆离子引入Ce6的卟啉环中得到一种钆修饰的用于近红外光激活的多功能脂质体。所制备的响应型脂质体颗粒尺寸均一，且具有良好的水溶性、分散性和生物相容性。该多功能脂质体在生物多模态成像指导的光热‑光动力‑化疗的协同治疗领域具有广阔的应用前景。
Description
技术领域
本发明涉及一种近红外光激活的多功能脂质体及其制备方法与应用，可用于生物医学技术领域。
背景技术
动力治疗(PDT)作为光响应治疗方式之一，因为非侵入性、安全性和组织选择特异性，正逐渐取代传统的放疗、化疗和手术治疗。作为PDT的三要素(光敏剂、光源、氧气)之一，以小分子存在的光敏剂因为具有很差的光稳定性、水溶性，缺乏肿瘤靶向性以及浓度依赖性聚集等缺点直接影响了PDT的治疗效果。因此，开发解决上述缺点的光敏剂和优化传统的光敏剂以增强PDT效果成为光敏剂发展的一大趋势。
除了光敏剂，PDT还受到其他因素的制约，一方面，在正常阳光和室内光照下，PDT治疗后在皮肤和眼睛等正常组织中残留的光敏剂也会被激发产生细胞毒性的活性氧，从而对这些组织和器官产生持久的光毒性，导致晒伤和疼痛等并发症。为了克服这一缺点，在光敏剂富集到目标部位之前，需要设计一种策略，将光敏剂的荧光淬灭或减弱来减少对正常组织不必要的损伤。
另一方面，作为需氧的癌症治疗方法，PDT过程中不断消耗氧气导致的肿瘤环境的缺氧严重影响了PDT效果。传统的解决方法包括运用智能纳米药物输送系统将氧气递送进肿瘤细胞和采取化学方法原位产生氧气，被用来缓解肿瘤缺氧。然而，这些方法所产生的氧气效率仍然很低，无法满足单一的PDT中的氧气供应。因此，开发氧气依赖性较低的PDT成为目前研究的重点。
发明内容
本发明的目的就是为了解决现有技术中存在的上述问题，提出一种近红外光激活的多功能脂质体及其制备方法与应用，该材料可用作近红外光双重响应的光热/光动力/化疗协同治疗。
本发明的目的将通过以下技术方案得以实现：一种近红外光激活的多功能脂质体，首先将已有的光敏剂小分子Ce6通过PEG共轭和延长碳链得到两亲性的Ce6聚合物，然后将Ce6聚合物、环装RGD功能化的脂质体与吲哚菁绿、替拉扎明混合，通过薄膜水合法和自组装的方式得到一种两亲性的脂质体，最后将顺磁性钆离子引入Ce6的卟啉环中得到一种钆修饰的用于近红外光激活的多功能脂质体。
本发明揭示了一种近红外光激活的多功能脂质体的制备方法，该方法包括以下步骤：
S1：聚乙二醇修饰Ce6；
将Ce6、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、N-羟基琥珀酰亚胺(NHS)按一定的摩尔比溶于5～10ml氯仿中，搅拌2～5h，活化Ce6的羧基，将一定量的甲氧基聚乙二醇氨基(mPEG-NH2)溶于5～10ml氯仿，将Ce6溶液和mPEG-NH2的氯仿溶液混合，避光搅拌反应24h，旋转蒸发除去氯仿，加入5～10ml二甲亚砜溶解，放入去离子水中透析，冷冻干燥得到mPEG-Ce6粉末，甲氧基聚乙二醇氨基(mPEG-NH2，分子量为2000；
S2：两亲性Ce6聚合物的合成；
首先将mPEG-Ce6、EDC、NHS按一定的摩尔比溶于5～10ml氯仿中，搅拌2～5h，然后将一定量的硬脂胺和一定体积的三乙胺加入溶液中，避光搅拌24h，旋转蒸发除去氯仿，加入5～10ml超纯水，超声水合至完全溶解，放入去离子水中透析，冷冻干燥得到mPEG-Ce6-C18粉末；
