18F Conjugated Maltodextrins for the Detection of Medical Device Infections

18F 共轭麦芽糖糊精用于检测医疗器械感染

• 批准号: 9056161
• 负责人: Mark Myron Goodman
• 金额: $ 61.11万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-04 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056161
• 关键词: Aftercare; Animal Model; Bacteria; Bacterial Infections; Cardiac; Cells; Clinical; Contrast Media; Defibrillators; Detection; Devices; Diagnosis; Environment; Enzymes; Escherichia coli; Family; Food; Glucose; Health; Health Care Costs; Healthcare; Human; Hydrolysis; Image; Implant; Infection; Inflammation; Inflammatory; Judgment; Label; Mammalian Cell; Medical Device; Metabolic; Metabolism; Methodology; Modeling; Morbidity - disease rate; Oligosaccharides; Pacemakers; Pathway interactions; Patients; Positron-Emission Tomography; Rattus; Relative (related person); Resistance; Risk; Sensitivity and Specificity; Serum; Source; Specificity; Staging; Staphylococcus aureus; Staphylococcus epidermidis; Sterility; Techniques; Technology; Testing; Vertebral column; base; comparative; cost; economic impact; imaging agent; imaging modality; imaging probe; implantable device; in vivo; in vivo imaging; maltodextrin; medical implant; microbial; mortality; novel; research study; soft tissue; uptake

 DESCRIPTION (provided by applicant): Bacterial infections of implanted medical devices are a growing problem in health care today and have a significant impact on morbidity, mortality and health care costs. For example, approximately 1 million patients acquire a nosocomial implant infection in the US every year, and the financial impact of these infections is in the billions of dollars annually. A major challenge in treating bacterial implant infections is diagnosing them at an early stage. At present, the diagnosis of an infection associated with a medical device is made on the basis of clinical criteria, such as physical exam and microbial cultures, which is problematic because this methodology can only detect late stage infections that are challenging to treat. Medical device infections are therefore frequently undiagnosed and allowed to progress to an advanced stage, resulting in significant morbidity and mortality. Conversely, medical devices with sterile inflammation may be inappropriately removed, based on clinical judgment alone, incurring increased morbidity and healthcare costs. In this clinical environment, a technology that can specifically detect infected implanted devices at an early stage, and distinguish them from sterile inflammation has the potential to have a significant clinical and economic impact. The central objective of this proposal is to develop and rigorously evaluate a new family of PET imaging contrast agents that can image implant infections by targeting the maltodextrin transporter. We have termed these agents the 18F-MDPs as they are composed of 18F conjugated to maltodextrins. 18F-MDPs have high specificity and sensitivity for bacteria because they are internalized by bacteria as a food source via the maltodextrin transport pathway, but are not internalized by mammalian cells as mammalian cells lack maltodextrin transporters. The experiments in this proposal focus on developing a novel conjugate of maltodextrin for use in PET imaging of bacteria and determining its efficacy in imaging infected medical implants. The central hypothesis of this proposal is that: Conjugates of maltodextrins with 18F will detect bacterial infections of implanted medical devices in a highly specific and sensitive manner. The following Specific Aims are proposed: Specific Aim 1: Synthesis and metabolism of 18F-labeled maltohexaose, 18F-thiomaltose and 18F- deoxythiomaltose Specific Aim 2: Internalization and metabolism of 18F-labeled maltohexaose, 18F-thiomaltose and 18F-deoxythiomaltose by bacteria known to cause medical device infections Specific Aim 3: Comparative in vivo imaging of medical device infections in rats with 18F-MDPs

 描述（由申请人提供）：植入医疗器械的细菌感染是当今医疗保健中日益严重的问题，对发病率、死亡率和医疗保健费用产生重大影响。例如，在美国，每年约有 100 万患者发生院内植入物感染，这些感染每年造成的财务影响达数十亿美元。治疗细菌植入物感染的一个主要挑战是早期诊断。目前，与医疗器械相关的感染的诊断是根据临床标准（例如体检和微生物培养）进行的，这是有问题的，因为这种方法只能检测难以治疗的晚期感染。因此，医疗器械感染经常未被诊断并进展至晚期，导致显着的发病率和死亡率。相反，仅根据临床判断，可能会不恰当地移除具有无菌炎症的医疗器械，从而导致发病率和医疗费用增加。在这种临床环境中，一种能够在早期阶段专门检测受感染的植入设备并将其与无菌炎症区分开来的技术有可能产生重大的临床和经济影响。 该提案的中心目标是开发并严格评估一个新的 PET 成像造影剂系列，该造影剂可以通过靶向麦芽糖糊精转运蛋白来对植入物感染进行成像。我们将这些试剂称为 18F-MDP，因为它们由与麦芽糖糊精缀合的 18F 组成。 18F-MDP 对细菌具有高特异性和敏感性，因为它们通过麦芽糖糊精转运途径作为食物来源被细菌内化，但由于哺乳动物细胞缺乏麦芽糖糊精转运蛋白，因此不能被哺乳动物细胞内化。该提案中的实验重点是开发一种新型麦芽糖糊精缀合物，用于细菌 PET 成像，并确定其在受感染医疗植入物成像中的功效。该提案的中心假设是：麦芽糖糊精与 18F 的缀合物将以高度特异性和灵敏的方式检测植入医疗器械的细菌感染。提出以下具体目标： 具体目标 1：18F 标记麦芽六糖、18F-硫代麦芽糖和 18F-脱氧硫代麦芽糖的合成和代谢 具体目标 2：已知会引起医疗器械感染的细菌内化和代谢 18F 标记麦芽六糖、18F-硫代麦芽糖和 18F-脱氧硫代麦芽糖 具体目标 图3：18F-MDP大鼠医疗器械感染的体内成像比较