Bone Targeting Peptides for the Prevention and Treatment of Infection

靶向给药一直是生物医学科学的长期目标。特别值得关注的是，这些药物是否具有强大的治疗效果，但由于在全身输送过程中有有害的副作用而不能显著使用？由于1)其独特的矿化结构，将其与其他组织区分开来；2)领先的骨治疗方法，如放射药物和骨质疏松症治疗通常具有严重的全身效应，骨已成为一种特殊的靶向递送组织。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，证明在许多体外研究和体内动物模型中，局部药物递送到骨是可能的。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、毁灭性的，而且数量太多。因此，在这个拟议的I期研究计划中，我们将尝试使用affinenergy的核心技术来识别能够结合骨骼的肽，作为我们双功能肽递送系统的组成部分。然后，我们将把这些新的骨结合肽与抗生素结合肽偶联，抗生素结合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已经开发出一种通用的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）结合到合成表面（金属、塑料、聚合物等）或组织上。这些指定和接枝的生物聚合物被称为“界面生物材料”（IFBMs）。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)使用强大的化学方法进行组装，以实现广泛的应用；c)提供在单一材料或表面上指定广泛生物活性的能力。IFBM技术解决了以前抗生素包衣方法的局限性，因为1)连接肽可以在护理点的短暂孵育期间附着在任何组织或医疗植入物表面，2)新的IFBM设计用于结合多种抗生素，将允许临床医生根据特定的临床情况选择合适的抗生素。因此，我们提出的目标是产生双功能肽，能够将抗生素与骨非共价连接，满足骨组织局部抗生素递送的未满足需求。在成功实现这一目标后，我们将瞄准其他治疗方法，如造血药物、骨质疏松抑制剂和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，在随后的第二阶段资助期间，该计划将扩大到包括新的抗生素和商业化战略。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被污染引起，或作为骨科手术过程中的医院感染。虽然有许多治疗方法可以用于骨骼，但我们选择抗生素作为我们的初始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、毁灭性的，而且数量太多。Affinergy已经开发出一种通用的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）结合到合成表面（金属、塑料、聚合物等）或组织上。因此，我们提出的目标是利用我们的平台技术，生成双功能肽，能够将抗生素与骨非共价连接，满足骨组织局部抗生素递送的未满足需求。在成功完成I期目标后，我们将立即启动II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方法的肽，如造血剂、骨质疏松抑制剂和局部骨递送的成骨因子。

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.