Multifunctional siRNA/antibody nanocarriers to treat metastatic triple-negative breast cancer

多功能siRNA/抗体纳米载体治疗转移性三阴性乳腺癌

• 批准号: 10414778
• 负责人: Emily S Day
• 金额: $ 34.23万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-07 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414778
• 关键词: 4T1; ANXA5 gene; Address; Adverse effects; Animals; Antibodies; Apoptosis; BALB/cJ Mouse; Behavior; Binding; Binding Sites; Biological; Biological Assay; Blood Chemical Analysis; Bone Tissue; Breast Cancer Cell; Breast cancer metastasis; Cancer Biology; Cell Nucleus; Cell Proliferation; Cell Survival; Cell surface; Cells; Clinical; Cyclin D1; Data; Development; Disease; Distant; Fatty acid glycerol esters; Future; Gene Expression; Genes; Gold; Growth; Histologic; Histology; Histopathology; Human; Immunocompetent; In Vitro; Individual; Intravenous; Knowledge; Ligand Binding; Ligands; Luciferases; Lung; MDA MB 231; Malignant Neoplasms; Mammary Gland Parenchyma; Measures; Mediator of activation protein; Metabolic; Metastatic Neoplasm to the Lung; Modeling; Molecular; Monitor; Mus; Neoplasm Metastasis; Normal Cell; Nude Mice; Organ; Outcome; Patients; Penetration; Play; Positioning Attribute; Primary Neoplasm; Propidium Diiodide; Quality of life; Quantitative Reverse Transcriptase PCR; RNA Interference; Regulator Genes; Research; Role; Safety; Saline; Small Interfering RNA; Snails; Stains; Structure of parenchyma of lung; Supporting Cell; Survival Rate; Tail; Testing; Veins; WNT Signaling Pathway; Weight; Western Blotting; Work; base; beta catenin; bioluminescence imaging; bone cell; c-myc Genes; cancer subtypes; cell behavior; combat; cytotoxicity; driving force; effective therapy; hormone therapy; improved; innovation; insight; lung metastatic; malignant breast neoplasm; mammary; migration; mouse model; nanocarrier; nanomedicine; nanoparticle; nanoparticle delivery; nanoshell; new technology; overexpression; prevent; receptor; slug; stem; stemness; survivin; targeted treatment; tool; triple-negative invasive breast carcinoma; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT Triple-negative breast cancer (TNBC) is an aggressive disease that grows quickly and metastasizes early. There are no effective therapies for metastatic TNBC, so new strategies are needed. We will meet this need using nanoparticles (NPs) we developed that interfere with Wnt signaling, the key driving force behind TNBC growth and metastasis. The main effector of Wnt signaling is β-catenin, and it is activated in TNBC cells when wnt ligands bind frizzled7 (FZD7) receptors that are overexpressed on TNBC cells relative to normal cells. Active β-catenin promotes TNBC growth and metastasis by amplifying the expression of genes that support cell survival, proliferation, stem-like behavior, migration, and invasion. Our central hypothesis is that suppressing Wnt signaling at two levels will reduce TNBC cells’ metastatic potential, so we have created Wnt inhibitory NPs coated with both FZD7 antibodies and β-catenin small interfering RNAs (siRNAs) to accomplish this task. The FZD7 antibodies enable TNBC cell binding and prevent Wnt signaling from being activated by blocking wnt ligands from binding FZD7. The siRNAs further suppress Wnt signaling by directly inhibiting β- catenin through RNA interference. Our preliminary studies indicate that these NPs can enter existing TNBC lung metastases in mouse models to inhibit their growth. In the proposed work we will elucidate the mechanism of action of these NPs in greater detail by studying their interaction with TNBC cells in vitro (Aim 1), validate that they can penetrate existing metastases in mice to halt their growth (Aim 2), and show that they can safely prevent the formation of new metastases in immune competent tumor-bearing mice (Aim 3). All aims will compare NPs that co-deliver FZD7 antibodies and β-catenin siRNAs to NPs that deliver either agent individually in order to reveal if their combined effects are additive or synergistic. In addition to studying the NPs’ impact on TNBC cells, we will also evaluate their effect on non-cancerous cells from breast, lung, and bone tissue in order to confirm they have negligible off-target effects. We will further study their safety in Aim 3 by monitoring animal weight, blood chemistry, and major organ histopathology. We expect to find that these NPs can inhibit Wnt signaling in TNBC cells to reduce their metastatic potential without impacting non- cancerous cells, enabling them to be used as tools to either treat existing metastases or prevent formation of new metastases. We also expect for NPs that co-deliver FZD7 antibodies and β-catenin siRNAs to be more effective than NPs that deliver either agent individually. In summary, this project will evaluate Wnt inhibitory NPs as tools to treat and/or prevent TNBC metastasis. Unlike current therapies, which have unpredictable and insufficient results, our NPs will directly target TNBC cells and reduce their ability to grow and metastasize by suppressing Wnt signaling. If successful, this therapy will improve survival and quality of life for patients with metastatic TNBC, and it may ultimately be expanded to other cancers with different molecular drivers by altering the antibodies and siRNAs that are delivered with the NPs.

