Nanoscale Electrostatic Assemblies for Multi-Agent Drug Delivery from

用于多药剂药物输送的纳米级静电组件

• 批准号: 8055469
• 负责人: Paula T Hammond
• 金额: $ 29.5万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055469
• 关键词: Address; Adsorption; Angiogenic Factor; Animal Model; Animals; Anti-Bacterial Agents; Antibiotics; Architecture; Area; Arthroplasty; Arts; Bacteria; Biological; Biological Preservation; Blood Vessels; Bone Growth; Bone Tissue; Buffers; Cell Culture Techniques; Cells; Charge; Chemical Engineering; Collaborations; Communicable Diseases; Complex; Consultations; Defect; Dependency; Devices; Diffusion; Disinfection; Dose; Drug Delivery Systems; Electrostatics; Ensure; Environment; Evaluation; Failure; Film; Fracture; Gene Delivery; Genes; Gentamicins; Goat; Growth; Growth Factor; Healed; Hip region structure; Hospitalization; Human; Implant; Implantation procedure; In Vitro; Infection; Injury; Investigation; Ionic Strengths; Joint Prosthesis; Joints; Knee; Lead; Literature; Measures; Mechanics; Medicine; Methicillin Resistance; Methods; Modeling; Modification; Molecular; Molecular Weight; Myron; Open Fractures; Operative Surgical Procedures; Orthopedics; Oryctolagus cuniculus; Osteoblasts; Osteomyelitis; Patients; Pharmaceutical Preparations; Plasmids; Polymers; Procedures; Process; Production; Property; Prosthesis; Proteins; Recombinant Proteins; Recovery; Replacement Arthroplasty; Research; Series; Serum; Site; Solutions; Solvents; Staphylococcus aureus; Stents; Structure; Surface; Surgical sutures; System; Therapeutic; Time; Tissues; Toxic effect; Transfection; Trauma; Universities; Vancomycin; Vascular Endothelial Growth Factors; Vascularization; Wisconsin; Work; aqueous; base; biodegradable polymer; bone; bone cell; bone healing; cell growth; clinically relevant; controlled release; cost; design; drug efficacy; healing; implant coating; implantable device; in vivo; interest; methicillin resistant Staphylococcus aureus; nano; nanofabrication; nanoscale; novel strategies; polycation; polyion; professor; remediation; repaired; resistant strain; response; stem; success; therapeutic protein; tool

DESCRIPTION (provided by applicant): There is a strong need for biomedical implant coatings which can act to deliver the appropriate therapeutics, including sensitive biologic drugs, to localized areas in the body with a level of precision and control. The current state-of-art for drug-coated implants is essentially limited to those which elute a single drug over a given time period, usually with a drug release profile based on the rate of diffusion of the drug component from the thin film coating or the rate of degradation of a homogeneous bulk polymer. In either case, it is not possible to introduce complex release profiles such as the sequential release or two or more drugs utilizing standard methods; yet there are many situations in which more than one therapeutic is needed, and must be introduced at different times during the lifetime of the implant. Furthermore, it is considerably more difficult to deliver pH or solvent sensitive recombinant protein drugs or growth factors often needed for implant applications using traditional degradable polymers such as PLGA, which can expose the drug to low pH and harsh processing conditions. The primary aim of this work is to utilize the enabling nanofabrication tool of electrostatic multilayer assembly to create coatings one nanoscale layer at a time by alternating drugs with degradable polyions such that complex, multicomponent, sequential or graduated release of drugs takes place from implant surfaces in a layer-by-layer fashion. This method is simple, low cost, and allows infinite tuning of film composition using an alternate electrostatic assembly process, resulting in films that degrade under biological conditions to release series of drugs layers at a time. Specific Aims include the control of degradable polyion composition, multilayer film assembly conditions, and manipulation of nanometer scale structure of the thin films to ensure delivery in inverse order to construction of the film. In vitro cell culture studies of release of antibacterial agents and growth factors will be used to determine efficacy and optimal dose levels of these systems. Animal models that include a small animal large scale rabbit study will be used to determine efficacy of antibacterial, growth factor, and combination coatings that delivery 2 or 3 agents will be performed. A large animal goat model that better replicates human bone mechanics will be performed on the most promising nanoscale coatings. Preservation of sensitive biologic drug efficacy will be key to these studies. This novel approach has several important high- impact applications, including coatings of stents, sutures, bone and other surgical implants. The focus of this work will be on orthopedic implants, an area where the controlled delivery of multiple therapeutics could eliminate additional surgeries and promote rapid healing. We will investigate the coating of prostheses with therapeutic quantities of antibiotics, angipgenic factors, and bone morphogenetic growth factors that can be released sequentially to enable disinfection of the joint area, bone healing and growth respectively. The concept of highly controlled, passive coatings on implants is both commercially feasible and disruptive, and promises molecular level control of delivery from the device surface, which should lead to broader applications for a number of implant devices.

