Combined In vitro Experimental and Computational Approaches for Predicting the Identity and Behaviour of Protein Corona-Adsorbed Nanoparticles

结合体外实验和计算方法来预测蛋白质电晕吸附纳米颗粒的特性和行为

• 批准号: RGPIN-2020-05679
• 负责人: Labouta, Hagar
• 金额: $ 2.04万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762136
• 关键词: Combined; vitro; Experimental; Computational; Approaches

Despite years of excellent individual investigations, our ability to predict the behaviour of nanoparticles (NPs) in the body based on their engineered properties is still limited. The aim of this NSERC Discovery research program is to develop a global understanding of the interaction of NPs with different cellular and acellular biological barriers following surface adsorption of plasma proteins, and generate predictive models of those different interactions. There is inconsistency in relating the engineered properties of NPs injected intravenously (vast applications of NPs) to either of NP transport through the extracellular matrix (after exiting the circulation), NP cytotoxicity and cell uptake of NPs. This is partly related to the interaction of NPs with the blood plasma resulting in a corona of proteins being deposited on the NP surface. There is a limited understanding of the kinetics of NP corona formation for specific engineered NP design properties in a condition simulating the physiological environment. However, it has been shown that the kinetics of NP corona formation determines the behaviour of NPs in the body. In this research program, my team will undertake a comprehensive investigation to unravel the relationships between engineered NP design properties, kinetics of plasma protein deposition (corona formation) and subsequent transport through the extracellular matrix and cell interactions. These relationships have not been described in literature. I will guide and train my team to use a combination of in vitro experiments that mimic the dynamic physiological environment, and machine learning approaches in order to develop these relationships. My research program is divided into two research themes: mechanistic understanding of the interaction of NPs with plasma proteins, and studying the extracellular matrix and cell interactions of protein corona-adsorbed NPs using in vitro models, and modelling algorithms. These proposed scientific endeavours will generate critical new insights into the determinants of corona formation and its role in the subsequent behaviour of NPs. No previous work has demonstrated an ability to separate and accurately predict the different individual efficacy end-points of corona-adsorbed NPs using in vitro models that mimic the dynamic physiological environment. Combining this with machine learning approaches will result in validated results and observation of subtle relationships that are not obvious by traditional approaches. We will provide new knowledge that will enable engineers to develop new generations of NPs that are both effective- and safe-by-design.

尽管经过多年的个人调查，但我们根据其工程性能预测体内纳米颗粒（NP）行为的能力仍然有限。该NSERC发现研究计划的目的是在血浆蛋白的表面吸附之后对NP与不同细胞和细胞生物学屏障的相互作用进行全球了解，并产生这些不同相互作用的预测模型。 在通过细胞外基质（退出循环后），NP细胞毒性和NP的细胞吸收的NP传输的NP静脉内注射的NP（NP的广泛应用）与NP转运的NP相关性不一致。这部分与NP与血浆的相互作用有关，导致蛋白质的电晕沉积在NP表面上。在模拟生理环境的条件下，对特定工程NP设计特性的NP电晕组的动力学动力学的理解有限。但是，已经表明，NP电晕形成的动力学决定了NP在体内的行为。在该研究计划中，我的团队将进行全面的调查，以揭示工程NP设计特性，血浆蛋白沉积动力学（Corona组）（Corona形成）以及随后通过细胞外基质和细胞相互作用进行运输之间的关系。这些关系尚未在文献中描述。我将指导和培训团队使用模仿动态生理环境的体外实验的组合以及机器学习方法，以发展这些关系。我的研究计划分为两个研究主题：对NP与血浆蛋白相互作用的机械理解，并研究了使用体外模型的蛋白质电晕吸附NP的细胞外基质和细胞相互作用，以及建模算法。这些提出的科学努力将对电晕形成的决定因素及其在随后的NP的行为中的作用产生关键的新见解。以前的工作还没有表现出使用模仿动态生理环境的体外模型，可以准确地分离和准确预测电晕吸附的NP的不同个体功效终点。将其与机器学习方法相结合将导致验证的结果并观察到传统方法并不明显的微妙关系。我们将提供新的知识，使工程师能够开发出既有生效又可以安全设计的新一代NP。