Enhanced Efficacy Photodynamic Disinfection

项目总结 这项提议是对NIAID先进技术SBIR(PA-10-123)资助机会的回应。 此第一阶段可行性研究是一个先进技术项目，其产品标识明确，将导致 在临床相关的局部AM治疗方式中。所要求的授权期和金额由 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，SSI的减少 病例每年可挽救约4431人的生命和约16亿美元的医疗成本。多项措施 然而，SSI的预防和治疗仍然是一个重大挑战，因为出现了 多药耐药。鉴于局部AM疗法的优势(更低的成本、更低的潜力 对于全身毒性等)，继续需要增强临床上有用的局部用药的武器库 AM治疗。光动力消毒(PD)就是这样一种疗法。在典型的治疗中，一种无毒剂 (光敏剂或PS)应用于目标伤口。在光照下，PS会产生有毒的反应 影响微生物细胞失活的氧物种(ROS)。此外，帕金森病有效地减少了 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， 尽管体外测试的结果并不表明需要任何额外的PS功能，但来自体内的结果 测试表明，为了有效的治疗，需要通过宿主细胞增加选择性的PS与微生物的结合。 目前，任何观察到的选择性结合都是由两种物质之间摄取速率的内在差异驱动的 细菌和哺乳动物细胞(细菌对PS的吸收更快)，这通常需要严格控制 药物-光间隔(PS给药和随后的照射之间的时间间隔)。控制不充分 往往会导致疗效不佳。这一问题多年来一直困扰着帕金森病的临床应用。Lynntech-MGH团队 开创了先进的PS技术平台，具有重新定义PD限制的潜力 在体外和体内的疗效。我们的团队已经获得了一种先导化合物的专利，并提交了更多 围绕这一平台技术的专利申请。在这项第一阶段的工作中，我们的目标是推动 AM PD领域和Lynntech的PS平台(一个明确标识的产品)的当前状态，通过耦合时间- 我们的铅PS结构具有独立的微生物结合选择性，用于预防和治疗 党卫军。微生物选择性多肽(MSP)将与我们的PS偶联，得到的偶联物将是 评价其在体外和体内的AM活性和抗内毒素活性。三个具体目标将使这一目标得以完成 1)合成一系列PS-MSP共轭化合物；2)表征PS-MSP共轭化合物 体外活性；3)评价PS-MSP AM PD的体内疗效。这一努力是更多 《预算理由》中所述的全面技术发展计划。

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.