Multifunctional nanoparticles: Nano-knives and nano-pullies for enhanced drug del

多功能纳米颗粒：用于增强药物去除的纳米刀和纳米拉轮

• 批准号: 7687743
• 负责人: Hugh David Smyth
• 金额: $ 35.97万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687743
• 关键词: Acceleration; Active Biological Transport; Activities of Daily Living; Address; Aerosols; Alveolar Macrophages; Antibiotics; Area; Asthma; Bacteriology; Biocompatible; Biocompatible Materials; Biological; Biopolymers; Breathing; Cell Proliferation; Cells; Chronic; Chronic Obstructive Airway Disease; Cleaved cell; Clinic; Clinical; Communicable Diseases; Cystic Fibrosis; DNA; Data; Data Set; Deposition; Development; Diffusion; Disease; Disease model; Dose; Drug Delivery Systems; Drug Kinetics; Drug Transport; Engineering; Environment; Evaluation; Evaluation Studies; Exhibits; Exploratory/Developmental Grant; Failure; Genes; Goals; Heating; Histopathology; Image; In Vitro; Individual; Infection; Inflammation; Inherited; Injury; Investigation; Lead; Learning; Life Expectancy; Lung; Lung Inflammation; Lung Transplantation; Lung diseases; Magnetism; Malignant neoplasm of lung; Measurable; Metabolism; Methods; Microbial Biofilms; Microbiology; Microscopy; Modeling; Modification; Molecular Genetics; Mucous body substance; Nanotechnology; Outcome; Particle Size; Pathology; Penetration; Performance; Pharmaceutical Preparations; Phase; Physiological; Pneumonia; Powder dose form; Preparation; Process; Production; Property; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis; Quality of life; Rattus; Relative (related person); Research; Respiratory physiology; Safety; Scheme; Screening procedure; Site; Solvents; Surface; Symptoms; System; Technology; Therapeutic; Therapeutic Agents; Time; Toxic effect; Translating; Tuberculosis; Work; aerosolized; airway obstruction; biomaterial compatibility; chemical release; clinically relevant; cystic fibrosis airway; cystic fibrosis patients; cytotoxicity; design; drug distribution; engineering design; falls; gene therapy; hazard; high risk; improved; improved functioning; in vivo; in vivo Model; inflammatory marker; innovation; magnetic field; microsystems; mouse model; mucoid; nano; nanoparticle; nanoscale; nanosized; nanosystems; non-drug; novel; novel therapeutics; particle; phase 2 study; public health relevance; quantum; research study; success; translational study; treatment strategy; vector

DESCRIPTION (provided by applicant): Significant improvements in the treatment of cystic fibrosis (CF) have occurred over the past 30 years due to drug delivery via inhalation aerosols. However, the efficacy inhaled therapies is dramatically reduced in CF patients because of the presence of a viscous mucus transport barrier within the airways, extensive degradation and metabolism of inhaled drug prior to exerting its pharmacological action, and the development mucoid Pseudomonas aeruginosa colonies. Often drugs or gene vectors cannot reach the intended target before their activity has been reduced or eliminated. Poor transport efficiencies in drug delivery have lead to the failure of therapies including the inability to attain the relatively low efficiencies required for gene therapy success. Applying the unique transport and active properties of nanoscale systems in drug delivery is a promising strategy for overcoming the biological barriers in CF lung disease. In particular, the ability of nanoparticles systems to exert strong influences on their environment using heat (a nanoknife) and magnetic fields (nano-pullies) are attractive functional attributes for increasing transport and drug distribution in CF lung disease. The long term objectives are to overcome these barriers and achieve critical improvements in CF therapy. The CENTRAL HYPOTHESIS of the proposed research is that novel multifunctional nanoparticles will facilitate significant enhancement of the efficacy of model therapeutic agents due to increased diffusion and penetration through mucus and biofilm barriers in cystic fibrosis when administered as an aerosol. Our