基于FRET的嵌段共聚物胶束输送药物的稳定性研究
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摘要
两亲性嵌段共聚物通过在水溶液中的自组装行为,形成具有核壳结构的聚合物胶束,可将疏水性药物包裹入核内作为药物载体,具有增大药物利用率、提高靶向性、降低毒副作用等优点,展现出广泛的应用前景。但是,目前纳米药物面临的困境是：纳米药物在一定程度上可减轻毒副作用,但疗效较原药并没有明显提高。因此如何显著提高胶束的靶向性和在肿瘤处的蓄积,是提高其疗效的关键。而提高胶束在肿瘤内蓄积的关键是其能够在血液循环系统中在较长时间内能够以胶束的形式存在。因此,阐明聚合物纳米胶束在血液中的解离过程、解离动力学及其影响因素,是进一步设计制备物理稳定的聚合物胶束、获得高效胶束型纳米药物的基础。
本课题利用一对近红外双荧光分子Cy5和Cy5.5,基于荧光共振能量转移(FRET)技术,通过将其共价键合在共聚物胶束核内,来研究在不同生理条件下聚合物胶束的动态变化情况。
首先考察共聚物胶束在体外稳定性的影响因素。我们发现血浆蛋白、球蛋白以及血液中的剪切应力均会对PEG-b-PCL-FRET自组装胶束的稳定性产生一定的影响。而浓度稀释较前几者来说,影响最大。聚合物和其单分子链在溶液中呈现动态平衡的过程。当浓度降到胶束的CMC值以下时,其平衡向着解离方向移动,FRET效率即溶液中以胶束形态存在的聚合物仅有60%左右。新鲜提取的小鼠血液、血浆均对PEG-b-PCL-FRET自组装胶束的稳定性没有影响。将共聚物胶束与肿瘤细胞共同孵育,FRET光谱曲线证明胶束在细胞膜上时依然是以完整的胶束形态存在,一旦进入胞浆内,则解离开来,释放出核内药物。
在体内稳定性研究中,我们利用多种不同的条件来探索共聚物胶束在血液中的解离和清除动态过程。当PEG-b-PCL-FRET胶束通过尾静脉注射至小鼠体内后,通过活体成像仪和FRET光谱曲线实时监控其动态。胶束在血液中的快速解离(24h时仅剩20%的以胶束形态存在)及快速清除(24h时仅剩3.7%的聚合物残留)证明其还未到达靶向组织之前,核内物质便释放出来。我们通过用不同方法如利用疏水链端PLLA代替PCL的方法、增加胶束给药剂量、利用混合胶束以改变胶束形貌、预注射致哑剂量的PEG-b-PCL胶束以及利用氯化钆,地塞米松等巨噬细胞抑制剂来探索PEG-b-PCL-FRET自组装胶束在体内快速解离以及快速清除的基本机理。结果证明,增加给药剂量,预注射致哑剂量的PEG-b-PCL胶束以及利用氯化钆,地塞米松等巨噬细胞抑制剂均可以显著延长胶束在体内的循环时间,但是对其稳定性没有影响。由此说明饱和血浆中血浆蛋白对自组装胶束的吸附以及抑制其被吞噬细胞识别均可以减缓血液循环中聚合物胶束的清除速率,但不影响胶束稳定性。包裹了抗癌药物PTX的PEG-b-PCL-FRET胶束因其疏水核之间的作用增强,在血液中可以长时间维持其胶束形态,并且血浆清除慢。这证明增加共聚物胶束本身结构中的疏水核作用对清除和解离都有较大影响。肿瘤切片的FRET光谱图证明,尽管只有很少数的共聚物胶束可以通过EPR效应最终到达肿瘤部位,但在肿瘤组织中,大部分共聚物仍保留其胶束完整性,直到将药物输送至靶点。综上所述,我们的研究结果揭示了聚合物胶束通过静脉注射后在体内的解离动力学以及清除的机理,认清了一些关键的基本问题。希望本课题工作能为进一步设计制备物理稳定的聚合物胶束、获得高效胶束型纳米药物打下坚实的基础。
本论文的第二部分内容诣在解决传统阳离子聚合物基因载体不可降解,合成繁琐,毒性较高等缺点。通过双环氧化合物与胺进行类点击反应,合成一种制作方便简单,低毒并且高效的阳离子聚合物。其聚合反应时间段,后处理纯化易操作,极大的提高了反应效率。根据筛选,挑取的两种聚合物细胞毒性明显低于PEI25Kda的细胞毒性,并可以成功转染质粒DNA,其转染效率高于PEI-25Kda的转染效率,是一种潜在的有利的阳离子基因载体。
Understanding the in vivo behavior of polymeric micelles is critical for the translation of nanomedicine from laboratory research to clinical trials. It is generally assumed that polymeric micelles, upon administration into the blood stream, carry drug molecules until they are taken up into cells followed by intracellular release. The current work revisits this conventional wisdom. The study used dual-labeled polymeric micelles containing a pair of near-infrared fluorescent probes Cy5and Cy5.5, which were conjugated in the polymeric micelle core via fluorescence resonance energy transfer (FRET) to provide insights into the dynamics of the polymeric micelles in different biological conditions. We find that the serum albumins, immunoglobulin (including alpha and beta) and shear stress have moderate effects on the integrity of self-assembled