Carbon nanotubes: an insight into the mechanisms of their potential genotoxicity

After the health catastrophe resulting from the widespread use of asbestos which was once hailed as a new miracle material, the increasing use of carbon nanotubes (CNTs) has spawned major concern due to their similarities in terms of size, shape and poor solubility. Assessment of genotoxicity has shown that CNTs can damage DNA in vitro and in vivo. The genotoxic potential of different CNT samples varies considerably, however, with negative findings reported in a number of studies, probably due to the enormous heterogeneity of CNTs. The observed spectrum of genotoxic effects shows similarities with those reported for asbestos fibres. Mutagenicity has been found in vivo but in bacterial assays both asbestos and CNTs have mostly tested negative. An overview of key experimental observations on CNT-induced genotoxicity is presented in the first half of this review.In the second part, the potential mechanisms of CNT-elicited genotoxicity are discussed. Whereas CNTs possess intrinsic ROS-scavenging properties they are capable of generating intracellular ROS upon interaction with cellular components, and can cause antioxidant depletion. These effects have been attributed to their Fenton-reactive metals content. In addition, CNTs can impair the functionality of the mitotic apparatus. A noteworthy feature is that frustrated phagocytosis, which is involved in asbestos-induced pathology, has been observed for specific CNTs as well. The involvement of other mechanisms generally implicated in particle toxicity, such as phagocyte activation and impairment of DNA repair, is largely unknown at present and needs further investigation

A systematic review of in vitro models of drug-induced kidney injury

Drug-induced nephrotoxicity is a major cause of kidney dysfunction with potentially fatal consequences and can hamper the research and development of new pharmaceuticals. This emphasises the need for new methods for earlier and more accurate diagnosis to avoid drug-induced kidney injury. Here, we present a systematic review of the available approaches to study drug-induced kidney injury, as one of the most common reasons for drug withdrawal, in vitro. The systematic review approach was selected to ensure that our findings are as objective and reproducible as possible. A novel study quality checklist, named validation score, was developed based on published regulatory guidance and industrial perspectives, and models returned by the search strategy were analysed as per their overall complexity and the kidney region studied. Our search strategy returned 1731 articles supplemented by 337 from secondary sources, of which 57 articles met the inclusion criteria for final analysis. Our results show that the proximal tubule dominates the field (84%), followed by the glomerulus and Bowman's capsule (7%). Of all drugs investigated, the focus was most on cisplatin (n = 29, 50.1% of final inclusions). We found that with increasing model complexity the validation score increased, reflecting the value of innovative in vitro models. Furthermore, although the highly diverse usage of cell lines and modelling approaches prevented a strong statistical verification through a meta-analysis, our findings show the downstream potential of such approaches in personalised medicine and for rare diseases where traditional trials are not feasible

The potential of multi-organ-on-chip models for assessment of drug disposition as alternative to animal testing

The development of new medicines suffers from attrition, especially in the development pipeline. Eight out of nine drug candidates entering the clinical testing phase fail, mostly due to poor safety and efficacy. The low predictive value of animal models, used in earlier phases of drug development, for effects in humans poses a major problem. In particular, drug disposition can markedly differentiate in experimental animals versus humans. Meanwhile, classic in vitro methods can be used but these models lack the complexity to mimic holistic physiological processes occurring in the human body, especially organ–organ interactions. Therefore, better predictive methods to investigate drug disposition in the preclinical phase are needed, for which recent developments in multiorgan-on-chip methods are very promising. To be able to capture human physiology as good as possible, multiorgan-on-chips should feature 1) human cells endogenously expressing main transporters and metabolizing enzymes; 2) organ models relevant for exposure route; 3) individual organs-on-chip connected in a physiologically relevant manner; 4) a tight cellular barrier between the compartments; 5) organ models properly polarized in 3D; 6) allow for sampling in all major compartments; 7) constructed from materials that do not absorb or adsorb the compound of interest; 8) cells should grow in absence of fetal calf serum and Matrigel; 9) validated with a panel of compounds with known characteristics in humans; 10) an integrated computer model translating concentrations to the human situation. Here, an overview of available systems is presented and the difficult route towards a fully validated system is discussed

The potential of multi-organ-on-chip models for assessment of drug disposition as alternative to animal testing

The development of new medicines suffers from attrition, especially in the development pipeline. Eight out of nine drug candidates entering the clinical testing phase fail, mostly due to poor safety and efficacy. The low predictive value of animal models, used in earlier phases of drug development, for effects in humans poses a major problem. In particular, drug disposition can markedly differentiate in experimental animals versus humans. Meanwhile, classic in vitro methods can be used but these models lack the complexity to mimic holistic physiological processes occurring in the human body, especially organ–organ interactions. Therefore, better predictive methods to investigate drug disposition in the preclinical phase are needed, for which recent developments in multiorgan-on-chip methods are very promising. To be able to capture human physiology as good as possible, multiorgan-on-chips should feature 1) human cells endogenously expressing main transporters and metabolizing enzymes; 2) organ models relevant for exposure route; 3) individual organs-on-chip connected in a physiologically relevant manner; 4) a tight cellular barrier between the compartments; 5) organ models properly polarized in 3D; 6) allow for sampling in all major compartments; 7) constructed from materials that do not absorb or adsorb the compound of interest; 8) cells should grow in absence of fetal calf serum and Matrigel; 9) validated with a panel of compounds with known characteristics in humans; 10) an integrated computer model translating concentrations to the human situation. Here, an overview of available systems is presented and the difficult route towards a fully validated system is discussed

A systematic review of in vitro models of drug-induced kidney injury

Drug-induced nephrotoxicity is a major cause of kidney dysfunction with potentially fatal consequences and can hamper the research and development of new pharmaceuticals. This emphasises the need for new methods for earlier and more accurate diagnosis to avoid drug-induced kidney injury. Here, we present a systematic review of the available approaches to study drug-induced kidney injury, as one of the most common reasons for drug withdrawal, in vitro. The systematic review approach was selected to ensure that our findings are as objective and reproducible as possible. A novel study quality checklist, named validation score, was developed based on published regulatory guidance and industrial perspectives, and models returned by the search strategy were analysed as per their overall complexity and the kidney region studied. Our search strategy returned 1731 articles supplemented by 337 from secondary sources, of which 57 articles met the inclusion criteria for final analysis. Our results show that the proximal tubule dominates the field (84%), followed by the glomerulus and Bowman's capsule (7%). Of all drugs investigated, the focus was most on cisplatin (n = 29, 50.1% of final inclusions). We found that with increasing model complexity the validation score increased, reflecting the value of innovative in vitro models. Furthermore, although the highly diverse usage of cell lines and modelling approaches prevented a strong statistical verification through a meta-analysis, our findings show the downstream potential of such approaches in personalised medicine and for rare diseases where traditional trials are not feasible