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

基本信息

批准号：
10532735
负责人：
ZHENG-RONG LU
金额：
$ 34.98万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10532735
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

项目摘要

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双靶向脂质ECO/siRNA自组装靶向致癌长非编码RNA（lncRNA）的纳米粒子作为一种新疗法治疗转移性和耐药性三阴性乳腺癌（TNBC）。转移与药物耐药是TNBC女性高死亡率的主要原因全世界。尽管已经开发出靶向疗法来治疗某些亚型乳腺癌中，TN 亚型对这些疗法特别难治。致癌性 lncRNA在肿瘤发生、干性、侵袭、转移和药物中发挥着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 有前途的新治疗靶点。我们将开发智能双靶向脂质 ECO/siRNA 纳米颗粒来调节确定了与癌症 EMT、干性、转移和耐药性相关的 lncRNA TNBC 的一种新疗法。这种致癌 lncRNA 在 TNBC 肿瘤中高表达，但是不在正常组织中，使这种智能纳米颗粒疗法成为一种高度可行且有前途的疗法有效治疗 TNBC 且不对健康组织产生任何副作用的方法。我们有证明了沉默致癌 lncRNA 以抑制存活的可行性和 TNBC 细胞的侵袭性，并完全抑制 TNBC 中的肿瘤增殖鼠标模型。在这个项目中，我们将优化和开发智能ECO/siRNA 纳米颗粒可改善治疗性 siRNA 的肿瘤特异性胞质递送，并在治疗 TNBC 时有效沉默促癌 lncRNA。我们还将探索沉默lncRNA与智能纳米颗粒和化疗的联合疗法具有抑制转移、减轻多药耐药性的协同作用加强化疗以达到治疗效果并最终根除 TNBC。该项目的具体目标是1）设计和优化智能双目标 ECO/siRNA 纳米颗粒可通过全身系统有效且特异性地沉默癌细胞中的基因行政; 2) 确定用智能双-沉默致癌lncRNA的效果靶向ECO/siRNA纳米粒子对TNBC细胞侵袭性和耐药性的影响体外； 3) 确定智能双靶向ECO/siRNA纳米粒子单独的功效并与化疗联合用于动物模型中的 TNBC 治疗。我们的长期目标是开发一种基于智能纳米颗粒的新颖且可行的疗法来治疗生命- 威胁转移性和耐药性乳腺癌。