S3：药物自组装；
将一定质量的卵磷脂、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-环肽(DSPE-PEG2000-cRGD)、两亲分子mPEG-Ce6-C18和ICG混合溶解于5～10mL氯仿中，搅拌溶解一段时间后，通过旋转蒸发除去氯仿，形成脂质薄膜；
S4：乏氧药物的负载；
加入5～10ml超纯水，剧烈超声水合20～30min，待分散均匀后，继续超声10～20min，同时逐滴加入TPZ水溶液，实现乏氧药物的负载，最后，通过透析过夜除去未被包封的ICG、TPZ，透析袋的截止分子量为3000；
S5：Gd3+修饰；
称取一定量的GdCl3·6H2O溶解于于5ml水中，加入S4步骤中得到的ICG/TPZ@Ce6-cRGD溶液搅拌6～10h，透析过夜，得到ICG/TPZ@Ce6-Gd NPs。
优选地，所述S1步骤中，Ce6/EDC的摩尔比为1∶2～1∶5，Ce6/NHS的摩尔比为1∶2～1∶4，Ce6/mPEG-NH2的摩尔比为1∶1～2∶1，透析的截留分子量为1000～2000Da，透析时间为2～3天。
优选地，所述S2步骤中，mPEG-Ce6/EDC的摩尔比为1∶6～1∶12，mPEG/NHS的摩尔比为1∶6～1∶12，mPEG-Ce6/硬脂胺的摩尔比为1∶2～1∶6，透析袋的截留分子量为2000～3000Da，透析时间为2～3天。
优选地，所述S3步骤中，mPEG-Ce6-C18/卵磷脂的质量比为3∶1～2∶1，mPEG-Ce6-C18/DSPE-PEG2000-cRGD的摩尔比为8∶1～5∶1，mPEG-Ce6-C18/ICG的摩尔比为8∶1～5∶1。
优选地，所述S4步骤中，TPZ水溶液浓度为1mg/ml，加入的TPZ与ICG的质量比为1∶1。
优选地，所述S5步骤中，加入的GdCl3·6H2O/mPEG-Ce6-C18的摩尔比为1∶1～5∶1，透析的截留分子量为2000～3000Da，透析后的脂质溶液经过孔径0.22～0.45μm的无表面活性剂的醋酸纤维素膜过滤后得到多功能脂质纳米颗粒。。
本发明还揭示了一种近红外光激活的多功能脂质体的应用，应用于靶向药物递送。
本发明还揭示了一种近红外光激活的多功能脂质体的应用，应用于生物多模态成像和光触发的乏氧激活的协同治疗，生物多模态成像包括荧光成像、光声成像和磁共振成像。
本发明还揭示了一种近红外光激活的多功能脂质体的应用，用作近红外光双重响应的光热/光动力/化疗协同治疗。
本发明采用以上技术方案与现有技术相比，具有以下技术效果：本发明致力于通过对传统光敏剂Ce6的PEG化修饰和碳链延伸增强其光稳定性、水溶性和分散性，然后将光热试剂ICG和乏氧前药TPZ共同封装在Ce6为壳层的脂质体中，通过荧光共振能量转移，实现ICG对Ce6荧光的部分淬灭，缓解Ce6在正常光源下受激后对正常组织不必要的损伤。在ICG诱导的光热分解脂质体重新打开Ce6的光动力治疗后，产生的肿瘤环境的缺氧激发TPZ的细胞毒性用于癌症的化疗，这种顺序激活的双重响应探针的制备解决了PDT中的一大瓶颈。
附图说明
图1为本发明的两亲性Ce6聚合物mPEG-Ce6-C18的1HNMR谱图。
图2为本发明的mPEG-Ce6-C18的红外光谱图。
图3为本发明的ICG/TPZ@Ce6-GdNPs的透射电子显微镜图像。
