A novel nanodialysis platform for inner ear detoxification

一种用于内耳排毒的新型纳米透析平台

• 批准号: 10675694
• 负责人: Daqing Li
• 金额: $ 49.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675694
• 关键词: Acute; Affect; Animal Model; Apical; Auditory; Auditory Brainstem Responses; Binding; Biocompatible Materials; Blood; Cell Survival; Chitosan; Cisplatin; Clinic; Clinical; Cochlea; Complex; Detoxification Process; Development; Dialysis procedure; Dose; Drug Delivery Systems; Drug Metabolic Detoxication; Ear; Early Diagnosis; Early treatment; Endolymph; Evaluation; Frequencies; Glutathione; Glycerophosphates; Goals; Hearing Tests; Hydrogels; In Vitro; Incubated; Interruption; Laboratories; Labyrinth; Life; Ligands; Lipids; Magnetic nanoparticles; Membrane; Organ; Organism; Otology; Otoscopes; Outpatients; Patient Care; Patients; Perilymph; Pharmaceutical Preparations; Polymers; Prevention; Prophylactic treatment; Quality of life; Research Personnel; Role; Safety; Scanning Electron Microscopy; Surface; Symptoms; System; Testing; Therapeutic; Therapeutic Effect; Time; Tinnitus; Toxin; Translating; Treatment Protocols; base; biomaterial compatibility; cancer type; chemotherapy; clinical translation; early onset; effective therapy; experimental study; flexibility; hearing impairment; innovation; iron oxide; iron oxide nanoparticle; light microscopy; magnetic devices; middle ear; mouse model; nanodialysis; nanoparticle; novel; ototoxicity; particle; prevent; progressive hearing loss; prophylactic; receptor; round window; superparamagnetism; therapy outcome; translational impact; treatment duration

Despite being the first-line therapy for many types of cancer, Cisplatin can alter the course of chemotherapy through ototoxicity as well as decrease a patient's quality of life. Cisplatin-induced ototoxicity represents an important challenge to patient care because of the lack of effective treatment. Based on extensive studies in our laboratory, the Principle Investigator (PI) has developed a stable, safe, regulated, and controllable hydrogel-based delivery system of drugs, biomaterials, or nanoparticles to the inner ear from the middle ear. The application is performed simply by applying a hydrogel on the round window membrane (RWM) with a flexible otoscope in the outpatient setting. This platform also has the advantage of an enzymatic “off-switch,” which allows for controlled degradation of the hydrogel and rapid cessation of payload delivery to the inner ear. Magnetic nanoparticles (NPs) composed of superparamagnetic iron oxide (SPIO) have been widely used for many biomedical applications. These SPIO NPs (SPIONs) are typically encased in biocompatible coatings, such as polymers or lipids, which increase retention time of the particle within the organism and allow for surface functionalization. The resulting “MultiFunctional NanoParticles (MFNPs)” can be conjugated to a multitude of targeting ligands (forming targeted (t)MFNPs) to sequester any number of identified toxins. The proposed study is to develop an inner ear nanodialysis detoxification platform for drug-induced ototoxicity. Synthesized glutathione-conjugated tMFNPs (G-tMFNPs) are capable of binding with cisplatin. During the detoxification process, G-tMFNPs will be noninvasively delivered to the inner ear through the RWM by a chitosan glycerophosphate (CGP) hydrogel system. With a rotatory magnetic device (RMD), these G- tMFNP will then be distributed from the base to the apex of the entire cochlea consequently sequestering cisplatin in the perilymph and endolymph. Once cisplatin has entered the inner ear, G-tMFNAs will bind to cisplatin and form G-tMFNP-cisplatin complexes; The G-tMFNP-cisplatin complexes will be safely removed from the inner ear by RMD and external magnet application. Furthermore, this proposed system is modular and easily modifiable; therefore, it can be used for the elimination of a variety of ototoxic agents. The proposed study will be evaluated in an animal model with cisplatin-induced ototoxicity in clinical settings. The PI believes that the proposed inner ear nanodialysis system, to our knowledge, is the first system that serves as a platform for detoxification in cisplatin-induced ototoxicity. If this innovative system proves effective and safe, it will represent a major breakthrough in the prevention and treatment of drug-induced ototoxicity, where a noninvasive inner ear dialysis system is desperately needed.

尽管顺铂是治疗许多类型癌症的一线药物，但它可以改变 通过耳毒性进行化疗以及降低患者的生活质量。顺铂致耳毒性 由于缺乏有效的治疗，这对病人护理来说是一个重要的挑战。 在实验室广泛研究的基础上，首席调查员(PI)开发出了一种稳定、安全、 以水凝胶为基础的可调控的药物、生物材料或纳米粒内给药系统 耳朵从中耳出来。只需在圆窗上涂抹水凝胶即可完成涂抹 门诊环境下使用柔性耳镜进行耳膜(RWM)治疗。该平台还具有以下优势： 酶促“开关”，允许水凝胶的受控降解和有效载荷的快速停止 输送到内耳。 由超顺磁性氧化铁(SPIO)组成的磁性纳米颗粒(NPs)得到了广泛的应用 用于许多生物医学应用。这些SPIO纳米颗粒(SPION)通常被包裹在生物兼容涂层中， 例如聚合物或脂类，它们增加了颗粒在生物体内的保留时间，并允许 表面功能化。由此产生的“多功能纳米颗粒(MFNPs)”可以与一种 大量靶向配体(形成靶向(T)MFNPs)以隔离任何数量的已识别毒素。 本研究拟开发一种内耳纳米透析戒毒平台。 耳毒性。合成的谷胱甘肽偶联tMFNPs(G-tMFNPs)能够与顺铂结合。 在排毒过程中，G-tMFNPs将通过RWM非侵入性地输送到内耳 通过壳聚糖甘油磷酸(CGP)水凝胶体系。使用旋转磁性装置(RMD)，这些G- 然后，tMFNP将从底端分布到整个耳蜗尖，从而隔离 外淋巴液和内淋巴液中的顺铂。一旦顺铂进入内耳，G-tMFNAs将结合到 并形成G-tMFNP-顺铂络合物；G-tMFNP-顺铂络合物将被安全移除 从内耳通过RMD和外加磁铁应用。此外，提出的系统是模块化的。 且易改性，可用于消除多种耳毒性物质。建议数 这项研究将在临床环境下用顺铂引起的耳毒性的动物模型进行评估。 PI认为，据我们所知，拟议的内耳纳米透析系统是第一个 在顺铂引起的耳毒性中作为解毒的平台。如果这个创新的系统被证明是有效的 而且安全，这将是预防和治疗药物所致耳毒性的重大突破， 在那里迫切需要一种非侵入性的内耳透析系统。