polymeric micelles of poly (ethylene glycol)-b-poly (caprolactone)(PEG-b-PCL) copolymers whereas dilution of the concentration lead the main reason for disassembly of the micelles. During the incubation with cancer cells, FRET spectroscopy showed that micelles stayed intact while extracellular or on the cell membrane and dissembled once inside cells. When the micelles were administrated into the blood stream, FRET imaging and spectroscopy were used to monitor this process in real time. A decrease of FRET efficiency was observed indicating a fast release of core-loaded molecules from micelles in blood circulation due to the loss of micelle integrity. Increasing the micelles dose, pre-treated with micelles and pre-injection with GdCl3could prolong the micelles'blood retention time, but have minor effects on the micelles integrity. The drug-loaded polymeric micelles are able to retain their assembly structure and have a slower decreased of FRET ratio. Moreover, although only a few micelles could finally reach to tumor sites via EPR effect, but the FRET spectroscopy showed micelles in tumor still retain intact and may release the loaded drug at the target site. Taken together, our results reveal that the fate of the injected micelles in vivo and the mechanism of micelle clearance. It may contribute to discovering the pharmacokinetic properties and improving the therapeutic outcome of polymeric micelles.
本课题利用一对近红外双荧光分子Cy5和Cy5.5,基于荧光共振能量转移(FRET)技术,通过将其共价键合在共聚物胶束核内,来研究在不同生理条件下聚合物胶束的动态变化情况。
首先考察共聚物胶束在体外稳定性的影响因素。我们发现血浆蛋白、球蛋白以及血液中的剪切应力均会对PEG-b-PCL-FRET自组装胶束的稳定性产生一定的影响。而浓度稀释较前几者来说,影响最大。聚合物和其单分子链在溶液中呈现动态平衡的过程。当浓度降到胶束的CMC值以下时,其平衡向着解离方向移动,FRET效率即溶液中以胶束形态存在的聚合物仅有60%左右。新鲜提取的小鼠血液、血浆均对PEG-b-PCL-FRET自组装胶束的稳定性没有影响。将共聚物胶束与肿瘤细胞共同孵育,FRET光谱曲线证明胶束在细胞膜上时依然是以完整的胶束形态存在,一旦进入胞浆内,则解离开来,释放出核内药物。
在体内稳定性研究中,我们利用多种不同的条件来探索共聚物胶束在血液中的解离和清除动态过程。当PEG-b-PCL-FRET胶束通过尾静脉注射至小鼠体内后,通过活体成像仪和FRET光谱曲线实时监控其动态。胶束在血液中的快速解离(24h时仅剩20%的以胶束形态存在)及快速清除(24h时仅剩3.7%的聚合物残留)证明其还未到达靶向组织之前,核内物质便释放出来。我们通过用不同方法如利用疏水链端PLLA代替PCL的方法、增加胶束给药剂量、利用混合胶束以改变胶束形貌、预注射致哑剂量的PEG-b-PCL胶束以及利用氯化钆,地塞米松等巨噬细胞抑制剂来探索PEG-b-PCL-FRET自组装胶束在体内快速解离以及快速清除的基本机理。结果证明,增加给药剂量,预注射致哑剂量的PEG-b-PCL胶束以及利用氯化钆,地塞米松等巨噬细胞抑制剂均可以显著延长胶束在体内的循环时间,但是对其稳定性没有影响。由此说明饱和血浆中血浆蛋白对自组装胶束的吸附以及抑制其被吞噬细胞识别均可以减缓血液循环中聚合物胶束的清除速率,但不影响胶束稳定性。包裹了抗癌药物PTX的PEG-b-PCL-FRET胶束因其疏水核之间的作用增强,在血液中可以长时间维持其胶束形态,并且血浆清除慢。这证明增加共聚物胶束本身结构中的疏水核作用对清除和解离都有较大影响。肿瘤切片的FRET光谱图证明,尽管只有很少数的共聚物胶束可以通过EPR效应最终到达肿瘤部位,但在肿瘤组织中,大部分共聚物仍保留其胶束完整性,直到将药物输送至靶点。综上所述,我们的研究结果揭示了聚合物胶束通过静脉注射后在体内的解离动力学以及清除的机理,认清了一些关键的基本问题。希望本课题工作能为进一步设计制备物理稳定的聚合物胶束、获得高效胶束型纳米药物打下坚实的基础。
