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: 10755865
• 负责人: ZHENG-RONG LU
• 金额: $ 7.54万
• 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/10755865
• 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; Disease; Drug Sensitization; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor; Epigenetic Process; Estrogen Receptors; Evaluation; Extracellular Matrix; Formulation; Gene Expression Regulation; Gene Silencing; Genetic Transcription; Goals; Growth; Hormones; In Vitro; Injections; Invaded; 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; Proliferating; 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; beta catenin; cancer cell; cancer drug resistance; cancer subtypes; cancer survival; chemotherapy; clinical development; colorectal cancer progression; design; effective therapy; efficacy evaluation; 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 nanoparticles; 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.

该项目的目的是开发智能双重靶向脂质生态/siRNA自组装 纳米颗粒以靶向致癌长的非编码RNA（LNCRNA）作为一种新型治疗 治疗转移性和耐药的三重阴性乳腺癌（TNBC）。转移和药物 抵抗是诊断为TNBC的妇女死亡率高死亡率的主要原因 全世界。尽管已经开发了靶向疗法来治疗一些亚型 乳腺癌，TN亚型尤其对这些疗法难治性。致癌 lncRNA在肿瘤发生，干性，侵袭，转移和药物中起关键作用 通过同时操纵多个癌症相关的信号传导来抵抗癌症 途径。因此，LNCRNA是TNBC的新型治疗靶标。我们将 开发智能双靶向脂质生态/siRNA纳米颗粒以调节 鉴定出与癌症EMT，干性，转移和耐药性相关的lncRNA TNBC的新型疗法。这种致癌性lncRNA在TNBC肿瘤中高度表达，但 不在普通组织中，使这种智能的纳米颗粒疗法成为一种高度可行且有希望的 有效治疗TNBC而没有任何不利影响的方法。我们有 证明了沉默的致癌lncrna抑制生存的可行性 TNBC细胞的侵略性以及用于TNBC中肿瘤增殖的完全抑制 鼠标模型。在这个项目中，我们将优化和开发智能生态/siRNA 纳米颗粒改善治疗性siRNA的肿瘤特异性胞质递送和 有效地使促进癌症的LNCRNA在治疗TNBC中。我们还将探索 沉默lncRNA与智能纳米颗粒的结合疗法和化学疗法 具有抑制转移的协同作用，减轻多药的耐药性和 增强化学疗法以实现治疗结果并最终根除TNBC。 该项目的具体目的是1）设计和优化智能双重目标 生态/siRNA纳米颗粒，用于通过全身性癌细胞中有效和特定的基因沉默 行政; 2）确定用智能双重 - 针对TNBC细胞在侵袭性和抗药性中的靶向生态/siRNA纳米颗粒 体外3）单独确定智能双靶向生态/siRNA纳米颗粒的功效 并与动物模型中TNBC治疗的化学疗法结合使用。我们的长期 目标是基于智能纳米颗粒来开发一种新颖且可行的疗法来治疗生活 - 威胁转移性和耐药性乳腺癌。