Bone Targeting Peptides for the Prevention and Treatment of Infection

用于预防和治疗感染的骨靶向肽

• 批准号: 7596800
• 负责人: Hanne Gron
• 金额: $ 30.39万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-11 至 2011-03-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596800
• 关键词: Address; Adverse effects; Affinity; Animal Model; Antibiotics; Aspartic Acid; Binding; Biocompatible Materials; Biopolymers; Bone Tissue; Cells; Chemistry; Clinical; Drug Delivery Systems; Family suidae; Funding; Goals; Growth; Growth Factor; Hand; Healed; Hematinics; Human; Implant; In Vitro; Infection; Libraries; Link; Mediating; Metals; Methods; Nosocomial Infections; Open Fractures; Orthopedic Surgical Procedures; Osteoblasts; Osteogenesis; Osteomyelitis; Osteoporosis; Pain; Peptides; Phage Display; Pharmaceutical Preparations; Phase; Plastics; Polymers; Prevention; Relative (related person); Research; Research Contracts; Sampling; Science; Site; Specific qualifier value; Specificity; Structure; Surface; System; Technology; Testing; Tetracyclines; Therapeutic; Therapeutic Effect; Tissues; To specify; Trauma; Vancomycin; antimicrobial; base; biomaterial compatibility; bisphosphonate; bone; commercialization; density; design; efficacy testing; healing; in vitro testing; in vivo; inhibitor/antagonist; interest; interfacial; medical implant; novel; osteogenic; point of care; programs; protein aminoacid sequence; public health relevance; targeted delivery; tricalcium phosphate

DESCRIPTION (provided by applicant): Summary Targeted drug delivery has been a long-term goal for biomedical science. Of specific interest, are those drugs which exert powerful therapeutic effects but cannot be prominently used due to harmful side- effects during systemic delivery? Bone has become a tissue of specific interest for targeted delivery, due to 1) its unique mineralized structure, distinguishing it from other tissues and 2) leading bone therapeutics such as radiodrug and osteoporosis treatments often have harsh systemic effects. The use of general bone-binding moieties such as bisphosphonates, poly-aspartic acid and tetracycline provides preliminary evidence that localized drug delivery to bone is possible in numerous in vitro studies and in vivo animal models. While a number of therapeutics could be delivered to bone, we have chosen antibiotics for two key reasons: 1) we have an effective drug-binding peptide in hand and 2) bone infections are painful, devastating and far too numerous. During this proposed Phase I research program, we will therefore attempt to use Affinergy's core technology to identify peptides capable of binding bone, to be used as a component in our bifunctional peptide delivery systems. We will then couple these novel bone-binding peptides to antibiotic-binding peptides, which have already demonstrated the ability to bind, retain and release bioactive antibiotics from biomaterial surfaces. Affinergy has developed a generalized approach to creating target-specific modular peptides that bind bioactive agents (drugs, growth factors, cells, etc.) to synthetic surfaces (metals, plastics, polymers, etc.) or tissues. These specifying and grafting biopolymers are termed "interfacial biomaterials" (IFBMs). A bi- functional IFBM has the unique advantages of a) providing high surface binding affinity and specificity, b) assembly using robust chemistry for broad-based applications, and c) offering the capacity to specify a wide range of biologic activities onto a single material or surface. IFBM technology addresses limitations of previous antibiotic coating methods because 1) linker peptides can be attached to potentially any tissue or medical implant surface during a short incubation at point of care, and 2) new IFBMs designed to bind multiple antibiotics, would allow clinicians to choose the appropriate antibiotic for a specific clinical situation. Our proposed goal is to therefore generate bifunctional peptides, capable of non-covalently linking antibiotics to bone, satisfying the unmet need for localized antibiotic delivery to bone tissues. After successfully accomplishing this goal we would target other therapeutics, such as hematopoietic agents, osteoporosis inhibitors and osteogenic factors for localized bone delivery. We feel the aims presented here represent a proof-of-principle research program, which would be expanded to include new antibiotics and commercialization strategies during a subsequent Phase II funding period. PUBLIC HEALTH RELEVANCE: Osteomyelitis is a challenging infection of bone tissue, most often caused by a contaminated open fracture site after trauma, or as a nosocomial infection during an orthopedic surgical procedure. While a number of therapeutics could be delivered to bone, we have chosen antibiotics as our initial target for two key reasons: 1) we have an effective drug-binding peptide in hand and 2) bone infections are painful, devastating and far too numerous. Affinergy has developed a generalized approach to creating target-specific modular peptides that bind bioactive agents (drugs, growth factors, cells, etc.) to synthetic surfaces (metals, plastics, polymers, etc.) or tissues. Our proposed goal is to therefore use our platform technology, to generate bifunctional peptides, capable of non-covalently linking antibiotics to bone, satisfying the unmet need for localized antibiotic delivery to bone tissues. After successfully accomplishing our Phase I aims, we would immediately initiate a Phase II research program, testing the efficacy of this peptide-mediated delivery system in vivo, and designing peptides targeting other therapeutics, such as hematopoietic agents, osteoporosis inhibitors and osteogenic factors for localized bone delivery.