本论文的第二部分内容诣在解决传统阳离子聚合物基因载体不可降解,合成繁琐,毒性较高等缺点。通过双环氧化合物与胺进行类点击反应,合成一种制作方便简单,低毒并且高效的阳离子聚合物。其聚合反应时间段,后处理纯化易操作,极大的提高了反应效率。根据筛选,挑取的两种聚合物细胞毒性明显低于PEI25Kda的细胞毒性,并可以成功转染质粒DNA,其转染效率高于PEI-25Kda的转染效率,是一种潜在的有利的阳离子基因载体。
Understanding the in vivo behavior of polymeric micelles is critical for the translation of nanomedicine from laboratory research to clinical trials. It is generally assumed that polymeric micelles, upon administration into the blood stream, carry drug molecules until they are taken up into cells followed by intracellular release. The current work revisits this conventional wisdom. The study used dual-labeled polymeric micelles containing a pair of near-infrared fluorescent probes Cy5and Cy5.5, which were conjugated in the polymeric micelle core via fluorescence resonance energy transfer (FRET) to provide insights into the dynamics of the polymeric micelles in different biological conditions. We find that the serum albumins, immunoglobulin (including alpha and beta) and shear stress have moderate effects on the integrity of self-assembled polymeric micelles of poly (ethylene glycol)-b-poly (caprolactone)(PEG-b-PCL) copolymers whereas dilution of the concentration lead the main reason for disassembly of the micelles. During the incubation with cancer cells, FRET spectroscopy showed that micelles stayed intact while extracellular or on the cell membrane and dissembled once inside cells. When the micelles were administrated into the blood stream, FRET imaging and spectroscopy were used to monitor this process in real time. A decrease of FRET efficiency was observed indicating a fast release of core-loaded molecules from micelles in blood circulation due to the loss of micelle integrity. Increasing the micelles dose, pre-treated with micelles and pre-injection with GdCl3could prolong the micelles'blood retention time, but have minor effects on the micelles integrity. The drug-loaded polymeric micelles are able to retain their assembly structure and have a slower decreased of FRET ratio. Moreover, although only a few micelles could finally reach to tumor sites via EPR effect, but the FRET spectroscopy showed micelles in tumor still retain intact and may release the loaded drug at the target site. Taken together, our results reveal that the fate of the injected micelles in vivo and the mechanism of micelle clearance. It may contribute to discovering the pharmacokinetic properties and improving the therapeutic outcome of polymeric micelles.
引文
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