Engineered imaging nanoparticle for realtime detection of cancer in the tumor bed

描述(申请人提供)：这项提案的总体目标是开发一种显像剂和检测系统，用于标记和实时检测肉瘤切除手术中肿瘤床上的残留癌症，该系统将迅速被外科医生/医院采用，因为它可以消除或显著减少二次手术和局部复发。手术中未能清除癌细胞是局部肿瘤复发和随后再次手术的主要风险因素。对于35%的肉瘤患者，在冰冻切片的支持下进行保肢手术，只分析了切除的肿瘤的一小部分，在没有辅助治疗的情况下会导致局部复发，这表明微观上的残癌已经被遗留下来。此外，在其他癌症手术中，如乳房肿块切除术，切缘阳性和二次手术的可能性超过50%。可以评估手术过程中肿瘤细胞是否被充分移除的技术可以对全球的癌症治疗产生重大影响，因为每年有200多万人接受癌症手术。这种技术可以降低局部复发率，消除二次手术和辅助放射的需要，降低相关的医疗成本。Lumicell已经开发出一种可注射的成像剂和手持成像器，可以检测到大视野的单个细胞。我们的新检测技术由麻省理工学院开发并授权给Lumicell，在小鼠肉瘤切除手术中可靠地检测到体内微小的癌细胞残留。基于小鼠和狗的测试，并使用我们对显像剂性能的计算机模拟，我们预测人类在注射后36-48小时达到峰值对比度。对于目前的癌症手术前程序来说，这一时间框架并不理想，我们希望重新设计成像试剂，以在注射后18-24小时内实现最大的肿瘤与背景信号对比度。我们建议重新设计我们的癌症激活显像剂，增强药代动力学，以快速到达肿瘤并增加血液清除率。为了达到我们认为可以达到的信号水平，我们建议在特定目标1上设计几种成像试剂，并在小鼠和狗身上表征它们的性能，然后在人类身上模拟它们的性能。在具体目标2上，我们将在注射后18-24小时内选择一到两种具有所需性能的候选显像剂，并在小鼠身上进行验证研究(手术和病理)。 公共卫生相关性：拟议的项目旨在解决癌症患者大体肿瘤切除后肿瘤床中残留癌细胞的术中评估的未满足的临床需求。通过设计一种适合于典型医院的显像剂，将开发一种新的快速、彻底的实时检查肿瘤床的方法 手术方案。这将需要Lumicell分子显像剂设计的改进，以在注射后18-24小时(当前性能为36-48小时)实现峰值激活。这项技术有可能挽救生命，防止二次手术，将患者的不适和手术风险降至最低，并大幅节省医疗成本。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop an imaging agent and detection system for labeling and real- time detection of residual cancer in the tumor bed during sarcoma resection surgery that will be quickly adopted by surgeons/hospitals because it can eliminate or significantly reduce secondary surgeries and local recurrence. Failure to remove cancer cells during surgery is a leading risk factor for local tumor recurrence and subsequent reoperation. For 35% of sarcoma patients, limb-sparing surgery supported by frozen sections, which only analyze a small fraction of the resected tumor, results in local recurrence in the absence of adjuvant therapy, indicating microscopic residual cancer has been left behind. Furthermore, in other cancer surgeries, as in breast lumpectomies, positive margins and secondary surgeries can occur more than 50% of the time. Technology that can assess whether tumor cells have been adequately removed during surgery can have major impact on cancer therapy worldwide as more than two million people undergo cancer surgery every year. Such technology can reduce rates of local recurrence and eliminate the need for secondary surgeries and adjuvant radiation, reducing associated healthcare costs. Lumicell has developed an injectable imaging agent and hand-held imager that can detect single cells with a wide field of view. Our novel detection technology, developed at MIT and licensed to Lumicell, reliably detects microscopic residual cancer cells in vivo during sarcoma resection surgeries in mice. Based upon mouse and dog tests and using our computer simulation of the imaging agent performance we forecast a peak contrast in humans at 36-48 hours from injection. This timeframe is not ideal with the current preoperative procedures for cancer surgery and we wish to re-engineer the imaging agent to achieve the maximum tumor-to-background signal contrast within 18-24 hours from injection. We propose to re-design our cancer-activatable imaging agent with enhanced pharmacokinetics to rapidly reach the tumor and to increase clearance rates from the blood. To reach the level of signal that we believe can be achieved, we propose on Specific Aim 1 to engineer several designs of imaging agents and to characterize their performance in mice and dogs, and then simulate their performance in humans. On Specific Aim 2 we will select one or two candidate imaging agents with the desired performance between 18-24 hours after injection and conduct validation studies in mice (surgery and pathology). PUBLIC HEALTH RELEVANCE: The proposed project aims to address the unmet clinical need for intraoperative assessment of residual cancer cells in the tumor bed after gross tumor resection in cancer patients. A novel method for fast and thorough examination of the tumor bed in real-time will be developed by engineering an imaging agent suitable to for the typical hospital surgical protocols. This will require the refinement of the Lumicell molecular imaging agent design to achieve peak activation in 18-24 hours (current performance is 36-48 hours) from injection. This technology has the potential to save lives, prevent secondary surgeries, minimize patient discomfort and surgical risks, and provide substantial savings in healthcare costs.