A Novel Regulated Nanohydrogel Delivery System for Targeted Inner Ear Application

一种用于靶向内耳应用的新型调节纳米水凝胶输送系统

• 批准号: 9017993
• 负责人: Daqing Li
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9017993
• 关键词: Affect; Anatomy; Antibodies; Biocompatible; Biocompatible Materials; Caliber; Cells; Cellular Structures; Chemistry; Chitosan; Development; Disease; Drug Delivery Systems; Drug or chemical Tissue Distribution; Ear; Effectiveness; Enzymes; Etiology; Exposure to; Formulation; Functional disorder; Glycerophosphates; Health; Hearing; Hour; Human; Hydrogels; Immune system; In Vitro; Label; Labyrinth; Length; Ligands; Ligation; MAPK8 gene; Measures; Medical; Membrane; Methods; Modality; Modeling; Molecular; Mus; Noise; Pharmaceutical Preparations; Population; Prevention; Preventive treatment; Property; Regulation; Research Personnel; Risk; Safety; Scientist; Sensorineural Hearing Loss; Sensory; Site; Specificity; Steroids; System; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; base; chitosanase; controlled release; effective therapy; improved; in vivo; inhibitor/antagonist; inner ear diseases; innovation; interest; local drug delivery; mouse model; nanoformulation; nanoparticle; novel; particle; prevent; protein expression; research study; round window; targeted treatment

 DESCRIPTION (provided by applicant): Sensorineural Hearing loss (SNHL) is one of the most common sensory deficits in humans, affecting millions of people worldwide, and is primarily attributed to inner ear dysfunction. Although a lot of progress has been made recently in understanding the etiology and molecular mechanisms of this disease, there are almost no non-invasive therapeutic approaches targeting to the pathological sites of the inner ear that are responsible for the majority of SNHL. A targeted multifunctional nanoparticle (MFNP) system (called nanohydrogel) proposed in this study is, to our knowledge, the first system to serve as a platform for the non-invasive delivery of biomaterials into specific inner ear structures for the treatment of the inner ear diseases. The MFNPs are usually smaller than 200 nm in diameter, and can be equipped with several functions, such as the ability to target specific cells, evade the immune system, and deliver the payload across different barriers. Unfortunately, current nanoparticle delivery systems are unable to efficiently deliver biomaterials to the to specific inner ear structures. These issues can be solved through the use of a biocompatible and biodegradable chitosan-glycerophosphate (CGP) hydrogel, which the principle investigator (PI) has shown to be capable of attaching to the round window membrane (RWM) and efficiently releasing therapeutic agents across the intact membrane in a controlled and sustained manner, and can be regulated using a glycolytic enzyme called chitosanase. Additionally, using innovative "click"-chemistry, MFNPs can incorporate targeting ligands to allow for better selectivity or targeting of these particles to cells of interest. In this proposal, the PI hypotheizes that the use of a regulated CGP-hydrogel-MNFP system (nanohydrogel) would result in a controlled, targeted, and highly effective delivery platform, bringing therapeutic biomaterial agents to specific cellular structures within the inner ear for the treatment of inner ear diseases This unique system has the potential to select ligands or therapeutic biomaterials depending on the need for different therapeutic approaches. The hypothesis is evaluated using a mouse model with different nanohydrogel formulations on the RWM to slowly and steadily release the MFNP into the inner ear. The ability to target specific inner ear cells will be evaluated by measuring the distribution of MFNPs in inner ear structures. To test the effectiveness and safety of this delivery system, the nanohydrogel system will be used to deliver MFNPs to the inner ear for the prevention of noise-induced SNHL in a mouse model. If the use of this novel nanohydrogel system proves to be an effective method of drug delivery for prevention of SNHL, it would signify a major step forward in the non-invasive treatment of inner ear diseases, which are currently untreatable. Moreover, this modular nanohydrogel system would allow for the development of better targeted therapies, extending it to a large variety of targeting moieties and treatment options, for this important functional region that has been marked by limited anatomic access. If this innovative system proves effective and safe, it will represent a major breakthrough in the treatment of the inner ear diseases, where a non-invasive delivery system carrying biomaterials or molecular agents is desperately needed.

 描述（由申请人提供）：感觉神经性听力损失（SNHL）是人类最常见的感觉缺陷之一，影响全球数百万人，主要归因于内耳功能障碍。 尽管近年来对该病的病因学和分子机制的研究取得了很大进展，但几乎没有针对导致大多数SNHL的内耳病理部位的非侵入性治疗方法。 据我们所知，本研究中提出的靶向多功能纳米颗粒（MFNP）系统（称为纳米水凝胶）是第一个将生物材料非侵入性递送到特定内耳结构中以治疗内耳疾病的平台。 MFNP的直径通常小于200 nm，并且可以配备有几种功能，例如靶向特定细胞的能力，逃避免疫抑制剂的能力，以及免疫抑制剂的能力。 免疫系统，并通过不同的屏障传递有效载荷。 不幸的是，目前的纳米颗粒递送系统不能有效地将生物材料递送到特定的内耳结构。 这些问题可以通过使用生物相容性和可生物降解的壳聚糖-甘油磷酸盐（CGP）水凝胶来解决，主要研究者（PI）已经证明该水凝胶能够附着到圆窗膜（RWM）上，并以受控和持续的方式有效地释放治疗剂穿过完整的膜，并且可以使用称为壳聚糖酶的糖酵解酶来调节。 此外，使用创新的“点击”化学，MFNP可以掺入靶向配体，以允许这些颗粒更好地选择性或靶向感兴趣的细胞。 在该提案中，PI假设使用受监管的CGP-水凝胶-MNFP系统（纳米水凝胶）将产生受控的、靶向的和高效的递送平台，将治疗性生物材料试剂引入内耳内的特定细胞结构以治疗内耳疾病该独特的系统具有根据不同治疗方法的需要选择配体或治疗性生物材料的潜力。 使用在RWM上具有不同纳米水凝胶制剂的小鼠模型来评估该假设，以缓慢且稳定地将MFNP释放到内耳中。 靶向特定内耳细胞的能力将通过测量MFNP在内耳结构中的分布来评估。 为了测试该递送系统的有效性和安全性，纳米水凝胶系统将用于将MFNP递送至内耳，以在小鼠模型中预防噪声诱导的SNHL。 如果使用这种新型纳米水凝胶系统被证明是预防SNHL的有效药物递送方法，这将意味着在目前无法治疗的内耳疾病的非侵入性治疗方面迈出了重要一步。 此外，这种模块化纳米水凝胶系统将允许开发更好的靶向治疗，将其扩展到各种各样的靶向部分和治疗选择，用于这个重要的功能区域，该区域已被标记为有限的解剖学通路。 如果这种创新系统被证明是有效和安全的，它将代表内耳疾病治疗的重大突破，其中迫切需要携带生物材料或分子制剂的非侵入性递送系统。