preliminary data have demonstrated that (1) marked increases in particle and bulk transport of nanoparticles can be attained during nano-pulley mode, (2) we prove that our nanoparticles can be heated and they act like nanoknives cutting through biopolymers such as DNA that causes CF mucus to be diffusion limiting, (3) we demonstrate also our ability to synthesize a number of different types of magnetic nanoparticles for use in these studies: core-shell composites for use in image studies and surface functionlized particles for drug conjugation (4) we then functionalized these particles, attaching a model drug to the surface using a bio- cleavable conjugation scheme, (5) Drug release could be triggered using magnetic fields, (6) and finally, we then loaded the nanoparticles into inhalable microparticles suitable for aerodynamic lung targeting. These exciting preliminary data strongly support the rationale and feasibility of the proposed approach. Moreover, the interdisciplinary team has a very strong record in each of the critical areas of the project: pulmonary drug delivery, nanoparticles design and engineering, and the molecular genetics and microbiology of CF. The main objective of the proposed research is to develop, synthesize, characterize, and evaluate novel particle systems that simultaneously allow controlled lung deposition and enhanced transport in CF disease. These systems will provide high drug concentrations delivered directly to the site of action and will therefore facilitate significant improvements in drug and gene therapies in CF, prolonging survival and enhancing quality of life. Therefore, the SPECIFIC AIMS of the exploratory R21 phase of the project are (i) Prepare and characterize multifunctional nanoparticles and incorporate them into micro-systems suitable for inhalation via a dry powder aerosolization, (ii) Characterize drug transport and delivery performance of particles for CF therapy in vitro, and (iii) Evaluate in vivo efficacy and safety of the multifunctional nanoparticle pulmonary delivery system versus aerosolized controls. The results of the R21 phase will demonstrate the initial feasibility of this approach. The R33 phase of the proposed work will be focused on optimization of the nanosystems and biocompatibility evaluation. This innovative application of nanotechnologies to CF lung disease will also have potential in other lung diseases where transport barriers to drug delivery exist: tuberculosis, lung cancer, COPD, etc. The proposed studies will fill important gaps in our understanding of the systems of pulmonary drug delivery of nanosystems and subsequently how controlled administration of drug and gene therapies may impact CF treatment strategies. PUBLIC HEALTH RELEVANCE: Cystic Fibrosis (CF) is one of the most common fatal inherited diseases. There is no cure for CF, and most individuals with cystic fibrosis die young - in their 20s and 30s from lung failure. Ultimately, lung transplantation is often necessary as CF worsens. Lung disease results from clogging of airways due to inflammation. Inflammation and infection cause injury to the lungs and structural changes that lead to a variety of symptoms. One of the major reasons for the poor life expectancy is the inability of therapies to overcome barriers within the airways (obstruction, poor penetration through mucus, extensive degradation of therapeutic). Thus new therapeutic options are urgently required that are more efficacious and have improved targeting. We are using CF as a model disease to develop the nanotechnologies described in this application given that this disease: (1) is well studied, (2) has a number of transport barriers to be overcome, (3) relevant in vitro and in vivo models are available. However, the findings of these studies will be directly relevant and applicable to many lung diseases such as TB, COPD, asthma, and chronic lung infections. Moreover, the ability to enhance drug transport through biofilms is widely applicable to many infectious diseases.

