Bioluminecence-activated photodynamic therapy of breast cancer

 这项研究的长期目标是降低乳腺癌治疗的复发率和提高生存率。在早期乳腺癌中，手术可以切除原发性肿瘤，但未被发现的残留癌细胞会发展成危及生命的复发。拟议的研究将开发和测试新型光动力疗法（PDT），用于杀死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的损伤最小（高治疗指数）。传统的PDT使用光敏剂作为药物，当被光激活时，产生自由基，对细胞造成损伤。通过这种独特的机制，PDT可以成为杀死化疗耐药细胞和TNBC亚型的有效方式。然而，目前的PDT并不是乳腺癌治疗的可行选择，因为光在组织中的有限穿透使其在超过几毫米的深度上无效。该项目探索了一种创新的解决方案，其中局部注射到组织中的分子的生物发光（BL）使PDT能够在外部光照明无法到达的深层区域进行。这种称为BL-PDT的技术将在最先进的小鼠模型中开发和评估，包括患者来源的异种移植小鼠模型和遗传诱导的自发性乳腺癌模型，以及各种异质性乳腺癌细胞系体外。具体目标有三个：（1）开发和测试转移性乳腺癌治疗用的转移酶-光敏剂缀合物。将开发和测试无毒有机剂。(2)建立乳腺癌靶向BL-PDT的最佳治疗指数。(3)开发并验证辅助BL-PDT治疗乳腺和淋巴结残留疾病，以降低复发率并提高生存率。该项目预计将证明BL-PDT作为一种新型，有效，微创，辅助治疗的临床前可行性，并将增加现有的工具库来对抗乳腺癌。该项目的长期影响很大，因为它可以减少复发并改善预后。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性癌症。BL-PDT消除了目前PDT中所需的近红外试剂的限制。此外，BL能量的生物化学活化可能在PDT之外的基于光的光医学中具有深远的影响。

 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.