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）：由于通过吸入气溶胶递送药物，在过去30年中，囊性纤维化治疗（CF）的治疗显着改善。然而，由于在航空道中存在粘性粘液传输屏障，吸入药物的广泛降解和代谢，在发育其药物学作用以及发育粘液酸莫诺果酸酯菌落之前，吸入粘液传输屏障，广泛的降解和代谢，因此，CF患者的功效吸入疗法大大降低。通常，药物或基因载体在降低或消除活性之前无法达到预期的靶标。药物输送的运输效率不佳导致疗法失败，包括无法获得基因治疗成功所需的相对较低的效率。在药物输送中应用纳米级系统的独特运输和主动性能是克服CF肺部疾病中生物障碍的有前途策略。特别是，纳米颗粒系统使用热量（纳米菌）和磁场（Nano-Pullies）对环境产生强大影响是有吸引力的功能属性，可增加CF肺部疾病中的运输和药物分布。长期目标是克服这些障碍，并在CF治疗方面取得重要改善。拟议研究的中心假设是，新型的多功能纳米颗粒将促进模型治疗剂的功效显着增强，这是由于囊性纤维化中通过粘液和生物膜屏障的增加而导致的囊性纤维化效果，当囊性纤维化中施用时。我们的初步数据表明，（1）在纳米 - 普鲁利模式下可以达到纳米颗粒的颗粒和大量运输的显着增加，（2）我们证明我们的纳米颗粒可以加热，它们的作用就像纳米粒子一样，它们的作用就像纳米成分一样，使诸如DNA（例如DNA）（例如DNA）导致CF Mucus griband grom in Dibles flomige dible contime contime contime（3）我们的综合（3）我们的综合体系（3），我们（3）我们的纳米聚合物（3）我们的纳米粒子（3）我们的纳米聚合物（3）的范围（3）在这些研究中用于使用的纳米颗粒：用于图像研究和表面功能性颗粒用于药物结合的核心壳复合材料（4），我们将这些颗粒功能化，将模型药物连接到表面上，使用生物裂解的共轭方案（5）可以使用磁场（6）和NAN的磁场来触发（5）药物释放，并最终加载，（6）和Nan lungs iNAN，nan lungs inan lung inan lung inan lane lung inan lyapiles，定位。这些令人兴奋的初步数据强烈支持所提出方法的理由和可行性。此外，跨学科团队在项目的每个关键领域都有非常良好的记录：肺部药物输送，纳米颗粒设计和工程以及CF的分子遗传学和微生物学。拟议研究的主要目的是开发，合成，表征和评估新型颗粒系统，同时允许控制肺部沉积并增强CF疾病的运输。这些系统将提供直接传递到作用部位的高药物浓度，因此将促进CF中药物和基因疗法的显着改善，延长生存并提高生活质量。因此，该项目的探索性R21阶段的具体目的是（i）准备和表征多功能纳米颗粒，并将其纳入适合通过干粉式增气化的适用于吸入的微型系统，（ii）表征药物运输和粒子在PULMON和PURMONS INTAR中的CF疗法的颗粒性能以及（iii）的跨性别性能，以及（iii）的安全性。气燃化对照。 R21阶段的结果将证明这种方法的初始可行性。拟议工作的R33阶段将集中在纳米系统的优化和生物相容性评估上。纳米技术在CF肺部疾病中的这种创新应用也将在存在药物输送障碍的其他肺部疾病中具有潜力：结核病，肺癌，COPD等。拟议的研究将填补对我们对肺部药物递送纳米系统递送系统的理解，并在纳米系统的递送系统方面进行了影响。 公共卫生相关性：囊性纤维化（CF）是最常见的致命遗传疾病之一。 CF无法治愈，大多数患有囊性纤维化的人死于年轻的肺部衰竭。最终，由于CF恶化，通常需要进行肺移植。肺部疾病是由于炎症引起的气道堵塞而引起的。炎症和感染会导致肺部受伤，并导致各种症状。预期寿命差的主要原因之一是无法疗法克服气道内的障碍（阻塞，通过粘液渗透不良，治疗性广泛降解）。因此，迫切需要新的治疗选择，这些选择更有效，并且已经改善了目标。我们正在使用CF作为模型疾病来开发本应用中描述的纳米技术，因为该疾病已经很好地研究了：（2）（2）有许多要克服的运输障碍，（3）可用的体外和体内模型。但是，这些研究的发现将直接相关，并适用于许多肺部疾病，例如结核病，COPD，哮喘和慢性肺部感染。此外，通过生物膜增强药物运输的能力广泛适用于许多传染病。