Copper-depleting nanotheranostics for treating triple negative breast cancer

用于治疗三阴性乳腺癌的铜消耗纳米治疗剂

基本信息

批准号：
10231101
负责人：
Jianghong Rao
金额：
$ 53.56万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231101
关键词：
Adjuvant Affinity Binding Biochemical Reaction Biological Markers Blood Circulation Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Cancerous Cause of Death Cells Ceruloplasmin Chelating Agents Cisplatin Complex Copper Copper Chelation Disease Distant Dose Drug Kinetics Enzymes Goals Grant Growth Hepatotoxicity In Vitro Intervention Ions Malignant Neoplasms Measurement Metalloproteins Metals Methods Modeling Molecular Chaperones Monitor Nanostructures Nanotechnology Neoplasm Metastasis Oncogenes Optics Organ Outcome Patient Self-Report Pharmaceutical Preparations Play Polymers Porifera Primary Neoplasm Proteins Reporter Research Resistance Risk Role Serum Site Specificity Structure System Therapeutic Time Tissues Toxic effect Treatment Efficacy Tumor Tissue White Blood Cell Count procedure Woman Work angiogenesis anti-cancer base cancer cell cancer prevention cancer type clinically relevant cytotoxicity design improved in vivo innovation insight invention malignant breast neoplasm nanoparticle nanotechnology platform nanotheranostics novel programs research clinical testing response side effect small molecule systematic biology systemic toxicity theranostics therapy outcome tool trafficking treatment effect treatment planning triple-negative invasive breast carcinoma tumor tumor progression uptake

项目摘要

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).

抽象的乳腺癌是女性所有类型的癌症中死亡的第二名。最致命的亚型三重阴性的乳腺癌具有最高的转移风险和最差的结果目前的治疗方法。三阴性乳腺癌（TNBC）是一种本质上异质性疾病。靶向单个生物标志物或癌基通常在TNBC治疗中会产生不令人满意的治疗结果。到获得更广泛的治疗益处，我们的起点是铜离子，一种临界金属离子在广泛的生化反应中不可替代的作用。血清和癌组织中的铜过量长期以来在乳腺癌患者中得到认可。发现铜金属蛋白的失调是参与不受控制的生长，侵袭，癌细胞的传播，血管生成和继发性肿瘤在遥远的地点形成。尽管认识到很重要，但成功地试图治疗癌症铜螯合是相当有限的。该项目旨在建立一个自我报告的铜耗尽纳米板，以有效地耗尽铜 TNBC并最终抑制原发性肿瘤的进展和转移形成。此应用程序紧密与癌症纳米技术创新研究（IRCN）倡议的计划范围保持一致采用一种基于纳米技术的新型方法来了解铜在乳腺癌中的作用的目标生物学系统性地，为TNBC患者开发强大的疗法药物。我们将设计铜 - 具有高耗尽效率，低毒性和自我报告功能的纳米复合物耗尽的纳米复合物作为TNBC Theranostics（AIM 1），确定消耗铜纳米复合物的治疗效果，并确定体外的治疗机制（AIM 2），并定义耗尽铜纳米复合物的治疗功效用于原发性和转移性TNBC肿瘤模型（AIM 3）。