miR-205 Nanoparticle system circumvents docetaxel resistance in prostate cancer

miR-205纳米粒子系统规避前列腺癌中的多西紫杉醇耐药性

• 批准号: 10406861
• 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
• 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/10406861
• 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; 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; Western Blotting; 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

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.

目前的SC01申请旨在开发一项计划，以提高 亚拉普博士就职于德克萨斯大学格兰德河谷分校(UTRGV)。UTRGV具有历史使命和 来自生物医学研究中代表性不足的背景的学生的培训和毕业记录。 UTRGV授予本科生和/或研究生理科学位，并获得不到 在过去的两个财政年度中，每年为NIH R01提供600万美元的支持。雅拉普博士建议实现 一种可绕过前列腺癌多西他赛耐药的微RNA纳米粒制剂。损失 肿瘤细胞中的肿瘤抑制因子miRNAs促进肿瘤的发生和发展。然而， 有效地将miRNAs输送到靶肿瘤组织是miRNA治疗向 诊所。目前交付miRNAs的方法不仅引入了与基于病毒的 携带者还具有全身毒性和低治疗效果。要应对这些挑战和障碍 利用纳米颗粒介导的递送，可以保护血流中的miRNA 并在肿瘤部位蓄积，可提高治疗效率。因此，这一行动的目标是 研究是利用构建的双层磁性纳米颗粒系统在肿瘤部位释放miRNA。 这种纳米颗粒制剂可用于改善全身生物利用度、低毒性和肿瘤。 以治疗学为目标。纳米粒子疗法非常适合靶向和治疗耐药肿瘤。 (耐阉割前列腺癌，CRPC)，每年影响数千名男性。最新研究 证明miR-205缺失与前列腺癌(PrCa)进展、转移和药物有关 抵抗。MiR-205的修复诱导了促凋亡、抗增殖和表观遗传调节作用。 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 使细胞对化疗敏感，逆转耐药、EMT调节和抑制PrCa生长。 因此，这一提议的中心假设是双层磁性纳米颗粒可以增强 每粒miRNA的载量和运送到PrCa细胞的能力。这项研究旨在1)勾勒出 开发miR-205纳米颗粒配方，实现其物理化学和生物命运， MiRNA体外摄取、细胞间蓄积的机制研究，以及2)体内研究 纳米粒子中miR-205(MRI)的示踪和生物分布；3)检测靶基因 4)确定多西紫杉醇在耐药PrCa细胞中的化疗增敏潜力 以及相关的原位小鼠模型。临床结果使我们开发出一种独特的microRNA 纳米平台，可以有效地抑制与耐药性有关的致癌途径。 此外，这一奖项使雅拉普博士能够改进和获得高质量/高数量的初步数据 和出版物能够成功地获得非得分的研究支持。