miR-205 Nanoparticle system circumvents docetaxel resistance in prostate cancer

miR-205纳米颗粒系统规避前列腺癌中的多西紫杉醇耐药性

基本信息

批准号：
10088291
负责人：
Murali Mohan Yallapu
金额：
$ 36.33万
依托单位：
UNIVERSITY OF TEXAS RIO GRANDE VALLEY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-18 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10088291
关键词：
Address Affect Antigen Targeting Apoptotic Award Biodistribution Biological Biological Assay Biological Availability Biomedical Research Blood Cell Survival Cells Characteristics Chemoresistance Chemosensitization Clinic Clinical Clinical Oncology Complex Data Development Down-Regulation Drug resistance Environment Epigenetic Process Epithelial FDA approved FOLH1 gene Flow Cytometry Fluorescence Formulation Gel Genes Growth Human Immunoblotting Immunology In Vitro Investigation Link Literature Magnetic Resonance Imaging Magnetic nanoparticles Magnetism Malignant Neoplasms Malignant neoplasm of prostate Mediating Methods MicroRNAs Microbiology Mission Molecular Neoplasm Metastasis Normal tissue morphology Oncogenes Oncogenic Outcome Particle Size Pathway interactions Productivity Prostate Publications Recurrence Regulation Replacement Therapy Research Research Activity Research Support Resistance Risk Role Safety Science Shapes Signal Pathway Site Stream Surface System Texas Therapeutic Time Tissues Toxic effect Training Treatment Efficacy Tumor Suppressor Proteins Tumor Tissue United States National Institutes of Health Universities Virus Work Xenograft procedure anticancer research base beta Tubulin biomaterial compatibility cancer cell castration resistant prostate cancer chemotherapy contrast enhanced cost effective cost efficient docetaxel efficacy evaluation epithelial to mesenchymal transition graduate student improved in vivo malignant breast neoplasm medical schools men mid-career faculty mouse model nanoparticle nanotechnology platform neoplastic cell neovasculature novel particle patient derived xenograft model preclinical study programs prostate cancer cell prostate cancer cell line prostate cancer progression resistance mechanism restoration systemic toxicity targeted treatment theranostics therapeutic miRNA therapy outcome tumor tumorigenesis undergraduate student uptake zeta potential

项目摘要

The current SC01 application is aimed to develop a program that increase the research competitiveness of Dr. Yallapu at the University of Texas Rio Grande Valley (UTRGV). The UTRGV has historical mission and track record of training and graduating students from backgrounds underrepresented in biomedical research. The UTRGV awards science degrees to undergraduate and/or graduate students and have received less than 6 million dollars per year of NIH R01 support in each of the last 2 fiscal years. Dr. Yallapu proposed to achieve a microRNA Nanoparticle formulation which can circumvent docetaxel resistance in prostate cancer. Loss of tumor suppressor miRNAs in cancer cells promotes cancer tumorigenesis and progression. However, the efficient delivery of miRNAs to target tumor tissues is a major challenge in the transition of miRNA therapy to the clinic. The current approaches to deliver miRNAs not only introduce the risk, associated with virus-based carriers but also systemic toxicity and low therapeutic outcome. To address these challenges and barriers use of nanoparticle mediated delivery is implemented which can offer protection to miRNA in the blood stream and accumulation at the tumor site which can enhance efficiency of therapy. Thus, the objective of this study is to employ dual layer magnetic nanoparticle system that is constructed to release miRNA at tumor site. This nanoparticle formulation can be applied for improved systemic bioavailability, low toxicity, and tumor targeting of therapeutics. The nanoparticle therapies are highly suitable to target and treat resistant tumors (castration resistant prostate cancer, CRPC) that affects thousands of men each year. Recent studies demonstrate miR-205 loss is correlated with prostate cancer (PrCa) progression, metastasis, and drug resistance. Restoration of miR-205 induces pro-apoptotic, anti-proliferative, and epigenetic modulator roles. Literature and our preliminary data suggest re-expression of miR-205 in PrCa cells/tumors result in sensitizing cells to chemotherapy, reverses drug resistance, EMT regulation, and suppression of PrCa growth. Therefore, the central hypothesis of this proposal is that dual layered magnetic nanoparticles can enhance the loading capacity of miRNA per particle and delivery to PrCa cells. This study aims to 1) delineate development of miR-205 nanoparticle formulation, performing its physico-chemical and biological fate, mechanistic investigations of in vitro uptake, intercellular accumulation of the miRNA, and 2) study in vivo tracking and biodistribution miR-205 (MRI) that are in nanoparticles, and 3) examination target gene modulation, and 4) determine improved chemosensitization potential for docetaxel in drug resistant PrCa cells and relevant orthotopic mouse models. The clinical outcome led us to develop a unique microRNA nanoplatform, which can be efficient in inhibiting oncogenic pathways that are linked to drug resistance. Additionally, this award enables Dr. Yallapu to improve and obtain high quality/quantity of preliminary data and publications to be able to succeed in acquiring non-SCORE research support.

当前的SC01应用程序旨在制定一项计划，以提高研究的竞争力德克萨斯大学里奥格兰德山谷（UTRGV）的Yallapu博士。 UTRGV具有历史使命，来自生物医学研究的培训和毕业生的培训和毕业生的记录。 UTRGV授予本科和/或研究生的科学学位，并获得了低于在过去的两个财政年度中，每年每年600万美元的NIH R01支持。 Yallapu博士提议实现 microRNA纳米颗粒制剂，可以规避前列腺癌中多西他赛的耐药性。损失癌细胞中的肿瘤抑制miRNA促进癌症肿瘤发生和进展。但是，有效递送miRNA向靶向肿瘤组织是miRNA治疗过渡到的主要挑战诊所。当前提供miRNA的方法不仅引入了与基于病毒有关的风险携带者，也是系统性的毒性和低治疗结果。解决这些挑战和障碍实施了纳米颗粒介导的递送的使用，可以为血流中的miRNA提供保护并在肿瘤部位积累，这可以提高治疗效率。因此，这个目的研究是采用构建的双层磁性纳米颗粒系统，以在肿瘤部位释放miRNA。该纳米颗粒配方可用于改善全身生物利用度，低毒性和肿瘤靶向治疗学。纳米颗粒疗法非常适合靶向和治疗抗性肿瘤（抑制前列腺癌，CRPC）每年影响数千名男性。最近的研究证明miR-205损失与前列腺癌（PRCA）进展，转移和药物相关反抗。 miR-205的恢复诱导促凋亡，抗增殖和表观遗传调节剂的作用。文献和我们的初步数据表明MiR-205在PRCA细胞/肿瘤中的重新表达导致将细胞对化学疗法敏感，逆转耐药性，EMT调节和PRCA生长的抑制。因此，该提议的中心假设是双层磁性纳米颗粒可以增强 miRNA每个粒子的负载能力和向PRCA细胞递送。这项研究的目的是1）描述 MiR-205纳米颗粒制剂的开发，进行物理化学和生物命运，体外摄取，miRNA的细胞间积累和2）研究体内的机械研究在纳米颗粒中的跟踪和生物分布miR-205（MRI）和3）检查靶基因调节和4）确定耐药性PRCA细胞中多西他赛的化学敏化潜力的提高和相关的原位小鼠模型。临床结果使我们开发了独特的microRNA 纳米植物可以有效地抑制与耐药性有关的致癌途径。此外，该奖项使Yallapu博士能够改善并获得高质量/数量的初步数据和出版物，能够成功获得非分数研究支持。