Smart nanoparticles regulating oncogenic IncRNA for breast cancer therapy

智能纳米颗粒调节致癌 IncRNA 用于乳腺癌治疗

• 批准号: 10054176
• 负责人: ZHENG-RONG LU
• 金额: $ 35.78万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-12 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054176
• 关键词: Adverse effects; Affect; Animal Model; Attention; Biological Process; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer therapy; Cancer Patient; Cells; Cessation of life; Chemotherapy and/or radiation; Code; Combined Modality Therapy; Cytoplasm; Development; Diagnosis; Differentiation and Growth; Disease; Drug Sensitization; Drug resistance; ERBB2 gene; Effectiveness; Epidermal Growth Factor Receptor; Epigenetic Process; Estrogen Receptors; Evaluation; Extracellular Matrix; Formulation; Gene Expression Regulation; Gene Silencing; Genetic Transcription; Goals; Hormones; In Vitro; Injections; Lead; Life; Lipids; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic breast cancer; Multi-Drug Resistance; Neoplasm Metastasis; Normal tissue morphology; Nucleotides; Oncogenes; Oncogenic; Outcome; Patients; Phenotype; Play; Process; Progesterone Receptors; Prognosis; RNA; RNA Interference; Radiation therapy; Refractory; Regimen; Relapse; Resistance development; Role; Signal Pathway; Small Interfering RNA; Survival Rate; Therapeutic; Tissues; Transcript; Untranslated RNA; Up-Regulation; WNT Signaling Pathway; Woman; Xenograft Model; aggressive breast cancer; base; beta catenin; cancer cell; cancer drug resistance; cancer subtypes; cancer survival; chemotherapy; clinical development; colorectal cancer progression; design; effective therapy; environmental change; improved; in vivo; ineffective therapies; malignant breast neoplasm; migration; mortality; mouse model; nanoparticle; new therapeutic target; novel; novel therapeutics; overexpression; preclinical development; self assembly; siRNA delivery; side effect; standard of care; stemness; targeted treatment; therapeutic siRNA; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumorigenesis

The goal of this project is to develop smart dual-targeted lipid ECO/siRNA self-assembly nanoparticles to target oncogenic long non-coding RNAs (lncRNAs) as a novel therapy to treat metastatic and drug-resistant triple negative breast cancer (TNBC). Metastasis and drug resistance are the main causes for high mortality rate of women diagnosed with TNBC worldwide. Although targeted therapies have been developed to treat some subtypes of breast cancer, the TN subtype is particularly refractory to these therapies. Oncogenic lncRNAs play a critical role in tumorigenesis, stemness, invasion, metastasis, and drug resistance of cancer by simultaneously manipulating multiple cancer-associated signaling pathways. Hence, lncRNAs are promising novel therapeutic targets for TNBC. We will develop smart dual-targeted lipid ECO/siRNA nanoparticles to regulate the expression of an identified lncRNA associated with cancer EMT, stemness, metastasis, and drug resistance as a novel therapy for TNBC. This oncogenic lncRNA is highly expressed in TNBC tumors, but not in normal tissues, making this smart nanoparticle therapy a highly feasible and promising approach to effectively treating TNBC without any adverse effects in healthy tissues. We have demonstrated the feasibility of silencing the oncogenic lncRNA for suppressing the survival and aggressiveness of TNBC cells and for completely inhibiting tumor proliferation in a TNBC mouse model. In this project, we will optimize and develop the smart ECO/siRNA nanoparticles to improve tumor-specific cytosolic delivery of therapeutic siRNAs and to effectively silence the cancer-promoting lncRNA in treating TNBC. We will also explore the combination therapy of silencing lncRNA with the smart nanoparticles and chemotherapy to have the synergistic effects of inhibiting metastasis, alleviating multidrug resistance and enhancing chemotherapy to achieve curative outcomes and to eventually eradicate TNBC. The specific aims of this project are 1) to design and optimize smart dual-targeted ECO/siRNA nanoparticles for efficient and specific gene silencing in cancer cells via systemic administration; 2) to determine the effects of silencing oncogenic lncRNA with the smart dual- targeted ECO/siRNA nanoparticles on the invasiveness and drug-resistance of TNBC cells in vitro; 3) to determine the efficacy of the smart dual-targeted ECO/siRNA nanoparticles alone and in combination with chemotherapy for TNBC therapy in animal models. Our long-term goal is to develop a novel and feasible therapy based on the smart nanoparticles to treat life- threatening metastatic and drug-resistant breast cancer.

该项目的目标是开发智能的双靶向脂质eco/siRNA自组装。 靶向致癌长非编码RNA(LncRNAs)的纳米颗粒作为一种新的治疗方法 治疗转移性和耐药的三阴性乳腺癌(TNBC)。肿瘤转移与药物 耐药性是确诊为TNBC的妇女死亡率高的主要原因 全世界。尽管已经开发了靶向疗法来治疗某些亚型的 对于乳腺癌，TN亚型对这些治疗方法特别难治。致癌作用 LncRNAs在肿瘤的发生、干细胞分化、侵袭、转移和药物中起着关键作用。 通过同时操纵多个癌症相关信号来对抗癌症 小路。因此，lncRNAs有望成为治疗肿瘤的新靶点。我们会 开发智能双靶向脂类ECO/siRNA纳米粒来调控AN的表达 已发现与肿瘤EMT、干细胞、转移和耐药性相关的lncRNA为 一种治疗TNBC的新方法。这种致癌的lncRNA在TNBC肿瘤中高度表达，但 在正常组织中不存在，使这种智能纳米颗粒疗法成为一种高度可行和有前景的疗法 在健康组织中有效治疗TNBC而不产生任何不良反应的方法。我们有 证明了沉默致癌的lncRNA以抑制生存的可行性。 和侵袭性以及在TNBC中完全抑制肿瘤增殖 老鼠模型。在这个项目中，我们将优化和开发SMART ECO/siRNA 改善肿瘤特异性胞浆递送治疗性siRNA的纳米颗粒和 在治疗TNBC的过程中有效地沉默了致癌的lncRNA。我们还将探索 智能纳米粒沉默LncRNA与化疗联合治疗 具有抑制转移、缓解多药耐药和 加强化疗以取得疗效并最终根除TNBC。 本课题的具体目标是：1)设计和优化智能双靶标 ECO/siRNA纳米粒通过系统抑制肿瘤细胞基因沉默的研究 给药；2)确定用SMART DUAL-DUAL沉默致癌基因lncRNA的效果。 靶向ECO/siRNA纳米粒对人鼻咽癌细胞侵袭力和耐药性的影响 体外实验；3)单独测定智能双靶向eco/siRNA纳米粒的疗效。 并在动物模型上联合化疗进行TNBC治疗。我们的长期合作 目标是开发一种基于智能纳米颗粒的新颖而可行的疗法来治疗生命- 威胁到转移性和抗药性乳腺癌。