描述（由申请人提供）：摘要靶向药物递送一直是生物医学科学的长期目标。特别值得关注的是，那些具有强大治疗效果但由于全身给药过程中产生有害副作用而无法得到广泛使用的药物？骨骼已成为靶向递送特别感兴趣的组织，因为：1）其独特的矿化结构，使其有别于其他组织；2）领先的骨骼治疗方法（例如放射性药物和骨质疏松症治疗）通常会产生严重的全身效应。双膦酸盐、聚天冬氨酸和四环素等一般骨结合部分的使用提供了初步证据，表明在许多体外研究和体内动物模型中，局部药物递送至骨是可能的。虽然有许多治疗方法可以用于骨骼，但我们选择抗生素有两个主要原因：1）我们手头有有效的药物结合肽，2）骨骼感染是痛苦的、破坏性的，而且数量太多。因此，在拟议的第一阶段研究计划中，我们将尝试使用 Affinergy 的核心技术来识别能够结合骨的肽，将其用作我们的双功能肽递送系统的组件。然后，我们将这些新型骨结合肽与抗生素结合肽偶联，抗生素结合肽已被证明具有从生物材料表面结合、保留和释放生物活性抗生素的能力。 Affinergy 开发了一种通用方法来创建目标特异性模块化肽，将生物活性剂（药物、生长因子、细胞等）与合成表面（金属、塑料、聚合物等）或组织结合。这些指定和接枝生物聚合物被称为“界面生物材料”（IFBM）。双功能 IFBM 具有独特的优势：a) 提供高表面结合亲和力和特异性，b) 使用稳健的化学方法进行组装，以实现广泛的应用，以及 c) 能够在单一材料上指定多种生物活性或表面。 IFBM 技术解决了以前抗生素涂层方法的局限性，因为 1) 连接肽可以在护理点的短暂孵育过程中附着到任何组织或医疗植入物表面，2) 设计用于结合多种抗生素的新型 IFBM，将允许临床医生选择针对特定临床情况的适当抗生素。因此，我们提出的目标是生成双功能肽，能够将抗生素非共价连接到骨骼，以满足局部抗生素递送到骨组织的未满足的需求。成功实现这一目标后，我们将瞄准其他治疗方法，例如造血剂、骨质疏松抑制剂和用于局部骨输送的成骨因子。我们认为这里提出的目标代表了一个原理验证研究计划，该计划将在随后的第二阶段资助期间扩大到包括新的抗生素和商业化策略。公共卫生相关性：骨髓炎是一种具有挑战性的骨组织感染，最常由创伤后开放性骨折部位污染引起，或在骨科手术过程中作为院内感染引起。虽然有许多治疗方法可以作用于骨骼，但我们选择抗生素作为最初的目标有两个关键原因：1）我们手头有一种有效的药物结合肽，2）骨骼感染是痛苦的、破坏性的，而且数量太多。 Affinergy 开发了一种通用方法来创建目标特异性模块化肽，将生物活性剂（药物、生长因子、细胞等）与合成表面（金属、塑料、聚合物等）或组织结合。因此，我们提出的目标是利用我们的平台技术来生成双功能肽，能够将抗生素非共价连接到骨骼，满足局部抗生素递送到骨组织的未满足的需求。在成功完成一期目标后，我们将立即启动二期研究计划，在体内测试这种肽介导的递送系统的功效，并设计针对其他治疗药物的肽，例如造血剂、骨质疏松抑制剂和局部成骨因子。骨输送。