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

概述癌症与异常的受体信号和细胞转运途径有关，促进肿瘤的生存和生长。核黄素异常表达，包括异常过表达，会导致化疗抵抗和癌症预后不良。最近，我们使用现有乳腺癌临床数据集的生物信息学分析表明，Karyopherinα-2(KPNA2)表达的变化可以导致多种乳腺癌亚型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进行的体外分析表明，KPNA2在细胞代谢和DNA修复能力方面发挥着重要作用，其靶向可以被用来实现癌细胞死亡。本项目将考虑以核粘附素为靶点的基于脂质纳米颗粒的系统的设计，并研究其生物分析特性。这些递送系统的细胞相互作用和摄取将在体外被考虑。目的和目的本项目旨在设计基于基因编辑的新的药物递送系统，该系统将扰乱核粘附素的活性。这些输送系统和用于其设计的过程将被探索为乳腺癌的一种新的癌症治疗策略。为了实现这一项目目标，目标将包括(I)设计和制造新的原型粒子，(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颗粒物理化学性质和细胞命运的影响。深入了解制造工艺参数和对产品性能的影响，是改进新药输送技术的临床和商业转化的关键。

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.