Copper-depleting nanotheranostics for treating triple negative breast cancer

摘要 在女性所有类型的癌症中，乳腺癌是第二大死因。最致命的亚型 由于耐药，三阴性乳腺癌的转移风险最高，预后最差。 到目前的治疗方法。三阴性乳腺癌(TNBC)是一种本质异质性疾病。 在TNBC治疗中，靶向单一生物标记物或癌基因的治疗效果往往不理想。至 要获得更广泛的治疗益处，我们的起点是铜离子，这是一种关键的金属离子 在广泛的生化反应中发挥着不可替代的作用。血清和癌组织中铜含量过高 很早就在乳腺癌患者中得到了认可。铜金属蛋白的失调被发现是 参与不受控制的生长、侵袭、癌细胞扩散、血管生成和继发性肿瘤 在遥远的地点形成队形。尽管公认的重要性，但成功的治疗癌症的尝试 铜的络合作用相当有限。 该项目旨在建立一个自我报告的铜枯竭纳米平台，以有效地在 TNBC，并最终抑制原发肿瘤进展和转移形成。这个应用程序紧密地 与癌症纳米技术创新研究(IRCN)倡议的计划范围保持一致 目标是采用一种新的基于纳米技术的方法来了解铜在乳腺癌中的作用 生物学系统，并为TNBC患者开发一种强大的治疗药物。我们将设计铜- 具有高耗竭效率、低毒和自我报告功能的耗竭纳米复合体作为TNBC Theranostics(目标1)，确定耗铜纳米络合物的治疗效果，并确定 体外治疗机制(目标2)，并确定贫铜纳米络合物的治疗效果 用于原发和转移性TNBC肿瘤模型(目标3)。

ABSTRACT Breast cancer is the number two cause of death among all types of cancers in women. The deadliest subtype of breast cancer, triple-negative, carries the highest metastatic risk and poorest outcome due to the resistance to current therapeutic methods. Triple-negative breast cancer (TNBC) is an intrinsically heterogeneous disease. Targeting single biomarker or oncogene often yields unsatisfactory therapeutic outcome in TNBC treatment. To achieve a broader therapeutic benefit, our starting point is copper ion, one critical metal ion that plays irreplaceable roles in a broad range of biochemical reactions. Copper excess in serum and cancerous tissues has been long recognized in breast cancer patients. Dysregulation of copper metalloproteins is found to be involved in uncontrolled growth, invasion, dissemination of cancer cells, angiogenesis and secondary tumor formation at distant sites. Despite the well-recognized importance, successful attempts to treat cancer with copper chelation are rather limited. This project aims to establish a self-reporting copper depletion nanoplatform to effectively deplete copper in TNBC and ultimately inhibit primary tumor progression and metastasis formation. This application is tightly aligned with the program scope of the Innovative Research in Cancer Nanotechnology (IRCN) Initiative with the goal to employ a novel nanotechnology-based approach to understand copper's role in breast cancer biology systematically and to develop a powerful theranostic drug for TNBC patients. We will design copper- depleting nanocomplex with high depleting efficiency, low toxicity and self-reporting function as TNBC theranostics (Aim 1), determine the treatment effect of copper-depleting nanocomplex and identify the therapeutic mechanism in vitro (Aim 2), and define the therapeutic efficacy of copper-depleting nanocomplex for primary and metastatic TNBC tumor models (Aim 3).