项目摘要/摘要 三阴性乳腺癌（TNBC）是一种侵略性疾病，可快速生长并早日转移。 没有用于转移性TNBC的有效疗法，因此需要新的策略。我们将满足这种需求 使用纳米颗粒（NP），我们开发了对Wnt信号的干扰，这是TNBC背后的关键驱动力 生长和转移。 Wnt信号的主要效应子是β-catenin，当它在TNBC细胞中被激活 Wnt配体结合了毛躁7（FZD7）受体，这些受体相对于正常细胞在TNBC细胞上过表达。 活性β-catenin通过扩增支持的基因表达来促进TNBC的生长和转移 细胞存活，增殖，茎状行为，迁移和侵袭。我们的中心假设是 抑制两个级别的Wnt信号传导将降低TNBC细胞的转移性潜力，因此我们创建了Wnt 用FZD7抗体和β-catenin小干扰RNA（siRNA）涂有抑制性NP 这个任务。 FZD7抗体使TNBC细胞结合并防止Wnt信号传导被激活 阻止Wnt配体结合FZD7。 siRNA通过直接抑制β-进一步抑制Wnt信号传导 Catenin通过RNA干扰。我们的初步研究表明，这些NP可以进入现有的TNBC 小鼠模型中的肺转移抑制其生长。在拟议的工作中，我们将阐明 这些NP的作用机理通过研究其与TNBC细胞的相互作用在体外进行了更详细的详细范围（AIM 1），验证他们可以穿透小鼠现有转移以停止其生长（AIM 2），并证明他们 可以安全地防止在免疫能力肿瘤小鼠中形成新的转移（AIM 3）。全部 AIMS将比较NPS与输送任何一种药物的NPS共同使用FZD7抗体和β-catenin siRNA 单独揭示其组合效应是添加剂还是协同作用。除了研究 NPS对TNBC细胞的影响，我们还将评估它们对乳腺癌，肺和乳腺癌细胞的影响 骨组织以确认它们具有可忽略的脱靶作用。我们将进一步研究他们的AIM 3 通过监测动物体重，血液化学和主要器官组织病理学。我们希望找到这些 NP可以抑制TNBC细胞中的Wnt信号传导，以降低其转移潜力而不会影响非 - 癌细胞，使它们可以用作治疗现有转移或防止形成的工具 新转移。我们还期望将fzd7抗体和β-catenin siRNA共同使用的NP会更 比单独交付任何一个代理的NP生效。总而言之，该项目将评估Wnt抑制作用 NP作为治疗和/或预防TNBC转移的工具。与目前的疗法不同，这些疗法无法预测和 结果不足，我们的NP将直接靶向TNBC细胞，并降低其生长和转移的能力 抑制Wnt信号传导。如果成功，这种疗法将改善患者的生存和生活质量 转移性TNBC，它最终可以通过不同的分子驱动器扩展到其他癌症 改变用NPS传递的抗体和siRNA。