Enhanced Efficacy Photodynamic Disinfection

项目摘要 该提案是对NIAID先进技术SBIR（PA-10-123）资助机会的回应。 第一阶段可行性研究是一个先进的技术项目，具有明确的产品， 在临床相关的局部AM治疗模式中。奖励期限和所要求的金额由以下指导： 项目需要，并符合发布的指导方针。每年有5700万例门诊手术 发生在美国，其中，手术部位感染（SSI）是最常见的医院感染 感染研究表明，多达55%的SSI病例是可以预防的， 这些病例每年可以挽救约4，431人的生命，节省约16亿美元的医疗费用。各种措施 然而，由于新出现的疾病，预防和治疗SSI仍然是一个重大挑战。 多药耐药考虑到局部AM疗法的优点，特别是（较低的成本，降低的潜力， 对于全身毒性等），仍然需要增强临床上有用的局部药物库， AM疗法一种这样的疗法是光动力消毒（PD）。在典型的治疗中， (the光敏剂或PS）施加到目标伤口。在光照下，PS产生有毒的反应性物质， 影响微生物细胞灭活的氧物种（ROS）。此外，PD还有效地减少了 两种重要的细菌毒力因子（脂多糖和细菌蛋白酶）的效力。然而，在这方面， 尽管体外试验的结果并不表明需要任何额外的PS功能，但体内试验的结果表明， 测试表明，为了有效治疗，需要添加选择性PS结合微生物而不是宿主细胞。 目前，任何观察到的选择性结合都是由以下因素之间摄取速率的固有差异驱动的： 细菌和哺乳动物细胞（PS吸收在细菌中更快），这通常需要严格控制 药物-光照间隔（PS给药和随后光照之间的时间间隔）。控制不足 常常导致疗效差。多年来，这一直困扰着PD的临床应用。Lynntech-MGH团队 开创了先进的PS技术平台，具有重新定义PD极限的潜力 在体外和体内的功效。我们的团队已经获得了一项先导化合物的专利，并已提交了额外的申请。 围绕该平台技术的专利申请。在第一阶段的工作中，我们的目标是推动 AM PD领域和Lynntech的PS平台（一个明确识别的产品）的当前状态，通过耦合时间- 独立的微生物结合选择性与我们的领先PS结构，用于预防和治疗 SS.微生物选择性肽（MSP）将与我们的PS缀合，并且所得缀合物将是 在体外和体内评价它们的AM和抗LPS活性。三个具体目标将允许完成 提出的目标：1）开发一系列PS-MSP缀合物; 2）表征PS-MSP缀合物 体外活性，和; 3）体内评价PS-MSP AM PD功效。这一努力是一个更重要的组成部分， 预算论证中所述的综合技术开发计划。

PROJECT SUMMARY This proposal is in response to the NIAID Advanced Technology SBIR (PA-10-123) Funding Opportunity. This Phase I feasibility study is an advanced technology project with a clearly identified product that will result in a clinically relevant topical AM treatment modality. The award period and amount requested are guided by project needs and are in compliance with the issued guidelines. Every year, 57 million outpatient surgeries take place in the US, and among these, surgical site infections (SSIs) are the most common nosocomial infection. Studies show that as many as 55% of cases of SSI are preventable and that a reduction in SSI cases can contribute to saving ~4,431 lives and ~$1.6 billion in healthcare costs, annually. Various measures have been implemented however, prevention and treatment of SSI remains a major challenge due to emerging multi-drug resistance. Given the advantages of topical AM therapy in particular (lower costs, reduced potential for systemic toxicity, etc), there is a continuing need for enhancement of a clinically useful arsenal of topical AM therapies. One such therapy is Photodynamic Disinfection (PD). In a typical treatment, a non-toxic agent (the Photosensitizer or PS) is applied to the target wound. Upon illumination, the PS produces toxic reactive oxygen species (ROS) which effect microbial cell inactivation. Additionally, PD has been effective in reducing the potency of two important bacteria virulence factors (lipopolysaccharide and bacterial proteases). However, although results from in vitro testing do not suggest the need for any additional PS function, results from in vivo testing suggest the need for added selective PS binding to microbes over host cells for effective treatment. Currently, any observed selective binding is driven by an inherent difference in the uptake rates between bacteria and mammalian cells (PS uptake is faster in bacteria) which typically requires tight control over the drug-light interval (time lapse between PS administration and subsequent illumination). Inadequate control often results in poor efficacy. This has plagued the clinical utility of PD for years. The Lynntech-MGH team has pioneered an advanced PS technology platform with demonstrated potential to redefine the limits of PD efficacy, in vitro and in vivo. Our team has obtained a patent on a lead compound and has filed additional patent applications surrounding this platform technology. In this Phase I effort, our objective is to advance the field of AM PD and the current state of Lynntech'sPS platform (a clearly identified product) by coupling time- independent microbe binding selectivity with our lead PS structures for use in the prevention and treatment of SS. Microbe-selective peptides (MSP) will be conjugated with our PS, and the resulting conjugates will be evaluated for their AM and anti-LPS activity in vitro and in vivo. Three specific aims will permit the completion of the proposed objective: 1) Develop a series of PS-MSP conjugates; 2) Characterize PS-MSP conjugate activity in vitro, and; 3) Evaluate PS-MSP AM PD efficacy in vivo. This effort is an integral part of a more comprehensive Technology Development Plan that is described in the Budget Justification.