Bioluminecence-activated photodynamic therapy of breast cancer

 描述：这项拟议研究的长期目标是降低乳腺癌治疗的复发率和提高存活率。在早期乳腺癌中，手术可以切除原发肿瘤，但在未被发现的情况下，残留的癌细胞会发展成威胁生命的复发。这项拟议的研究将开发和测试新的光动力疗法(PDT)，以杀灭肿瘤边缘和区域淋巴结中的癌细胞，同时对正常组织和淋巴系统造成最小的损害(高治疗指数)。传统的PDT使用光敏剂作为药物，当被光激活时，会产生自由基，对细胞造成损害。有了这个独特的机制，光动力疗法可以成为一种有效的方式来杀死化疗耐药细胞和TNBC亚型。然而，目前的光动力疗法并不是乳腺癌治疗的可行选择，因为光在组织中的穿透性有限，使其在超过几毫米的深度无法发挥作用。该项目探索了这一问题的创新解决方案，其中局部注射到组织中的分子的生物发光(BL)使PDT能够在外部光线无法到达的深层区域进行。这项名为BL-PDT的技术将在最先进的小鼠模型中进行开发和评估，包括患者来源的异种小鼠模型和基因诱导的乳腺癌自发模型，以及各种体外异种乳腺癌细胞系。具体目标有三个：(1)开发和测试用于治疗转移性乳腺癌的荧光素酶-光敏剂结合物。无毒的有机试剂将被开发和测试。(2)建立乳腺癌靶向BL-PDT的最佳治疗指标。(3)开发和验证BL-PDT辅助治疗乳腺和淋巴结残留病变，以降低复发和提高存活率。该项目预计将证明BL-PDT作为一种新颖、有效、微创的辅助疗法的临床前可行性，并将增加现有的抗击乳腺癌的工具库。该项目的长期影响很高，因为它可以减少复发和改善预后。除浸润性乳腺癌外，BL-PDT有望应用于导管原位癌和其他类型的复发癌。BL-PDT消除了目前PDT所需的近红外线试剂的限制。此外，BL能量的生化激活可能会对光化学疗法以外的光医学产生深远的影响。

 DESCRIPTION: The long-term goal of this proposed research is to lower recurrence and improve survival in breast cancer treatment. In early breast cancer, surgery can remove primary tumors, but undetected, residual cancer cells develop into life-threatening recurrence. The proposed research will develop and test novel photodynamic therapy (PDT) for killing cancer cells in the tumor margin and regional lymph nodes with minimal damage to normal tissues and the lymphatic system (high therapeutic index). Conventional PDT uses photosensitizers as drug that, when activated by light, produce free radicals, causing damages to cells. With this unique mechanism, PDT can be an effective modality to kill chemo-resistant cells and TNBC subtypes. However, current PDT is not a viable option for breast cancer treatment because the limited penetration of light in tissue prevents it from being effective at depths beyond several millimeters. This project explores an innovative solution to this problem in which bioluminescence (BL) of molecules locally injected into the tissue enables PDT at deep regions that are not accessible by external light illumination. This technique termed BL-PDT will be developed and valuated in state-of-the-art murine models, including patient-derived xenograft murine models and genetically induced spontaneous models of breast cancer, as well as various heterogeneous breast cancer cell lines in vitro. There are three specific aims: (1) Develop and test luciferase-photosensitizer conjugates for treating metastatic breast cancer. Non-toxic organic agents will be developed and tested. (2) Establish optimal therapeutic index for targeted BL-PDT for breast cancer. (3) Develop and validate adjuvant BL-PDT to treat residual disease in the breast and LNs to lower recurrence and increase survival. This project is expected to demonstrate the preclinical feasibility of BL-PDT as a novel, effective, minimally invasive, adjuvant therapy and will add to the existing arsenal of tools to combat breast cancer. The long-term impact of this project is high as it can reduce recurrence and improve prognosis. Besides invasive breast cancer, BL-PDT is expected to be applicable to ductal carcinoma in situ and other types of recurrent cancers. BL-PDT removes the limitations of near infrared agents necessary in PDT currently. Furthermore, biochemical activation by BL energy may have far-reaching impacts in light- based photomedicine beyond PDT.