描述（由申请人提供）：非常需要生物医学植入物涂层，可以将适当的治疗剂（包括敏感的生物药物）运送到具有精度和控制水平的体内局部区域。当前的药物涂覆植入物的最新植入物基本上仅限于在给定时间段内洗脱一种药物的植入物，通常基于药物释放概况，基于药物成分从薄膜涂层或均质散装聚合物的降解速率。无论哪种情况，都不可能引入复杂的释放曲线，例如使用标准方法的顺序释放或两种或多种药物。然而，在许多情况下，需要多种治疗性，必须在植入物的一生中在不同时间引入。此外，使用传统可降解聚合物（例如PLGA）植入物应用通常需要使用pH或溶剂敏感的重组蛋白药物或生长因子，这要困难得多，这可以使该药物暴露于低pH值和恶劣的加工条件。这项工作的主要目的是利用静电多层组件的启用纳米制造工具一次创建涂料一次，通过与可降解的多元素交替交替使用可降解的药物的药物，以使得复杂的，多组分，顺序，顺序或渐变的药物从植入物中释放，逐层时尚。该方法是简单，低成本的，可以使用替代静电组装过程对膜组成进行无限调整，从而导致在生物条件下降解的膜一次释放一系列药物层。具体目的包括控制可降解的Polyion组成，多层膜组装条件以及对薄膜的纳米尺度结构的操纵，以确保按照膜的构造构建。抗菌剂和生长因子释放的体外细胞培养研究将用于确定这些系统的功效和最佳剂量水平。包括小型动物大型兔子研究的动物模型将用于确定将执行抗菌，生长因子和组合涂层的功效，该涂层将进行2或3个药物。可以更好地复制人骨力学的大型动物山羊模型将在最有希望的纳米级涂层上进行。敏感生物药物疗效的保留将是这些研究的关键。这种新型方法具有几种重要的高影响应用，包括支架，缝合线，骨骼和其他手术植入物的涂层。这项工作的重点将放在骨科植入物上，在该区域中，多种治疗剂的受控分娩可以消除其他手术并促进快速康复。我们将研究具有治疗量的抗生素，血管生成因子和骨形态发生生长因子的假体的涂层，这些因子可以依次释放，以分别对关节区域，骨骼愈合和生长进行消毒。高度控制的植入物上的被动涂料的概念在商业上是可行的和破坏性的，并且承诺从设备表面传递的分子水平控制，这应该导致许多植入器设备的更广泛应用。

项目成果

Osteoconductive protamine-based polyelectrolyte multilayer functionalized surfaces.

• DOI: 10.1016/j.biomaterials.2011.06.032
• 发表时间: 2011-10
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Samuel, Raymond E.;Shukla, Anita;Paik, Daniel H.;Wang, Mary X.;Fang, Jean C.;Schmidt, Daniel J.;Hammond, Paula T.
• 通讯作者: Hammond, Paula T.

Block copolymer micelles as nanocontainers for controlled release of proteins from biocompatible oil phases.

• DOI: 10.1021/bm800913r
• 发表时间: 2009-04-13
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Miller, Andrew C.;Bershteyn, Anna;Tan, Wui Siew;Hammond, Paula T.;Cohen, Robert E.;Irvine, Darrell J.
• 通讯作者: Irvine, Darrell J.

Layer-by-layer platform technology for small-molecule delivery.

• DOI: 10.1002/anie.200902782
• 发表时间: 2009
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Smith, Renee C.;Riollano, Mariawy;Leung, Amy;Hammond, Paula T.
• 通讯作者: Hammond, Paula T.

Characterization of tunable FGF-2 releasing polyelectrolyte multilayers.

• DOI: 10.1021/bm100413w
• 发表时间: 2010-08-09
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Macdonald, Mara L.;Rodriguez, Natalia M.;Shah, Nisarg J.;Hammond, Paula T.
• 通讯作者: Hammond, Paula T.

Tunable dual growth factor delivery from polyelectrolyte multilayer films.

• DOI: 10.1016/j.biomaterials.2011.04.036
• 发表时间: 2011-09
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Shah, Nisarg J.;Macdonald, Mara L.;Beben, Yvette M.;Padera, Robert F.;Samuel, Raymond E.;Hammond, Paula T.
• 通讯作者: Hammond, Paula T.