图4为本发明的ICG/TPZ@Ce6-Gd NPs的动态光散射图。
图5为本发明的各成分和最终产物的紫外-可见光谱吸收图。
图6为本发明的ICG的紫外-可见光谱吸收图和Ce6的荧光谱图。
图7为本发明的Ce6，mPEG-Ce6-C18形成的胶束，ICG/TPZ@Ce6-Gd NPs，ICG@Ce6-GdNPs的Ce6的荧光发射以及ICG/TPZ@Ce6-Gd NPs在808nm激光辐射5分钟后对应的Ce6的荧光发射。
图8为本发明的ICG/TPZ@Ce6-Gd NPs与ADPA混合后在808nm，0.5W/cm2的近红外光光照5min后，用660nm激光辐射4min，ADPA在378nm的紫外吸收特征峰的强度变化图。
图9为本发明的ICG/TPZ@Ce6-Gd NPs与ADPA混合后在808nm，0.5W/cm2的近红外光光照5min后，用660nm激光辐射4min，ADPA在378nm的紫外吸收特征峰的强度变化图。
图10为本发明的ICG/TPZ@Ce6-Gd NPs体外磁共振成像及其强度-浓度关系图。
图11为本发明的ICG/TPZ@Ce6-Gd NPs体外光声成像及其强度-浓度关系图。
图12为本发明的ICG/TPZ@Ce6-Gd NPs在近红外光双重响应刺激下的细胞毒性。
具体实施方式
本发明的目的、优点和特点，将通过下面优选实施例的非限制性说明进行图示和解释。这些实施例仅是应用本发明技术方案的典型范例，凡采取等同替换或者等效变换而形成的技术方案，均落在本发明要求保护的范围之内。
本发明揭示了一种近红外光激活的多功能脂质体及其制备方法与应用，一种近红外光激活的多功能脂质体，通过光热效应激活光动力效应，光动力进一步激活乏氧前药，实现化疗的的顺序激活响应机制，实现多模态成像指导的肿瘤协同治疗效果。
首先将已有的光敏剂小分子Ce6通过PEG修饰和延长碳链得到两亲性的Ce6聚合物，然后将Ce6聚合物、环装RGD功能化的脂质体与吲哚菁绿、替拉扎明混合，通过薄膜水合法和自组装的方式得到一种核壳结构的脂质体，最后将顺磁性钆离子引入Ce6的卟啉环得到一种钆修饰的具有近红外响应激活治疗的多功能脂质体。
所构建的脂质体在无近红外光照射下，Ce6的荧光和光动力效果通过能量共振转移原理被ICG淬灭，乏氧前药TPZ对肿瘤无细胞毒性。当暴露于808nm近红外光下，ICG诱导的高温使脂质体响应释放药物，淬灭的Ce6被激活，并在660nm激光照射下产生光动力治疗效果，光动力治疗产生的肿瘤缺氧进一步激活乏氧前药TPZ，使其产生细胞毒性，实现肿瘤的化疗。这种近红外光顺序激活的的多功能脂质体，为智能响应的诊疗探针的设计与合成提供了良好的借鉴。
一种顺序激活光动力和乏氧前药的脂质体制备方法，包括如下步骤：
S1：将Ce6、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、N-羟基琥珀酰亚胺(NHS)按一定的摩尔比溶于5～10ml氯仿中，搅拌2～5h，活化Ce6的羧基，将一定量的甲氧基聚乙二醇氨基(mPEG-NH2)溶于5～10ml氯仿，将Ce6溶液和mPEG-NH2的氯仿溶液混合，避光搅拌反应24h，旋转蒸发除去氯仿，加入5～10ml二甲亚砜溶解，放入去离子水中透析，冷冻干燥得到mPEG-Ce6粉末。
