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）。父母赠款的摘要 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 靶向致癌长的非编码RNA（LNCRNA）作为一种新的治疗转移性和耐药性的疗法 三重阴性乳腺癌（TNBC）。转移和耐药性是高死亡率的主要原因 全球诊断出患有TNBC的妇女。尽管已经开发了有针对性的疗法来治疗一些 乳腺癌的亚型，TN亚型尤其对这些疗法难治性。致癌性lncrnas播放 通过同时通过肿瘤发生，干性，侵袭，转移和耐药性的关键作用 操纵多个与癌症相关的信号通路。因此，lncrnas是有前途的新型治疗 TNBC的目标。我们将开发智能双重靶向脂质生态/siRNA纳米颗粒来调节表达 与癌症EMT，Stemness，转移和耐药性相关的已鉴定的lncRNA作为一种新颖 TNBC的治疗。这种致癌性lncRNA在TNBC肿瘤中高度表达，但在正常组织中不表达 这种智能纳米粒子疗法是一种有效治疗TNBC的高度可行且有希望的方法 健康组织中的任何不良反应。我们已经证明了沉默的致癌lncrna的可行性 用于抑制TNBC细胞的存活和攻击性并完全抑制肿瘤增殖 在TNBC鼠标模型中。在这个项目中，我们将优化和开发智能的生态/siRNA纳米颗粒 改善治疗性siRNA的肿瘤特异性胞质递送，并有效地静音癌症 lncRNA治疗TNBC。我们还将探索与智能的沉默lncrna的联合疗法 纳米颗粒和化学疗法具有抑制转移的协同作用，减轻了多药 耐药性，并增强化学疗法以实现治疗结果并最终消除TNBC。这 该项目的具体目的是1）设计和优化智能双目标的生态/siRNA纳米颗粒 通过全身给药中癌细胞中有效而特定的基因沉默； 2）确定 用智能双重靶向生态/siRNA纳米颗粒在侵入性和 TNBC细胞在体外的抗药性； 3）确定智能双重靶向Eco/siRNA的功效 单独使用纳米颗粒，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命 转移性和耐药性乳腺癌。