The development of novel bioanalytical pipelines for the evaluation of Karyopherin silencing drug delivery systems

用于评估核传递蛋白沉默药物输送系统的新型生物分析管道的开发

• 批准号: 2744957
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2744957
• 关键词: development; novel; bioanalytical; pipelines; evaluation

OverviewCancer is associated with aberrant receptor signalling and cellular trafficking pathways to promote survival and growth of tumours. Karyopherin dysregulation, including aberrant overexpression contributes to resistance to chemotherapy and poor cancer prognosis. Recently, we used bioinformatics analysis from existing breast cancer clinical datasets to show that alterations in Karyopherin alpha-2 (KPNA2) expression can result in poor prognostic outcomes for patients with breast cancer across multiple breast cancer sub-phenotypes. Moreover, our recent in vitro analyses in a panel of triple-negative breast cancer cell lines indicate that KPNA2 plays a significant role in cellular metabolism and DNA repair ability, the targeting of which can be exploited to achieve cancer cell death. This project will consider the design of lipid nanoparticle based systems targeting karyopherins, and study their bioanalytical properties. The cellular interactions and uptake of these delivery systems will be considered in vitro.Aims and ObjectivesThis project aims to design new drug delivery systems based on gene editing that will disrupt karyopherin activity. These delivery systems and the process used for their design will be explored as a novel cancer treatment strategy for breast cancer. To deliver on this project aim, the objectives will include the (i) design and manufacture of new prototype particles, (ii) their comprehensive bioanalytical evaluation, and (iii) evaluation of their biological activity. We will examine manufacture process parameters and their impact on nanoparticle physicochemical properties and their cellular fate. Developing a deeper understanding of manufacture process parameters and impact on product performance is key to improving the clinical and commercial translation of new drug delivery technologies.

癌症与异常受体信号和细胞运输途径相关，以促进肿瘤的生存和生长。核丝蛋白失调，包括异常过表达，是导致化疗耐药和癌症预后不良的原因之一。最近，我们利用现有乳腺癌临床数据集的生物信息学分析表明，核丝蛋白α -2 （KPNA2）表达的改变可能导致多种乳腺癌亚表型的乳腺癌患者预后不良。此外，我们最近对一组三阴性乳腺癌细胞系进行的体外分析表明，KPNA2在细胞代谢和DNA修复能力中起着重要作用，可以利用其靶向来实现癌细胞死亡。本项目将考虑设计基于脂质纳米颗粒的靶向核细胞蛋白系统，并研究其生物分析特性。细胞的相互作用和摄取这些递送系统将考虑在体外。目的和目标该项目旨在设计基于基因编辑的新型药物传递系统，该系统将破坏核细胞蛋白的活性。这些输送系统及其设计过程将作为一种新的乳腺癌治疗策略进行探索。为了实现该项目的目标，目标将包括(i)设计和制造新的原型颗粒，（ii）对其进行全面的生物分析评估，以及（iii）对其生物活性进行评估。我们将研究制造工艺参数及其对纳米粒子物理化学性质和细胞命运的影响。深入了解生产工艺参数及其对产品性能的影响是改善新药物输送技术临床和商业转化的关键。