Marie-Curie COFUND Fellowship, University of Liège, Liège, Belgium; i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB, Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB, Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal.
Adv Drug Deliv Rev. 2018 Jan 15;124:50-63. doi: 10.1016/j.addr.2017.07.019. Epub 2017 Jul 25.
The increasing interest in developing tools to predict drug absorption through mucosal surfaces is fostering the establishment of epithelial cell-based models. Cell-based in vitro techniques for drug permeability assessment are less laborious, cheaper and address the concerns of using laboratory animals. Simultaneously, in vitro barrier models that thoroughly simulate human epithelia or mucosae may provide useful data to speed up the entrance of new drugs and new drug products into the clinics. Nevertheless, standard cell-based in vitro models that intend to reproduce epithelial surfaces often discard the role of mucus in influencing drug permeation/absorption. Biomimetic models of mucosae in which mucus production has been considered may not be able to fully reproduce the amount and architecture of mucus, resulting in biased characterization of permeability/absorption. In these cases, artificial mucus may be used to supplement cell-based models but still proper identification and quantification are required. In this review, considerations regarding the relevance of mucus in the development of cell-based epithelial and mucosal models mimicking the gastro-intestinal tract, the cervico-vaginal tract and the respiratory tract, and the impact of mucus on the permeability mechanisms are addressed. From simple epithelial monolayers to more complex 3D structures, the impact of the presence of mucus for the extrapolation to the in vivo scenario is critically analyzed. Finally, an overview is provided on several techniques and methods to characterize the mucus layer over cell-based barriers, in order to intimately reproduce human mucosal layer and thereby, improve in vitro/in vivo correlation.
人们越来越关注开发用于预测通过黏膜表面吸收药物的工具，这促进了基于上皮细胞模型的建立。用于评估药物渗透性的基于细胞的体外技术不那么繁琐、成本更低，并且解决了使用实验动物的问题。同时，能够充分模拟人体上皮或黏膜的体外屏障模型可能会提供有用的数据，从而加速新药和新药物产品进入临床。然而，旨在复制上皮表面的标准基于细胞的体外模型通常忽略了黏液在影响药物渗透/吸收方面的作用。考虑到黏液产生的黏膜仿生模型可能无法完全复制黏液的数量和结构，从而导致对渗透性/吸收的偏置表征。在这些情况下，可以使用人工黏液来补充基于细胞的模型，但仍需要进行适当的识别和定量。在这篇综述中，讨论了在开发模拟胃肠道、宫颈阴道和呼吸道的基于细胞的上皮和黏膜模型时考虑黏液的相关性，以及黏液对渗透性机制的影响。从简单的上皮单层到更复杂的 3D 结构，都批判性地分析了黏液存在对体内外推的影响。最后，提供了几种用于表征基于细胞屏障上的黏液层的技术和方法的概述，以便能够更紧密地复制人体黏膜层，从而提高体外/体内相关性。
