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: 10440322
• 负责人: Daqing Li
• 金额: $ 48.69万
• 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/10440322
• 关键词: Acute; Affect; Animal Model; Auditory; Auditory Brainstem Responses; Binding; Biocompatible Materials; Blood; Cell Survival; Chitosan; Cisplatin; Clinic; Clinical; Cochlea; Complex; Custom; Detoxification Process; Development; Devices; Dialysis procedure; Dose; Drug Delivery Systems; Drug Metabolic Detoxication; Early Diagnosis; Early treatment; Endolymph; Evaluation; Frequencies; Glutathione; Glycerophosphates; Hearing Tests; Hydrogels; In Vitro; Incubated; Interruption; Laboratories; Labyrinth; Life; Ligands; Lipids; Magnetic nanoparticles; Magnetism; 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 Effect; Time; Tinnitus; Toxin; Translating; Treatment Protocols; base; biomaterial compatibility; cancer type; chemotherapy; early onset; effective therapy; experimental study; flexibility; hearing impairment; innovation; iron oxide; iron oxide nanoparticle; light microscopy; 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.

尽管顺铂是许多类型癌症的一线治疗，但它可以改变癌症的病程。 化疗通过耳毒性以及降低患者的生活质量。顺铂耳毒性 由于缺乏有效的治疗，这对病人护理是一个重要的挑战。 基于我们实验室的广泛研究，主要研究者（PI）已经开发出一种稳定，安全， 药物、生物材料或纳米颗粒向内部的调节和可控的基于水凝胶的递送系统 耳朵从中耳。该应用程序是简单地通过应用水凝胶上的圆窗 膜（RWM）与一个灵活的耳镜在门诊设置。该平台还具有 酶促“关闭开关”，其允许水凝胶的受控降解和有效载荷的快速停止 传递到内耳。 由超顺磁性氧化铁（SPIO）组成的磁性纳米粒子（NPs）已被广泛应用 用于许多生物医学应用。这些SPIO NP（SPION）通常包裹在生物相容性涂层中， 例如聚合物或脂质，其增加颗粒在生物体内的保留时间， 表面功能化所得的“多功能纳米颗粒（MFNP）”可以缀合至多功能纳米颗粒。 许多靶向配体（形成靶向（t）MFNP）以螯合任何数量的鉴定的毒素。 拟议的研究是开发一种用于药物诱导的内耳纳米透析解毒平台， 耳毒性合成的谷胱甘肽缀合的tMFNP（G-tMFNP）能够与顺铂结合。 在解毒过程中，G-tMFNPs将通过RWM非侵入性地递送到内耳 通过壳聚糖甘油磷酸（CGP）水凝胶系统。利用旋转磁装置（RMD），这些G- 然后，tMFNP将从整个耳蜗的基部分布到顶端， 外淋巴和内淋巴中的顺铂。一旦顺铂进入内耳，G-tMFNAs将结合至 顺铂并形成G-tMFNP-顺铂复合物; G-tMFNP-顺铂复合物将被安全地去除 通过RMD和外部磁体应用从内耳中移除。此外，该系统是模块化的 并且易于改变;因此，它可用于消除各种耳毒性剂。拟议 本研究将在临床环境中使用顺铂诱导的耳毒性动物模型进行评价。 PI认为，据我们所知，拟议的内耳纳米透析系统是第一个 在顺铂诱导的耳毒性中用作解毒的平台。如果这个创新系统被证明是有效的 和安全，它将代表预防和治疗药物引起的耳毒性的重大突破， 非侵入性内耳透析系统是迫切需要的。