Peptide-mediated Attachment of Drug-loaded Microparticles to Medical Devices

描述(申请人提供)：纵隔炎是心脏直视手术后常见的，有时甚至是毁灭性的并发症。尽管预防性全身抗生素的使用和手术技术的改进，细菌感染仍然是几乎所有手术后的严重并发症，包括胸骨正中切开。当手术部位发生感染时，它们可能是毁灭性的，带来巨大的经济和心理代价，特别是在糖尿病患者、吸烟者、老年人和免疫功能受损的高危患者中。防止手术部位高危组织微生物定植的新技术显然可以通过降低感染率而造福社会。在抗生素的本地传递方面进一步创新的需要是我们开发多肽介导的系统的动机，该系统将载药微粒附着到医疗设备上。AffinEnergy正在开发被称为界面生物材料(IFBMs)的双功能亲和肽，这种材料可以促进药物、蛋白质和细胞在医疗器械表面的附着和保持。利用噬菌体展示，我们已经鉴定出与许多材料和生物制品具有高亲和力的特定多肽序列。合成一对这样的多肽作为单一的IFBM可以促进药物、蛋白质或细胞直接附着在医疗设备的表面。虽然我们已经观察到了使用抗生素的这项技术的有希望的初步数据，但多肽介导的带有载药微粒的医疗器械涂层可能具有额外的优势。有可能有更多的药物和更多的医疗设备，我们可能会通过这种新的微粒包衣策略来瞄准。由于存在如此广泛的潜在多肽-微粒子装置组合，在本提案中，我们将重点开发一种用于胸骨钢丝的微粒子涂层以预防纵隔炎。因此，这项第一阶段研究计划的目标是首先在AffinEnergy优化载药聚(乳酸-乙醇酸)(PLGA)微粒制剂。然后，我们将描述和优化候选PLGA：金属IFBM。最后，我们将检查IFBM靶向微粒的抗菌效果和生物兼容性，确定这些微粒是否增加了AffinEnergy设备涂层技术的潜力。这里提出的目标代表了一个原则证明研究计划，该计划将在随后的第二阶段资助期扩大到包括新的抗生素和商业化战略。未来，微粒：医疗设备IFBMS可以用来附着装载了从抗生素到局部麻醉剂的各种治疗分子的微粒，以防止手术后感染局部麻醉药，以治疗手术后疼痛。 公共卫生相关性：心脏直视手术后感染是一种常见的，有时甚至是毁灭性的并发症。尽管预防性全身抗生素的使用和改进的手术技术，感染仍然是一个严重的并发症。在局部抗生素输送方面进一步创新的需要是我们开发多肽介导的将载药微粒附着到医疗设备上的动力。AffinEnergy正在开发被称为界面生物材料(IFBMs)的双功能亲和肽，这种材料可以促进药物、蛋白质和细胞在医疗器械表面的附着和保持。虽然我们已经观察到了使用抗生素的这项技术的有希望的初步数据，但多肽介导的带有载药微粒的医疗器械涂层可能具有额外的优势。有可能有更多的药物和更多的医疗设备，我们可能会以这种新的微粒包衣策略为目标。在这项提案中，我们重点开发了一种用于胸骨钢丝的微粒涂层，用于心脏直视手术后局部输送抗生素。未来，微粒子：医疗设备IFBMS可以用来附着装载了从抗生素到局部麻醉剂的各种治疗分子的微粒子，以防止手术后感染局部麻醉药，以治疗手术后疼痛。

DESCRIPTION (provided by applicant): Mediastinitis is a common and sometimes devastating complication following open heart surgery. Despite the use of prophylactic systemic antibiotics and improved surgical techniques, bacterial infection remains a serious complication following almost all surgical procedures including median sternotomy. When surgical site infections occur, they can be devastating with immense financial and psychological costs especially in at-risk patients such as diabetics, smokers, the elderly, and immunocompromised. New technologies that prevent microbial colonization of the at-risk tissues in a surgical site could clearly benefit society by decreasing infection rates. The need for further innovation in the local delivery of antibiotics is our motivation to develop a peptide-mediated system to attach drug-loaded microparticles to medical devices. Affinergy is developing bifunctional affinity peptides, called interfacial biomaterials (IFBMs), that promote the attachment and retention of drugs, proteins, and cells on the surface of medical devices. Using phage display, we have identified specific peptide sequences that bind with high affinity to a number of materials and biologics. Synthesizing a pair of these peptides as a single IFBM promotes the attachment of drug, protein, or cell directly to the surface of a medical device. While we have observed promising preliminary data with this technique using antibiotics, peptide-mediated coating of medical devices with drug loaded microparticles may hold additional advantages. There are likely additional drugs and additional medical devices we might target with this novel microparticle-coating strategy. Because there exist such a wide range of potential peptide-microparticle device combinations, in this proposal we will focus on the development of a microparticle coating for sternal wires to prevent mediastinitis. Therefore, the goal of this Phase I research plan is to first optimize drug loaded poly (lactic-co-glycolic acid) (PLGA) microparticle preparations at Affinergy. We will then characterize and optimize candidate PLGA: metal IFBMs. Finally, we will examine the antimicrobial efficacy and biocompatibility of IFBM targeted microparticles, determining if the microparticles increase the potential of Affinergy device coating technology. 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. In the future, microparticles: medical device IFBMs could be used to attach microparticles loaded with a wide variety of therapeutic molecules from antibiotics to prevent post-operative infection to local anesthetics to treat post- operative pain. PUBLIC HEALTH RELEVANCE: Post-operative infection is a common and sometimes devastating complication following open heart surgery. Despite the use of prophylactic systemic antibiotics and improved surgical techniques, infection remains a serious complication. The need for further innovation in localized antibiotic delivery is our motivation to develop a peptide-mediated attachment system for drug-loaded microparticles onto medical devices. Affinergy is developing bifunctional affinity peptides, called interfacial biomaterials (IFBMs), that promote the attachment and retention of drugs, proteins, and cells on the surface of medical devices. While we have observed promising preliminary data with this technique using antibiotics, peptide-mediated coating of medical devices with drug loaded microparticles may hold additional advantages. There are likely additional drugs and additional medical devices we might target with this novel microparticle coating strategy. In this proposal we focus on the development of a microparticle coating for sternal wires to deliver antibiotics locally following open heart surgery. In the future, microparticle: medical device IFBMs could be used to attach microparticles loaded with a wide variety of therapeutic molecules from antibiotics to prevent post-operative infection to local anesthetics to treat post-operative pain.