聚乙二醇修饰Ce6：20mg Ce6，10mg EDC，10mg NHS溶于5ml氯仿反应5h。68mgmPEG-NH2溶于5ml氯仿，搅拌溶解。将二氢卟吩e6溶液和mPEG-NH2的氯仿溶液混合，避光搅拌反应24h，旋转蒸发除去氯仿，加入10ml二甲亚砜溶解，放入去离子水中透析三天，透析袋的截留分子量为1000，冷冻干燥得到mPEG-Ce6粉末。
S2：两亲性Ce6聚合物的合成：首先将10mgmPEG-Ce6、8mg EDC、8mg NHS溶于10ml氯仿中，搅拌5h。然后5mg硬脂胺和80μl三乙胺加入溶液中，避光搅拌24h，旋转蒸发除去氯仿，加入10ml超纯水，超声水合至完全溶解，放入去离子水中透析三天，冷冻干燥得到mPEG-Ce6-C18粉末，透析袋的截留分子量为2000。如图1，图2所示，1HNMR谱图，红外光谱图有力证明了mPEG-Ce6-C18的结构。
S3：药物自组装：将一定质量的卵磷脂、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-环肽(DSPE-PEG2000-cRGD)、两亲分子mPEG-Ce6-C18和ICG混合溶解于5～10mL氯仿中，搅拌溶解一段时间后，通过旋转蒸发除去氯仿，形成脂质薄膜。
将5mg卵磷脂、2mg二硬脂酰基磷脂酰乙醇胺-聚乙二醇-环肽(DSPE-PEG2000-cRGD)、10mg两亲分子mPEG-Ce6-C18和2mg ICG混合溶解于10mL氯仿中，搅拌溶解一段时间后，通过旋转蒸发除去氯仿，形成脂质薄膜。
S4：乏氧药物的负载：加入5ml超纯水，剧烈超声水合20min。待分散均匀后，继续超声10min，同时逐滴加入1ml TPZ水溶液(1ml/mg)，实现乏氧药物的负载，最后，通过透析过夜除去未被包封的ICG、TPZ，透析袋的截留分子量为3000。
S5：Gd3+修饰：称取5mgGdCl3·6H2O溶解于于5ml水中，加入上述得到的10mgICG/TPZ@Ce6-cRGD溶液搅拌10h，透析过夜，得到ICG/TPZ@Ce6-Gd NPs，透析袋的截留分子量为2000。
最后，再将脂质体材料经过无表面活性剂的醋酸纤维素膜过滤，可得到大小均匀，分散性、水溶性和生物相容性良好的多功能脂质体，无表面活性剂的醋酸纤维素膜过滤的过滤孔径为0.22μm。如图3和图4所示，ICG/TPZ@Ce6-Gd NPs是均匀分散的球形，粒径约为100nm。图4中，纵坐标为纳米颗粒的数目，横坐标为颗粒直径大小。图5为本发明各组分和最终产物的紫外-可见光谱吸收图，纵坐标为吸收值，横坐标为波长。如图6所示，纵坐标为Ce6的荧光强度值(左)和ICG的紫外吸收值(右)，横坐标为波长，由于Ce6的荧光发射光谱和ICG的紫外吸收光谱存在较大重叠，所以当Ce6与ICG被共同封装在脂质体中时，通过荧光共振能量转移，Ce6的能量会转移给相邻的ICG，导致Ce6的荧光被淬灭。
如图7所示，纵坐标为荧光强度值，横坐标为波长，当形成最终产物ICG/TPZ@Ce6-Gd NPs时，Ce6的大部分荧光被ICG淬灭。当用808nm激光照射时，ICG诱导的高温使脂质体分解，使Ce6的荧光和光动力得到恢复，然后在660nm激光照射下，荧光恢复的Ce6产生单线态氧，使ADPA逐渐降解，如图8所示，纵坐标为ADPA在378nm的紫外吸收值，横坐标为波长范围，随着光照时间的增加，ADPA在378nm的紫外吸收峰逐渐降低。
