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）：摘要针对的药物输送一直是生物医学科学的长期目标。特别感兴趣的是，这些药物是否发挥强大的治疗作用但由于全身分娩过程中有害的副作用而无法突出使用？骨骼已成为针对靶向递送的特定感兴趣的组织，这是由于其独特的矿化结构，将其与其他组织区分开，2）诸如radiodrug和骨质疏松症等领先的骨治疗剂通常具有严格的系统作用。使用一般骨结合部分，例如双膦酸盐，多天冬氨酸和四环素提供了初步的证据，表明在许多体外研究和体内动物模型中，可以将局部药物递送到骨骼。虽然可以将许多治疗剂递送到骨骼中，但我们选择了抗生素的两个关键原因：1）手中有有效的药物结合肽，2）骨骼感染是痛苦的，毁灭性的，太多了。因此，在此拟议的I期研究计划中，我们将尝试使用Affinergy的核心技术来识别能够结合骨骼的肽，并将其用作双功能肽递送系统中的组成部分。然后，我们将将这些新型的骨结合肽与抗生素结合肽息息，这些肽已经证明了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开发了一种广泛的方法来创建靶标特异性的模块化肽，该肽将生物活性剂（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。这些指定和嫁接的生物聚合物称为“界面生物材料”（IFBMS）。双功能IFBM具有a）提供高表面结合亲和力和特异性的独特优势，b）使用可靠的化学用于广泛的应用化学组装，c）提供在单个材料或表面上指定广泛的生物学活动的能力。 IFBM技术解决了先前的抗生素涂层方法的局限性，因为1）连接器肽可以在护理点短期孵育期间附加到潜在的任何组织或医疗植入物表面，以及2）旨在结合多种抗生素的新的IFBM，允许临床医生为特定的临床情况选择适当的抗生素。我们提出的目标是因此产生双功能肽，能够非共价将抗生素与骨骼联系起来，从而满足对局部抗生素递送到骨组织的未满足的需求。成功实现了这一目标后，我们将针对其他治疗剂，例如造血剂，骨质疏松剂抑制剂和成骨因子，用于局部骨输送。我们认为这里提出的目标代表了原则研究计划，该计划将在随后的II阶段资金期间扩展，以包括新的抗生素和商业化策略。公共卫生相关性：骨髓炎是骨组织的挑战性感染，最常是由于创伤后被污染的开放裂缝部位引起的，或在整形外科手术过程中作为医生感染。虽然可以将许多治疗剂递送到骨骼，但我们选择了抗生素作为最初的靶标的，原因有两个：1）我们手中有一个有效的药物结合肽，2）骨骼感染是痛苦的，毁灭性的，太多了。 Affinergy开发了一种广泛的方法来创建靶标特异性的模块化肽，该肽将生物活性剂（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。我们提出的目标是使用我们的平台技术，产生双功能肽，能够将抗生素与骨骼无共价链接，从而满足对局部抗生素递送到骨组织的未满足的需求。在成功完成了I期目标之后，我们将立即启动II期研究计划，测试该肽介导的体内递送系统的功效，并设计针对其他疗法的肽，例如造血剂，骨质疏松剂抑制剂和骨化因子局部化骨骼骨输送。