Engineered imaging nanoparticles for real-time detection of cancer in the tumor b

描述（由申请人提供）：本申请的总体目标是评估新的显像剂(1)在小鼠原发性结肠癌和肺癌手术中实时检测肿瘤床残留肿瘤，以消除或显著减少重复手术和局部复发的需要，(2)指导犬自然发生的癌症患者切除手术。在一项初步研究中，我们还将测试我们的成像技术，以改善常规结肠镜检查时病变的检测。在手术过程中未能切除癌细胞是局部肿瘤复发和随后再手术的主要危险因素。由于阳性切缘而进行二次手术的比率在10-50%之间，这取决于癌症的类型、分级和解剖部位。在结肠癌筛查中，许多小病变在发展为恶性肿瘤后才被发现。此外，即使对于较大的癌，使用白光的结肠镜检查也无法在22%的情况下识别出这些肿瘤。因此，在每年有超过200万人接受癌症手术的情况下，一项能够评估手术中肿瘤细胞是否被充分移除或能够更高效地识别结肠病变的技术将对全球癌症治疗产生重大影响。在SBIR一期工作中，Lumicell通过使用我们新颖的数学模型来预测其跨物种性能，开发了几种显像剂。目标是开发高性能、低成本的显像剂，以满足结肠癌筛查和最终皮肤癌手术的需要。这些显像剂是基于我们用于肉瘤和乳腺癌适应症的主要候选药物LUM015的设计，LUM015已被FDA批准与我们在杜克大学医学中心的临床合作者开始首次人体临床试验。基于对LUM015的改进，新的显像剂的制造成本降低了66%，收率提高了。在我们的乳腺癌基线小鼠模型中进行测试后，这些新药证明了与LUM015相同或更好的性能。低成本的显像剂是我们进入几个新目标市场的必要条件，也将是我们为其他市场提供的额外产品。对于第二阶段，我们在目标1和2中建议与杜克大学和马萨诸塞州总医院的合作者一起评估这些显像剂在最先进的肺癌和结肠癌基因工程小鼠模型中的性能。在目标3中，我们将根据目标1和目标2的结果，将选定的主要候选药物推进到在卡罗来纳州杜克/兽医专科医院和塔夫茨大学卡明斯兽医学院进行的兽医临床试验中。患有任何类型癌症的犬患者将被招募来评估主要候选药物在自然发生癌症中的表现。目标4的重点是达到该提案的终点：提交IND以支持使用我们新的主要候选药物进行结肠癌和肺癌手术和结肠癌筛查的I期临床试验。

DESCRIPTION (provided by applicant): The overall goal of this application is to evaluate new imaging agents for (1) real-time detection of residual cancer in the tumor bed during surgery in primary colon and lung cancers in mice to eliminate or significantly reduce the need for repeat surgeries and local recurrence, and (2) guiding resection surgeries in canine patients with naturally occurring cancer. In a pilot study, we will also test our imaging technology to improve the detection of lesions during routine colonoscopy examination. Failure to remove cancer cells during surgery is a leading risk factor for local tumor recurrence and subsequent reoperation. Rates of secondary surgeries because of positive margins range between 10-50% depending on cancer type, grade and anatomical site. For colon cancer screening, many small lesions go undetected that are only found after progressing into malignant carcinomas. Furthermore, even for larger carcinomas, colonoscopy using white light will not identify these 22% of the time. Thus, a technology that can assess whether tumor cells have been adequately removed during surgery or can identify colon lesions with higher efficiency will have a major impact on cancer therapy worldwide as more than two million people undergo cancer surgery every year. During the SBIR Phase I work, Lumicell developed several imaging agents by using our novel mathematical model to predict their performance across species. The goal was to develop high-performance, lower cost imaging agents to satisfy the needs for colon cancer screening and eventually skin cancer surgeries. These imaging agents are based upon the design of our lead candidate for sarcoma and breast cancer indications, LUM015, which has been approved by the FDA to start first-in-human clinical trials with our clinical collaborators at Duke University Medical Center. Based upon modifications to LUM015, the new imaging agents cost about 66% less to manufacture with improved yields. After testing them in our baseline mouse model for breast cancer, these new agents proved equal or better performance than LUM015. A lower cost imaging agent is mandatory for entry into several of our new target markets and will be an additional offering for the other markets. For Phase II, we propose in Aims 1 and 2 to evaluate the performance of these imaging agents in state-of-the-art genetically engineered mouse models for lung cancer and colon cancer with our collaborators at Duke University and Massachusetts General Hospital. In Aim 3, we will move forward with the selected lead candidate (based upon results from Aims 1 and 2) into a veterinary clinical trial conducted at Duke/Veterinary Specialty Hospital of the Carolinas and Tufts University Cummings School of Veterinary Medicine. Canine patients suffering from any type of cancer will be recruited to evaluate the performance of the lead candidate in naturally occurring cancers. Aim 4 is focused on reaching the endpoint of this proposal: submit an IND to support a Phase I clinical trial for colon and lung cancer surgeries and colon cancer screening using our new lead candidate.