图9中，纵坐标为ADPA在378nm的紫外吸收值，横坐标为光照时间。表明在近红外光下，Ce6的光动力由ICG诱导的高温响应性激活。Ce6的光动力治疗消耗了肿瘤内大量的氧气，产生的缺氧环境再次激活纳米颗粒中乏氧前药TPZ，使其产生细胞毒性的自由基，用于化疗。图10中，纵坐标为磁共振强度值，横坐标为Gd浓度值，随着Gd浓度的增加，纳米颗粒的磁共振信号逐渐增强，表明ICG/TPZ@Ce6-Gd NPs可作为良好的磁共振造影剂。
图11中，纵坐标为光声强度值，横坐标为ICG浓度值，随着ICG浓度增加，纳米颗粒的光声信号逐渐增强，表明ICG/TPZ@Ce6-Gd NPs可作为良好的光声造影剂。如图12所示，在近红外光双重响应下，光热治疗顺序激活光动力和化疗，ICG/TPZ@Ce6-GdNPs达到最大的癌细胞死亡率和最佳的治疗效果。当ICG在近红外激发下产生光热治疗，同时诱导的高温分解脂质体时，Ce6的荧光被激活，产生光动力治疗效果。经过一段时间后，需氧的光动力治疗产生的肿瘤缺氧激活乏氧前药TPZ，用于化疗，进一步增强了光热、光动力治疗效果。
这种具有近红外光双重响应激活的脂质体由聚乙二醇(PEG)共轭的二氢卟吩e6(Ce6)和环状RGD功能化的脂质体通过薄膜水合法和自组装包覆光热试剂吲哚菁绿(ICG)和乏氧前药替拉扎明(TPZ)制备得到。所制备的响应型脂质体颗粒尺寸均一，且具有良好的水溶性、分散性和生物相容性。在近红外光的照射下，荧光染料ICG产生的局部高温可以实现光热治疗，同时分解脂质体，进而激活Ce6的光动力治疗。伴随着光动力治疗产生的肿瘤部位的乏氧环境，进一步激活乏氧前药TPZ，从而实现化疗，最终实现癌症的协同治疗效果。总之，该多功能脂质体在生物多模态成像指导的(荧光成像、光声成像和磁共振成像)光热-光动力-化疗的协同治疗领域具有广阔的应用前景。
本发明致力于通过对传统光敏剂Ce6的PEG化修饰和碳链延伸增强其光稳定性、水溶性和分散性。然后将光热试剂ICG和乏氧前药TPZ共同封装在Ce6为壳层的脂质体中，通过荧光共振能量转移，实现ICG对Ce6荧光的部分淬灭，缓解Ce6在正常光源下受激后对正常组织不必要的损伤。在ICG诱导的光热重新打开其光动力治疗后，产生的肿瘤环境的缺氧激发TPZ的细胞毒性用于癌症的化疗，这种顺序激活的双重响应探针的制备解决了PDT中的一大瓶颈。该纳米复合材料在靶向药物递送、生物多模态成像(荧光成像、光声成像和磁共振成像)和光触发的乏氧激活的协同治疗等领域具有广阔的应用前景。
本发明尚有多种实施方式，凡采用等同变换或者等效变换而形成的所有技术方案，均落在本发明的保护范围之内。
Claims (10)
1.一种近红外光激活的多功能脂质体，其特征在于：首先将已有的光敏剂小分子Ce6通过PEG共轭和延长碳链得到两亲性的Ce6聚合物，然后将Ce6聚合物、环装RGD功能化的脂质体与吲哚菁绿、替拉扎明混合，通过薄膜水合法和自组装的方式得到一种两亲性的脂质体，最后将顺磁性钆离子引入Ce6的卟啉环中得到一种钆修饰的用于近红外光激活的多功能脂质体。
2.一种近红外光激活的多功能脂质体的制备方法，其特征在于：该方法包括以下步骤：
S1：聚乙二醇修饰Ce6；
将Ce6、EDC、NHS按一定的摩尔比溶于5～10ml氯仿中，搅拌2～5h，活化Ce6的羧基，将一定量的mPEG-NH2溶于5～10ml氯仿，将Ce6溶液和mPEG-NH2的氯仿溶液混合，避光搅拌反应24h，旋转蒸发除去氯仿，加入5～10ml二甲亚砜溶解，放入去离子水中透析，冷冻干燥得到mPEG-Ce6粉末；
