18F Conjugated Maltodextrins for the Detection of Medical Device Infections

 描述（由申请人提供）：植入式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、死亡率和医疗保健成本有显著影响。例如，在美国，每年约有100万患者获得医院植入物感染，并且这些感染的经济影响每年以数十亿美元计。治疗细菌植入物感染的一个主要挑战是在早期诊断它们。目前，与医疗器械相关的感染的诊断是基于临床标准，例如体检和微生物培养，这是有问题的，因为这种方法只能检测到难以治疗的晚期感染。因此，医疗器械感染经常无法诊断，并允许进展到晚期，导致严重的发病率和死亡率。相反，仅基于临床判断，可能会不适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保健成本增加。在这种临床环境中，一种可以在早期阶段特异性检测受感染的植入器械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和严格评估一种新的PET成像造影剂家族，该造影剂可以通过靶向麦芽糊精转运蛋白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被细菌内化为食物来源，但不被哺乳动物细胞内化，因为哺乳动物细胞缺乏麦芽糖糊精转运蛋白。该提案中的实验集中于开发用于细菌PET成像的新型麦芽糊精缀合物，并确定其在感染的医疗植入物成像中的功效。该提案的中心假设是：麦芽糊精与18 F的结合物将以高度特异性和灵敏度的方式检测植入式医疗器械的细菌感染。提出了以下具体目的：具体目的1：18 F标记的麦芽六糖、18 F-硫代麦芽糖和18 F-脱氧硫代麦芽糖的合成和代谢具体目的2：已知引起医疗器械感染的细菌对18 F标记的麦芽六糖、18 F-硫代麦芽糖和18 F-脱氧硫代麦芽糖的内化和代谢具体目的3：18 F-MDP在大鼠中对医疗器械感染的比较体内成像

 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