“导航式”生物纳米囊共载药系统用于脑梗死精准三位一体治疗研究

Therapeutic drugs are difficult to reach the site of cerebral infarction leads to the low treatment efficiency, to solve this problem, a drug delivery system with precise positioning of cerebral infarction capability is constructed, and this system can achieve effective, rapid treatment. We choose mesenchymal stem cell-secreted exosome (MSC-EXO) as the drug carrier, which has good biocompatibility, low neurotoxicity, the abilities of crossing the blood-brain barrier and biotherapy for cerebral infarction; Mouse nerve growth factor (neurotrophic agent) and edaravone (free radical scavenger) are loading into MSC-EXO at the same time; Then LBD polypeptide which is specific target to cerebral infarction is used to decorate the drug delivery system, herein, a precise drug delivery system for trinitarian treatment of cerebral infarction is constructed, and the advantages of this system are as follows: 1) MSC-EXO has the double functions—drug delivery and biotherapy; 2) Dual specific targeting, MSC-EXO has the ability of crossing the blood-brain barrier and the specific targeting to cerebral infarction of LBD polypeptide, making the system have a long retention in the site of cerebral infarction for precise treatment; 3) Trinitarian synergistic treatment, the biotherapy of MSC-EXO, nerve nutrition of mouse nerve growth factor and micro environment improvement of edaravone, synergistic effect can enhance the treatment efficacy. The system is expected to improve the drug delivery efficiency, biocompatibility, treatment efficacy and it is also expected to reduce the neurotoxicity, in vivo immunogenicity etc. of the current cerebral infarction drug delivery system. This study provides relevant theoretical and experimental foundations for clinical treatment of cerebral infarction.

针对脑梗死治疗因药物难以到达梗死部位而致疗效欠佳问题，拟构建一种脑梗死精准药物递送系统并实现高效、快速治疗。以生物相容性好、神经毒性低并具跨过血脑屏障与生物治疗脑梗死能力的间质干细胞外泌体（MSC-EXO）为转运载体；共装载鼠神经生长因子（神经营养剂）和依达拉奉（自由基清除剂）；将靶向脑梗死部位靶头LBD多肽对其修饰，构建三位一体协同治疗脑梗死的精准药物递送系统，其特征为：1）MSC-EXO具有双重功能—转运药物与生物治疗；2）双重靶向，即MSC-EXO高效跨过血脑屏障能力和LBD脑梗死部位靶向，实现在脑梗死部位长时间滞留和精准治疗；3）三位一体协同治疗作用，即MSC-EXO生物治疗，鼠神经生长因子神经营养和依达拉奉对微环境改善，协同增强疗效。该系统有望提高目前脑梗死转运系统的药物递送效率、生物相容性和治疗效果，降低神经毒性、体内免疫原性等问题。为临床脑梗死的治疗提供相关的理论和实验基础。

本项目的预期研究计划和目标是开发具有高度体内跨血脑屏障的缺血性脑卒中快速治疗体系。在研究的过程中发现脑卒中的病理微环境对于溶栓治疗前后影响巨大。如缺血性脑卒中在溶栓前，是一个极度缺氧的微环境，此时补充氧气可有效抑制神经元凋亡。而在溶栓后，大量氧气随血液灌入，则会变为氧自由基，造成再灌注损伤，因此动态调控溶栓前后的差异病理微环境是脑梗治疗的关键。申请人创新性的利用天然红细胞能够感知环境氧分压且选择性释放和吸附氧气的性质，构建了氧气“纳米海绵”，该“纳米海绵”有效透过血脑屏障进入脑梗部位，在溶栓前释放氧气，保护神经细胞；溶栓后，吸附氧气，再次避免再灌注引起的氧自由基爆发，对病理微环境进行动态调控，分阶段保护神经细胞。该课题受此揭示了“纳米海绵”的波尔效应，探索了动态调控差异病理微环境对治疗的增效规律，为脑梗治疗提供了新的有力工具。此外，还围绕脑卒中及肿瘤治疗的病理微环境和天然生物囊泡独特的生物效应，研究了溶栓治疗及脑缺血再灌注一体化给药生物囊泡系统，发展了天然生物纳米囊的高效、快速捕获新方法，构建仿生型生物囊泡用于肿瘤高效治疗的给药体系等，为脑卒中及肿瘤的治疗提供新的思路和策略。