S2：两亲性Ce6聚合物的合成；
首先将mPEG-Ce6、EDC、NHS按一定的摩尔比溶于5～10ml氯仿中，搅拌2～5h，然后将一定量的硬脂胺和一定体积的三乙胺加入溶液中，避光搅拌24h，旋转蒸发除去氯仿，加入5～10ml超纯水，超声水合至完全溶解，放入去离子水中透析，冷冻干燥得到mPEG-Ce6-C18粉末；
S3：药物自组装；
将一定质量的卵磷脂、DSPE-PEG2000-cRGD、两亲分子mPEG-Ce6-C18和ICG混合溶解于5～10mL氯仿中，搅拌溶解一段时间后，通过旋转蒸发除去氯仿，形成脂质薄膜；
S4：乏氧药物的负载；
加入5～10ml超纯水，剧烈超声水合20～30min，待分散均匀后，继续超声10～20min，同时逐滴加入TPZ水溶液，实现乏氧药物的负载，最后，通过透析过夜除去未被包封的ICG、TPZ，透析袋的截止分子量为3000；
S5：Gd3+修饰；
称取一定量的GdCl3·6H2O溶解于于5ml水中，加入S4步骤中得到的ICG/TPZ@Ce6-cRGD溶液搅拌6～10h，透析过夜，得到ICG/TPZ@Ce6-Gd NPs。
3.根据权利要求1所述的一种近红外光激活的多功能脂质体的制备方法，其特征在于：所述S1步骤中，Ce6/EDC的摩尔比为1∶2～1∶5，Ce6/NHS的摩尔比为1∶2～1∶4，Ce6/mPEG-NH2的摩尔比为1∶1～2∶1，透析的截留分子量为1000～2000Da，透析时间为2～3天。
4.根据权利要求1所述的一种近红外光激活的多功能脂质体的制备方法，其特征在于：所述S2步骤中，mPEG-Ce6/EDC的摩尔比为1∶6～1∶12，mPEG/NHS的摩尔比为1∶6～1∶12，mPEG-Ce6/硬脂胺的摩尔比为1∶2～1∶6，透析袋的截留分子量为2000～3000Da，透析时间为2～3天。
5.根据权利要求1所述的一种近红外光激活的多功能脂质体的制备方法，其特征在于：所述S3步骤中，mPEG-Ce6-C18/卵磷脂的质量比为3∶1～2∶1，mPEG-Ce6-C18/DSPE-PEG2000-cRGD的摩尔比为8∶1～5∶1，mPEG-Ce6-C18/ICG的摩尔比为8∶1～5∶1。
6.根据权利要求1所述的一种近红外光激活的多功能脂质体的制备方法，其特征在于：所述S4步骤中，TPZ水溶液浓度为1mg/ml，加入的TPZ与ICG的质量比为1∶1。
7.根据权利要求1所述的一种近红外光激活的多功能脂质体的制备方法，其特征在于：所述S5步骤中，加入的GdCl3·6H2O/mPEG-Ce6-C18的摩尔比为1∶1～5∶1，透析的截留分子量为2000～3000Da，透析后的脂质溶液经过孔径0.22～0.45μm的无表面活性剂的醋酸纤维素膜过滤后得到多功能脂质纳米颗粒。
8.一种近红外光激活的多功能脂质体的应用，其特征在于：应用于靶向药物递送。
9.一种近红外光激活的多功能脂质体的应用，其特征在于：应用于生物多模态成像和光触发的乏氧激活的协同治疗，生物多模态成像包括荧光成像、光声成像和磁共振成像。
10.一种近红外光激活的多功能脂质体的应用，其特征在于：用作近红外光双重响应的光热/光动力/化疗协同治疗。
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