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Impact of soft protein interactions on the excretion, extent of receptor occupancy and tumor accumulation of ultrasmall metal nanoparticles: a compartmental model simulation

机译：软蛋白质相互作用对超微α金属纳米颗粒的排泄，受体占用率和肿瘤积累的影响：分区模型模拟

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Ultrasmall metal nanoparticles (NPs) are next-generation nano-based platforms for in vivo disease diagnosis and treatment. Due to their small size below the kidney filtration threshold and marked resistance to nonspecific serum protein adsorption, ultrasmall NPs can be rapidly excreted through the kidneys and escape liver uptake. However, although ultrasmall particles may be deemed highly resistant to protein adsorption, the real extent of this resistance is not known. Here, a simple compartmental model simulation was therefore implemented to understand how NP behavior in vivo could be modulated by soft, transient NP-plasma protein interactions characterized by dissociation constants in the millimolar range. In Model 1, ultrasmall NPs functionalized with a targeting probe, plasma proteins and target receptors were assumed to co-exist within a single compartment. Simulations were performed to understand the synergistic effect of soft interactions, systemic clearance and NP size on receptor occupancy in the single compartment. The results revealed the existence of a narrow range of ultraweak affinities and optimal particle sizes leading to greater target occupancy. In Model 2, simulations were performed to understand the impact of soft interactions on NP accumulation into a peripheral (tumor) compartment. The results revealed that soft interactions - but not active targeting - enhanced tumor uptake levels when tumor accumulation was limited by 'fast' plasma clearance and 'slow' vascular extravasation. The simple model presented here provides a basic framework to quantitatively understand the blood and tumor pharmacokinetics of ultrasmall NPs under the influence of transient protein interactions.
机译：超大金属纳米颗粒（NPS）是用于体内疾病诊断和治疗的下一代基于纳米平台。由于它们的小尺寸低于肾脏过滤阈值和标记抗非特异性血清蛋白质吸附，可以通过肾脏快速排出超大NPS并逸出肝脏吸收。然而，虽然可以认为超超颗粒对蛋白质吸附的高度耐抗性，但是该电阻的实际程度是未知的。这里，实施了简单的隔间模型模拟，以了解通过毫米摩尔范围中的解离常数的软，瞬时NP-血浆蛋白质相互作用来调节体内的NP行为。在模型1中，假设用靶向探针，血浆蛋白和靶受体官能化的超低释放NPS在单个隔室内共存。进行模拟以了解软相互作用，全身间隙和NP大小对单个隔间中受体占用率的协同效应。结果表明，存在窄范围的超低发与粒度和最佳粒度，导致靶占占用率更大。在模型2中，进行了模拟以了解软相互作用对NP积聚到外围（肿瘤）隔室的影响。结果表明，当肿瘤积聚受“快速”血浆间隙和“缓慢”血管外渗时，软相互作用 - 但未活性靶向增强肿瘤摄取水平。本文呈现的简单模型提供了在瞬态蛋白质相互作用的影响下定量地了解超大鼠NPS的血液和肿瘤药代动力学的基本框架。

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    《RSC Advances》 |2019年第46期|共15页
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  • 正文语种 eng
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