miR-205 Nanoparticle system circumvents docetaxel resistance in prostate cancer

目前的SC01申请旨在开发一个项目，以提高研究竞争力， 博士Yallapu在德克萨斯大学格兰德河谷（UTRGV）。UTRGV具有历史使命， 在生物医学研究中，来自背景不足的学生的培训和毕业记录。 UTRGV授予本科生和/或研究生科学学位， 在过去的两个财政年度中，每年有600万美元的NIH R01支持。Yallapu博士建议实现 一种可避免前列腺癌中多西他赛耐药性的微小RNA纳米颗粒制剂。损失 癌细胞中的肿瘤抑制miRNA促进癌症肿瘤发生和进展。但 将miRNA有效递送至靶向肿瘤组织是miRNA治疗向靶向肿瘤组织转移的主要挑战。 诊所目前递送miRNA的方法不仅引入了与基于病毒的表达相关的风险， 载体，而且还有全身毒性和低治疗效果。为了应对这些挑战和障碍， 使用纳米颗粒介导的递送，其可以对血流中的miRNA提供保护， 并在肿瘤部位积累，这可以提高治疗效率。因此，这一目标 研究是使用双层磁性纳米颗粒系统，其被构建为在肿瘤部位释放miRNA。 该纳米颗粒制剂可用于改善的全身生物利用度、低毒性和肿瘤抑制。 靶向治疗。纳米颗粒疗法非常适合靶向和治疗耐药肿瘤 （去势抵抗性前列腺癌，CRPC），每年影响成千上万的男性。最近的研究 证明miR-205丢失与前列腺癌（PrCa）进展、转移和药物治疗相关。 阻力miR-205的恢复诱导促凋亡、抗增殖和表观遗传调节剂作用。 文献和我们的初步数据表明，miR-205在PrCa细胞/肿瘤中的再表达导致了 使细胞对化疗敏感、逆转耐药性、EMT调节和抑制PrCa生长。 因此，该提议的中心假设是双层磁性纳米颗粒可以增强 每个颗粒的miRNA负载能力和递送至PrCa细胞。本研究的目的是：1）描述 开发miR-205纳米颗粒制剂，进行其物理化学和生物学命运， miRNA的体外摄取、细胞间积累的机制研究，和2）体内研究 追踪和生物分布纳米颗粒中的miR-205（MRI），和3）检查靶基因 调节，和4）确定多西他赛在耐药PrCa细胞中的改善的化学增敏潜力 以及相关的原位小鼠模型。临床结果使我们开发了一种独特的microRNA 纳米平台，其可以有效抑制与耐药性相关的致癌途径。 此外，该奖项使Yallapu博士能够改进并获得高质量/数量的初步数据 和出版物，以便能够成功地获得非SCORE研究支持。

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.