以香草酸受体亚型TRPV1为靶点的新型Capsaicin纳米探针的构建及其在心脑器官联合保护中的应用

It has been widely accepted that Transient Receptor Potential Vanilloid type 1, (TRPV1) acts combinational protective effects to heart and brain in patients suffering from ischemia and reperfusion injury via many mechanisms. However, traditional TRPV1 agonist Capsaicin is largely limited in in vivo application for many disadvantages including poor aqueous solubility, circulatory instability and short biological half-life. In our previous study, drug slow releasing systems have been synthesized based on nanoparticles. Utilizing exploited methods, the present study will employ the modified mesoporous ferric oxide nanoparticle as the carrier of Capsaicin, utilizing slow releasing technique, red membrane encapsulation and target-peptide modification. Then a novel circulatory stable, biocompatible, trackable, aqueous soluble, brain and vascular wall targeted, and controllable Capsaicin-releasing nanoprobe is expected to be synthesized, which can slowly release Capsaicin in vitro and in vivo and continually effect on TRPV1, with good ability to be real-time traced by MRI. We will further study the protective effects of the novel slow Capsaicin-releasing nanoprobe to both heart and brain using cardiomyocytes and neuron hypoxia/reoxygenation models and rat cardiac arrest/ restoration of spontaneous circulation model. This study will provide a unique platform for slow release of Capsaicin in vivo by systemic administration, and offer a new method for combinational myocardial and cerebral protection from ischemia and reperfusion injury, bringing potential benefits for patients.

研究证明，干预香草酸受体亚型TRPV1可联合保护缺血的心脑器官。然而传统TRPV1激动剂Capsaicin具有水溶性差、循环不稳定和生物半衰期短等缺点，限制了其全身性治疗应用。前期工作中，我们成功掌握了纳米缓释药物技术。本项目基于已开发技术，拟将生物可降解的介孔氧化铁纳米粒子作为载体，运用纳米载药、红细胞膜包裹和表面多肽修饰，构建一种新型的具备良好循环稳定性、生物安全性、水溶性、可追踪性、一定脑靶向和血管靶向性的Capsaicin纳米探针，其可在体内缓慢释放Capsaicin，并可通过磁共振实时追踪。我们拟将此探针应用于大鼠心肌细胞/神经元细胞的缺氧-复氧模型和大鼠心跳骤停-心肺复苏模型，评价其对心脑器官联合保护的效果及与游离Capsaicin对比的优势。本项目顺利实施将为Capsaicin的系统性给药和TRPV1体内研究创造良好的平台，更为缺血心脑器官的联合保护提供新的手段，以造福病人。

心肌和大脑是对缺血最敏感的器官。在心跳骤停、脑血管意外、严重复合伤和复杂心脑血管手术中常发生心脑器官的共同缺血。缺血再灌注损伤引起的心脑损害已成为心跳骤停和心脑疾病手术中患者急性死亡、慢性残障的主要原因，严重危害人类的健康。据统计，心肺复苏成功的病人中免除心脏和神经系统永久性损伤的比例不超过17%，这给疾病个体和社会带来了严重的健康和经济负担。如何有效保护缺血再灌注引起的心脑器官损害，已成为当今重症医学领域面临的重要课题。研究证明，干预香草酸受体亚型TRPV1可联合保护缺血的心脑器官。然而传统TRPV1激动剂Capsaicin具有水溶性差、循环不稳定和生物半衰期短等缺点，限制了其全身性治疗应用。. 在本项目研究中我们基于已开发技术将生物可降解的介孔氧化铁纳米粒子作为载体，运用纳米载药、红细胞膜包裹和表面多肽修饰，构建了一种新型的具备良好循环稳定性、生物安全性、水溶性、可追踪性、一定脑靶向和血管靶向性的Capsaicin纳米探针（粒径230 ± 32 nm，载药率＞44%），其可在体内缓慢释放Capsaicin，并可通过磁共振实时追踪。我们拟将此探针应用于大鼠心肌细胞/神经元细胞的缺氧-复氧模型和大鼠心跳骤停-心肺复苏模型，评价其对心脑器官联合保护的效果及与游离Capsaicin对比的优势。本项目为Capsaicin的系统性给药和TRPV1体内研究创造良好的平台，更为缺血心脑器官的联合保护提供新的手段。