Copper-depleting nanotheranostics for treating triple negative breast cancer

摘要 乳腺癌是妇女所有类型癌症中的第二大死亡原因。最致命的亚型 三阴性乳腺癌的转移风险最高，由于耐药， 目前的治疗方法。三阴性乳腺癌（TNBC）是一种本质上异质性的疾病。 靶向单一生物标志物或癌基因通常在TNBC治疗中产生不令人满意的治疗结果。到 为了获得更广泛的治疗益处，我们的出发点是铜离子，一种关键的金属离子， 在广泛的生物化学反应中具有不可替代的作用。血清和癌组织中的铜过量 在乳腺癌患者中早已被认可。铜金属蛋白的失调被发现是 参与癌细胞的不受控制的生长、侵袭、扩散、血管生成和继发性肿瘤 在遥远的地方形成。尽管公认的重要性，成功的尝试治疗癌症与 铜螯合作用相当有限。 该项目旨在建立一个自我报告的铜消耗纳米平台，以有效地消耗铜， TNBC并最终抑制原发性肿瘤进展和转移形成。该应用程序是紧密 与癌症纳米技术创新研究计划（IRCN）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 系统地研究生物学，并为TNBC患者开发一种强大的治疗诊断药物。我们将设计铜- 具有高消耗效率、低毒性和作为TNBC的自报告功能的消耗纳米复合物 治疗诊断学（目的1），确定铜消耗纳米复合物的治疗效果，并确定 体外治疗机制（目的2），并确定铜消耗纳米复合物的治疗效果 用于原发性和转移性TNBC肿瘤模型（Aim 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).