Nanomedicine-protein interactions: Understanding protein corona composition effects on nanomedicine cellular uptake

从实验室到临床，一种新的候选药物在其开发过程中会面临多种障碍和挑战。在肿瘤药物开发中，必须在实现肿瘤生物利用度和潜在的脱靶器官毒性之间取得平衡——纳米药物已经成为克服这些挑战的一个有希望的解决方案。当静脉给药时，纳米药物将暴露于血液中的各种生物分子中。其中一些分子将吸附在纳米药物表面，形成“电晕”，改变其化学特性和生物命运。疏水纳米药物具有较短的循环半衰期，这是由于在单核吞噬系统识别后具有较高程度的调理和随后的清除。为了通过减少免疫识别清除来改善循环半衰期，利用聚乙二醇等亲水分子进行隐形已经成为纳米医学研究的一种标准方法。本研究将研究纳米粒子的物理化学特性如何影响纳米粒子表面蛋白质电晕的形成，以及蛋白质电晕的形成对纳米药物物理化学特性和细胞相互作用的后续影响。正交粒子计量技术将应用于纳米药物在血浆和细胞裂解液中蛋白冠处理前后的物理化学特性表征。迄今为止，数量有限的研究评估了蛋白质电晕形成对纳米医学物理化学特性和随后的生物命运的影响。由于PLGA纳米颗粒作为纳米载体的广泛研究、已建立的安全性、临床成熟度以及缺乏关于NP电晕表征的已发表报告，因此将作为模型进行研究。这项工作的发现与平行蛋白质组学分析相结合，为开发纳米医学生物学命运的预测模型提供了范围。该研究将是第一个考虑纳米粒子蛋白质冠在不同时间尺度上作为纳米粒子物理化学属性函数的动态和终点特征的系列研究。了解蛋白质电晕组成已被认为是解决颗粒制造过程、关键质量属性和随后的体内性能之间相互作用的关键因素。最终，纳米药物生物学命运的预测模型将在设计和构建具有可调蛋白冠谱的新型纳米药物方面创造一个阶梯式的变化，这些纳米药物可以用来改善药物的生物分布和治疗效果。

From bench to clinic, a new drug candidate will face multiple roadblocks and challenges in its development. In oncology drug development, a balance has to be met between achieving tumour bioavailability and potential off-target organ toxicity- Nanomedicines have emerged as a promising solution to overcoming such challenges. When administered intravenously, a nanomedicine will be exposed to various biomolecules in blood. Some of these molecules will adsorb onto the nanomedicine surface, forming a 'corona', altering its chemical identity and biological fate. Hydrophobic nanomedicines have a shorter circulation half-life owing to a higher degree of opsonisation and subsequent clearance following recognition by the mononuclear phagocytic system. In a bid to improve circulation half-lives through reduced immune recognition clearance, stealthing with hydrophilic molecules such as PEG has been implemented as a standard approach in nanomedicine research.This studentship will investigate how nanoparticle physicochemical characteristics impact protein corona formation on nanoparticle surfaces, and the subsequent impact of protein corona formation on nanomedicine physicochemical characteristics and cellular interactions. Orthogonal particle metrology technologies will be applied to the characterization of nanomedicine physicochemical characteristics prior to and following protein corona treatment in plasma and cellular lysate. A limited number of studies to date have evaluated the impact of protein corona formation on nanomedicine physicochemical characteristics and subsequent biological fate. PLGA nanoparticles will be investigated as a model due to their extensive investigation as nanocarriers, established safety profile, maturity in the clinic, and significant lack of published reports on NP corona characterization. Findings from this work, in combination with parallel proteomics analysis offer the scope for developing predictive models of nanomedicine biological fate. This studentship will be the first of a series considering both dynamic and endpoint characterization of nanoparticle protein corona evolution over various timescales as a function of nanoparticle physicochemical attributes. Understanding protein corona composition has been recognized as a critical factor in deconvoluting the interplay between particle manufacture processes, critical quality attributes, and subsequent in vivo performance. Ultimately, predictive models of nanomedicine biological fate will create a step-change in the design and construction of novel nanomedicines with tunable protein corona profiles that can be exploited to improve drug biodistribution and therapeutic efficacy.