Jesus Sandra, Schmutz Mélanie, Som Claudia, Borchard Gerrit, Wick Peter, Borges Olga
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Laboratory for Technology and Society, Empa Swiss Laboratories for Materials Science and Technology, St. Gallen, Switzerland.
Front Bioeng Biotechnol. 2019 Oct 23;7:261. doi: 10.3389/fbioe.2019.00261. eCollection 2019.
The physicochemical properties of nanobiomaterials, such as their small size and high surface area ratio, make them attractive, novel drug-carriers, with increased cellular interaction and increased permeation through several biological barriers. However, these same properties hinder any extrapolation of knowledge from the toxicity of their raw material. Though, as suggested by the Safe-by-Design (SbD) concept, the hazard assessment should be the starting point for the formulation development. This may enable us to select the most promising candidates of polymeric nanobiomaterials for safe drug-delivery in an early phase of innovation. Nowadays the majority of reports on polymeric nanomaterials are focused in optimizing the nanocarrier features, such as size, physical stability and drug loading efficacy, and in performing preliminary cytocompatibility testing and proving effectiveness of the drug loaded formulation, using the most diverse cell lines. Toxicological studies exploring the biological effects of the polymeric nanomaterials, particularly regarding immune system interaction are often disregarded. The objective of this review is to illustrate what is known about the biological effects of polymeric nanomaterials and to see if trends in toxicity and general links between physicochemical properties of nanobiomaterials and their effects may be derived. For that, data on chitosan, polylactic acid (PLA), polyhydroxyalkanoate (PHA), poly(lactic-co-glycolic acid) (PLGA) and policaprolactone (PCL) nanomaterials will be evaluated regarding acute and repeated dose toxicity, inflammation, oxidative stress, genotoxicity, toxicity on reproduction and hemocompatibility. We further intend to identify the analytical and biological tests described in the literature used to assess polymeric nanomaterials toxicity, to evaluate and interpret the available results and to expose the obstacles and challenges related to the nanomaterial testing. At the present time, considering all the information collected, the hazard assessment and thus also the SbD of polymeric nanomaterials is still dependent on a case-by-case evaluation. The identified obstacles prevent the identification of toxicity trends and the generation of an assertive toxicity database. In the future, and harmonized toxicity studies using unloaded polymeric nanomaterials, extensively characterized regarding their intrinsic and extrinsic properties should allow to generate such database. Such a database would enable us to apply the SbD approach more efficiently.
纳米生物材料的物理化学性质，如尺寸小和高表面积比，使其成为具有吸引力的新型药物载体，能够增强细胞相互作用并提高穿过多种生物屏障的渗透率。然而，这些相同的性质阻碍了从其原材料毒性进行任何知识外推。不过，正如“设计即安全”（SbD）概念所建议的，危害评估应该是制剂开发的起点。这可能使我们能够在创新的早期阶段选择最有前景的聚合物纳米生物材料候选物用于安全的药物递送。如今，关于聚合物纳米材料的大多数报告都集中在优化纳米载体特性，如尺寸、物理稳定性和药物负载效率，以及使用最多样化的细胞系进行初步细胞相容性测试和证明负载药物制剂的有效性。探索聚合物纳米材料生物效应，特别是关于免疫系统相互作用的毒理学研究常常被忽视。本综述的目的是阐述关于聚合物纳米材料生物效应的已知情况，并查看是否可以得出毒性趋势以及纳米生物材料物理化学性质与其效应之间的一般联系。为此，将评估壳聚糖、聚乳酸（PLA）、聚羟基脂肪酸酯（PHA）、聚（乳酸 - 乙醇酸）（PLGA）和聚己内酯（PCL）纳米材料在急性和重复剂量毒性、炎症、氧化应激、遗传毒性、生殖毒性和血液相容性方面的数据。我们还打算确定文献中描述的用于评估聚合物纳米材料毒性的分析和生物学测试，评估和解释现有结果，并揭示与纳米材料测试相关的障碍和挑战。目前，考虑到收集到的所有信息，聚合物纳米材料的危害评估以及因此的SbD仍然依赖于逐案评估。所确定的障碍妨碍了毒性趋势的识别和可靠毒性数据库的生成。未来，使用未负载聚合物纳米材料进行的统一毒性研究，对其内在和外在性质进行广泛表征，应该能够生成这样的数据库。这样的数据库将使我们能够更有效地应用SbD方法。
