Drug Delivery and Translational Research ( IF 5.7 ) Pub Date : 2022-06-28 , DOI: 10.1007/s13346-022-01170-1 Melissa Anne Tutty 1, 2 , Gabriele Vella 1, 2 , Adriele Prina-Mello 1, 2, 3
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Nanobiomaterials, or NBMs, have been used in medicine and bioimaging for decades, with wide-reaching applications ranging from their uses as carriers of genes and drugs, to acting as sensors and probes. When developing nanomedicine products, it is vitally important to evaluate their safety, ensuring that both biocompatibility and efficacy are achieved so their applications in these areas can be safe and effective. When discussing the safety of nanomedicine in general terms, it is foolish to make generalised statements due to the vast array of different manufactured nanomaterials, formulated from a multitude of different materials, in many shapes and sizes; therefore, NBM pre-clinical screening can be a significant challenge. Outside of their distribution in the various tissues, organs and cells in the body, a key area of interest is the impact of NBMs on the liver. A considerable issue for researchers today is accurately predicting human-specific liver toxicity prior to clinical trials, with hepatotoxicity not only the most cited reasons for withdrawal of approved drugs, but also a primary cause of attrition in pre-launched drug candidates. To date, no simple solution to adequately predict these adverse effects exists prior to entering human experimentation. The limitations of the current pre-clinical toolkit are believed to be one of the main reasons for this, with questions being raised on the relevance of animal models in pre-clinical assessment, and over the ability of conventional, simplified in vitro cell–based assays to adequately assess new drug candidates or NBMs. Common 2D cell cultures are unable to adequately represent the functions of 3D tissues and their complex cell–cell and cell–matrix interactions, as well as differences found in diffusion and transport conditions. Therefore, testing NBM toxicity in conventional 2D models may not be an accurate reflection of the actual toxicity these materials impart on the body. One such method of overcoming these issues is the use of 3D cultures, such as cell spheroids, to more accurately assess NBM-tissue interaction. In this study, we introduce a 3D hepatocellular carcinoma model cultured from HepG2 cells to assess both the cytotoxicity and viability observed following treatment with a variety of NBMs, namely a nanostructured lipid carrier (in the specific technical name = LipImage™ 815), a gold nanoparticle (AuNP) and a panel of polymeric (in the specific technical name = PACA) NBMs. This model is also in compliance with the 3Rs policy of reduction, refinement and replacement in animal experimentation [1], and meets the critical need for more advanced in vitro models for pre-clinical nanotoxicity assessment.
Graphical abstract
Pipeline for the pre-clinical assessment of NBMs in liver spheroid model
中文翻译：
对一组纳米材料的临床前 2D 和 3D 毒性反应；NBM诱导的肝毒性的比较评估
纳米生物材料或 NBM 已在医学和生物成像中使用了数十年，其应用范围广泛，从用作基因和药物的载体，到用作传感器和探针。在开发纳米药物产品时，评估其安全性至关重要，确保同时实现生物相容性和功效，从而使其在这些领域的应用安全有效。在笼统地讨论纳米药物的安全性时，由于大量不同的人造纳米材料由多种不同材料制成，具有多种形状和尺寸，因此做出笼统的陈述是愚蠢的；因此，NBM 临床前筛查可能是一项重大挑战。除了分布在身体的各种组织、器官和细胞之外，一个重要的关注领域是 NBM 对肝脏的影响。当今研究人员面临的一个重要问题是在临床试验之前准确预测人类特异性肝毒性，肝毒性不仅是撤回批准药物的最常被引用的原因，也是预推出候选药物流失的主要原因。迄今为止，在进入人体实验之前，不存在充分预测这些不利影响的简单解决方案。目前临床前工具包的局限性被认为是造成这种情况的主要原因之一，人们对动物模型在临床前评估中的相关性以及传统的、简化的基于体外细胞的能力提出了质疑。分析以充分评估新的候选药物或 NBM。常见的 2D 细胞培养物无法充分代表 3D 组织的功能及其复杂的细胞-细胞和细胞-基质相互作用，以及在扩散和运输条件下发现的差异。因此，在传统 2D 模型中测试 NBM 毒性可能无法准确反映这些材料对身体的实际毒性。克服这些问题的一种方法是使用 3D 培养物（例如细胞球体）来更准确地评估 NBM-组织相互作用。在这项研究中，我们介绍了一个从 HepG2 细胞培养的 3D 肝细胞癌模型，以评估用各种 NBM（即纳米结构脂质载体）处理后观察到的细胞毒性和活力（具体技术名称 = LipImage 以及在扩散和运输条件中发现的差异。因此，在传统 2D 模型中测试 NBM 毒性可能无法准确反映这些材料对身体的实际毒性。克服这些问题的一种方法是使用 3D 培养物（例如细胞球体）来更准确地评估 NBM-组织相互作用。在这项研究中，我们介绍了一个从 HepG2 细胞培养的 3D 肝细胞癌模型，以评估用各种 NBM（即纳米结构脂质载体）处理后观察到的细胞毒性和活力（具体技术名称 = LipImage 以及在扩散和运输条件中发现的差异。因此，在传统 2D 模型中测试 NBM 毒性可能无法准确反映这些材料对身体的实际毒性。克服这些问题的一种方法是使用 3D 培养物（例如细胞球体）来更准确地评估 NBM-组织相互作用。在这项研究中，我们介绍了一个从 HepG2 细胞培养的 3D 肝细胞癌模型，以评估用各种 NBM（即纳米结构脂质载体）处理后观察到的细胞毒性和活力（具体技术名称 = LipImage 克服这些问题的一种方法是使用 3D 培养物（例如细胞球体）来更准确地评估 NBM-组织相互作用。在这项研究中，我们介绍了一个从 HepG2 细胞培养的 3D 肝细胞癌模型，以评估用各种 NBM（即纳米结构脂质载体）处理后观察到的细胞毒性和活力（具体技术名称 = LipImage 克服这些问题的一种方法是使用 3D 培养物（例如细胞球体）来更准确地评估 NBM-组织相互作用。在这项研究中，我们介绍了一个从 HepG2 细胞培养的 3D 肝细胞癌模型，以评估用各种 NBM（即纳米结构脂质载体）处理后观察到的细胞毒性和活力（具体技术名称 = LipImage™ 815)、金纳米颗粒 (AuNP) 和一组聚合物（在特定技术名称中 = PACA）NBM。该模型也符合动物实验中减少、细化和替代的3Rs政策[1]，满足了对更先进的体外模型进行临床前纳米毒性评估的迫切需求。
图形概要
用于肝球体模型中 NBM 临床前评估的管道
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