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: 10300425
• 负责人: ZHENG-RONG LU
• 金额: $ 35.02万
• 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/10300425
• 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.

本项目的目标是开发智能双靶向脂质ECO/siRNA自组装 纳米颗粒靶向致癌长非编码RNA（lncRNA）作为一种新的治疗， 治疗转移性和耐药性三阴性乳腺癌（TNBC）。转移与药物 耐药性是诊断为TNBC的妇女死亡率高的主要原因 国际吧尽管已经开发了靶向疗法来治疗某些亚型的 在乳腺癌中，TN亚型对这些疗法特别难治。致癌 lncRNA在肿瘤的发生、发展、侵袭、转移和药物治疗中起关键作用， 通过同时操纵多种癌症相关信号传导来抵抗癌症 途径。因此，lncRNA是TNBC有前途的新的治疗靶点。我们将 开发智能双靶向脂质ECO/siRNA纳米颗粒，以调节 已鉴定的与癌症EMT、干性、转移和耐药性相关的lncRNA， TNBC的新疗法。这种致癌lncRNA在TNBC肿瘤中高度表达，但 而不是在正常组织中，这使得这种智能纳米粒子疗法成为一种非常可行和有前途的方法。 这是一种有效治疗TNBC而对健康组织没有任何不良影响的方法。我们有 证明了沉默致癌lncRNA以抑制存活的可行性， 以及完全抑制TNBC细胞中的肿瘤增殖 小鼠模型本项目将优化和开发智能ECO/siRNA 纳米颗粒以改善治疗性siRNA的肿瘤特异性胞质递送， 在治疗TNBC中有效地沉默促癌lncRNA。我们亦会探讨 用智能纳米颗粒沉默lncRNA和化疗的联合治疗， 具有协同抑制肿瘤转移、缓解多药耐药的作用， 增强化疗以实现治愈性结果并最终根除TNBC。 本课题的具体目标是：1）设计和优化智能双靶向 ECO/siRNA纳米颗粒通过系统性途径在癌细胞中实现高效和特异性基因沉默 施用; 2）确定用smartdual-RNA沉默致癌lncRNA的效果。 靶向ECO/siRNA纳米颗粒对TNBC细胞侵袭力和耐药性的影响 体外; 3）确定单独的智能双靶向ECO/siRNA纳米颗粒的功效 以及与化学疗法组合用于动物模型中的TNBC治疗。我们的长期 我们的目标是开发一种基于智能纳米粒子的新型可行疗法来治疗生命， 威胁转移性和耐药性乳腺癌。