描述（由申请人提供）：过去 30 年来，由于通过吸入气雾剂输送药物，囊性纤维化 (CF) 的治疗取得了显着进步。然而，由于气道内存在粘性粘液转运屏障、吸入药物在发挥其药理作用之前的广泛降解和代谢以及粘液样铜绿假单胞菌菌落的形成，CF患者的吸入疗法的疗效显着降低。通常，药物或基因载体在其活性降低或消除之前无法到达预期目标。药物输送的运输效率差导致治疗失败，包括无法达到基因治疗成功所需的相对较低的效率。将纳米级系统独特的运输和活性特性应用于药物输送是克服 CF 肺病生物屏障的一种有前景的策略。特别是，纳米粒子系统利用热（纳米刀）和磁场（纳米拉力）对其环境产生强烈影响的能力对于增加 CF 肺病的转运和药物分布来说是有吸引力的功能属性。长期目标是克服这些障碍并实现 CF 治疗的重大改进。该研究的中心假设是，新型多功能纳米颗粒以气雾剂形式给药时，由于囊性纤维化中粘液和生物膜屏障的扩散和渗透增加，将有助于显着增强模型治疗剂的疗效。我们的初步数据表明（1）在纳米滑轮模式下可以显着增加纳米颗粒的颗粒和体积运输，（2）我们证明我们的纳米颗粒可以被加热，并且它们的作用就像纳米刀一样切割DNA等生物聚合物，导致 CF 粘液扩散限制，（3）我们还证明了我们合成用于这些研究的许多不同类型的磁性纳米颗粒的能力：用于图像研究的核壳复合材料和用于药物缀合的表面功能化颗粒(4) 然后我们对这些颗粒进行功能化，使用生物可裂解的缀合方案将模型药物附着到表面，(5) 可以使用磁场触发药物释放，(6) 最后，我们将纳米颗粒加载到可吸入微粒中适用于空气动力学肺部靶向。这些令人兴奋的初步数据有力地支持了所提出方法的基本原理和可行性。此外，跨学科团队在该项目的每个关键领域都拥有非常出色的记录：肺部药物输送、纳米粒子设计和工程以及CF的分子遗传学和微生物学。拟议研究的主要目标是开发、合成、表征和评估新型颗粒系统，该系统同时允许控制肺沉积并增强 CF 疾病的运输。这些系统将提供高浓度的药物直接输送到作用部位，因此将有助于显着改善 CF 的药物和基因疗法，延长生存期并提高生活质量。因此，该项目探索性 R21 阶段的具体目标是 (i) 制备和表征多功能纳米颗粒，并将其纳入适合通过干粉雾化吸入的微系统中，(ii) 表征颗粒的药物转运和递送性能CF 体外治疗，以及 (iii) 与雾化对照相比，评估多功能纳米粒子肺部递送系统的体内功效和安全性。 R21阶段的结果将证明该方法的初步可行性。拟议工作的 R33 阶段将重点关注纳米系统的优化和生物相容性评估。这种纳米技术在 CF 肺部疾病中的创新应用也将在其他存在药物输送障碍的肺部疾病中发挥潜力：结核病、肺癌、慢性阻塞性肺病等。拟议的研究将填补我们对肺部药物系统理解的重要空白。纳米系统的交付以及随后药物和基因疗法的控制管理如何影响 CF 治疗策略。 公共卫生相关性：囊性纤维化 (CF) 是最常见的致命遗传性疾病之一。 CF 无法治愈，大多数囊性纤维化患者在 20 多岁和 30 多岁的时候就死于肺衰竭。最终，随着 CF 恶化，肺移植通常是必要的。肺部疾病是由于炎症导致气道堵塞造成的。炎症和感染会导致肺部损伤和结构变化，从而导致各种症状。预期寿命低的主要原因之一是治疗方法无法克服气道内的障碍（阻塞、粘液渗透性差、治疗剂广泛降解）。因此，迫切需要更有效且靶向性更好的新治疗方案。我们使用 CF 作为模型疾病来开发本申请中描述的纳米技术，因为这种疾病：（1）经过充分研究，（2）有许多运输障碍需要克服，（3）相关的体外和体内型号可供选择。然而，这些研究的结果将直接相关并适用于许多肺部疾病，如结核病、慢性阻塞性肺病、哮喘和慢性肺部感染。此外，通过生物膜增强药物转运的能力广泛适用于许多传染病。