非膜电位依赖型线粒体靶向传递策略：治疗药物性耳聋

项目名称： 非膜电位依赖型线粒体靶向传递策略：治疗药物性耳聋

项目编号： No.81473162

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘洪卓

作者单位： 沈阳药科大学

项目金额： 70万元

中文摘要： 药物致聋是听力障碍的主要病因，而相关治疗研究却极为匮乏。药物致聋的关键环节是线粒体损伤导致的内耳毛细胞凋亡。本课题拟构建SS四肽修饰的PLGA线粒体靶向纳米粒，在不影响线粒体膜功能的同时，通过引导治疗分子递送入线粒体，逆转毛细胞凋亡以实现治疗目的。SS四肽是非依赖于线粒体膜电位的靶向序列，与常规线粒体靶向单元相比，这种新型的线粒体靶向分子不会诱发线粒体膜电位的耗散，有利于其膜结构的维持，这对以抑制细胞凋亡为目的的治疗十分关键。在内耳给药传递系统的研究工作基础上，申请者着重研究以下三个方面，来为药致耳聋治疗制剂的开发提供理论基础：①SS四肽靶向纳米粒理化性质对毛细胞摄取、线粒体靶向效率的影响；②靶向纳米粒的内涵体和溶酶体逃逸功能和机制分析；③从抑制凋亡信号、上调毛细胞内在保护机制和缓解氧化应激三个方面探讨所构建体系对逆转氨基糖甙类药物所致毛细胞凋亡的机制。

中文关键词： 线粒体靶向；纳米载体；药物传输；内耳给药系统；细胞凋亡

英文摘要： Certain clinically useful and essential pharmacological therapies may result in temporary or permanent hearing loss due to interactions of the drugs and cells of the inner ear. More than 70% cases of hearing loss in China are attributable to ototoxicity. However, the treatment of it is especially lack. Hearing loss due to ototoxicity is the result of apoptosis. In detail, the outer hair cells of the basal turn of the cochlea are highly sensitive to the drugs and seem to die from apoptosis. The mitochondria within human cells play a major role in a variety of critical processes involved in cell survival and death. Mitochondrial dysfunction is an acute or chronic disturbance in metabolism, bioenergetics, or signaling pathways that occur within mitochondria, which can give rise to a plethora of diseases with variable symptoms including hearing loss. That is to say, the mitochondrion is a major regulator of cell death pathway such as apoptosis. Clinical trials with mitochondria acting therapeutics have failed to show benefits in humans owing to the logistics of safe drug delivery to the mitochondria in sufficient amounts and the toxicity associated with high doses. Although several substances are known to act on mitochondria, their dependence on the membrane potential in mitochondria also constitutes a major drawback. As increasing numbers of lipophilic cations (such as TPP) enter the organelle, the potential gradients diminish and lead to mitophage. Furthermore, the uptake of these vectors is self-limiting due to the inevitable depolarization of mitochondria. A novel class of small cell permeable peptide antioxidants that target mitochondria in a potential independent manner were reported recently. The Szeto-Schiller (SS) peptides do not cause mitochondrial depolarization even at 1 mM. Thus, SS antioxidants peptides represent a novel approach, with targeted delivery of vector to the mitochondria. The potential of nanoparticles to improve any therapy lies in their ability to deliver payloads directly to the cells of interest and simultaneously enhance stability and pharmacokinetics. An equally important consideration is whether the same nanoparticles can deliver the therapeutic payload to the intended target inside the cells. Delivery of payloads using biodegradable and FDA approved PLGA based nanoparticles to the target sites has been well characterized, but the intracellular barriers that delivery carriers must overcome to reach subcellular targets are less well understood. In this project, we describe an engineering approach to the design and execution of a polymer-blending technology to fine-turn size and surface charges of the resultant nanoparticles to provide an optimized PLGA-based nanoparticles platform for mitochondria targeted delivery of therapeutics. We postulate that pharmaceutical interventions via mitochondria targeted therapy that inhibit apoptosis of hair cells will prevent the hearing loss due to ototoxicity.

英文关键词： mitochondrial targeting;nanocarrier;drug delivery;inner ear drug delivery;apoptosis