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: 10307922
• 负责人: ZHENG-RONG LU
• 金额: $ 2.37万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307922
• 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; Cells; Cessation of life; Chemotherapy and/or radiation; Code; Combined Modality Therapy; Cytoplasm; Development; Diagnosis; Differentiation and Growth; Doctor of Philosophy; Drug Sensitization; Drug resistance; ERBB2 gene; Effectiveness; Epidermal Growth Factor Receptor; Epigenetic Process; Estrogen Receptors; Evaluation; Extracellular Matrix; Gene Expression Regulation; Gene Silencing; Genetic Transcription; Goals; Human; In Vitro; Injections; Life; Lipids; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mentors; 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; Research; Resistance development; Role; Scientist; Signal Pathway; Small Interfering RNA; Survival Rate; Therapeutic; Tissues; Training; Transcript; Untranslated RNA; Up-Regulation; WNT Signaling Pathway; Woman; Xenograft Model; aggressive breast cancer; anticancer research; base; beta catenin; cancer cell; cancer drug resistance; cancer subtypes; career development; chemotherapy; 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; parent grant; self assembly; siRNA delivery; standard of care; stemness; targeted treatment; therapeutic siRNA; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumorigenesis

3.8.1 Research, mentoring and career development 1). Research Plan 1.1). Abstract of the parent grant 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.

3.8.1研究、指导和职业发展 1）。研究计划 1.1）。父母补助金摘要 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， 靶向致癌长链非编码RNA（lncRNA）作为治疗转移性和耐药性新疗法 三阴性乳腺癌（TNBC）。转移和耐药是导致高死亡率的主要原因 被诊断为TNBC的女性人数。尽管已经开发了靶向疗法来治疗一些 作为乳腺癌的一种亚型，TN亚型对这些疗法特别难治。致癌lncRNA发挥作用 在肿瘤的发生、发展、侵袭、转移和耐药性中起关键作用， 操纵多种与癌症相关的信号通路。因此，lncRNA是有希望的新型治疗药物， TNBC的目标我们将开发智能双靶向脂质ECO/siRNA纳米粒， 一种与癌症EMT、干性、转移和耐药性相关的已鉴定lncRNA， 治疗TNBC。这种致癌lncRNA在TNBC肿瘤中高度表达，但在正常组织中不表达，使得 这种智能纳米颗粒疗法是一种高度可行和有前途的有效治疗TNBC的方法， 对健康组织的任何不良影响。我们已经证明了沉默致癌lncRNA的可行性， 用于抑制TNBC细胞的存活和侵袭性以及用于完全抑制肿瘤增殖 在TNBC小鼠模型中。在本项目中，我们将优化和开发智能ECO/siRNA纳米颗粒， 改善治疗性siRNA的肿瘤特异性胞质递送，并有效地沉默促癌性siRNA， lncRNA治疗TNBC。我们还将探索沉默lncRNA与smart的联合治疗。 纳米粒与化疗药物具有协同作用，抑制肿瘤转移，缓解多药耐药， 耐药性和增强化疗以实现治愈性结果并最终根除TNBC。的 该项目的具体目标是1）设计和优化智能双靶向ECO/siRNA纳米颗粒， 通过全身给药在癌细胞中有效和特异性的基因沉默; 2）确定 用智能双靶向ECO/siRNA纳米颗粒沉默致癌lncRNA对侵袭性和 体外TNBC细胞的耐药性; 3）确定智能双靶向ECO/siRNA的功效 在动物模型中，单独的纳米颗粒和与化学疗法组合用于TNBC疗法。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，以治疗危及生命的疾病。 转移性和耐药性乳腺癌。