Animal simulations facilitate smart drug design through prediction of nanomaterial transport to individual tissue cells

Abstract

Smart drug design for antibody and nanomaterial-based therapies allows optimization of drug efficacy and more efficient early-stage preclinical trials. The ideal drug must display maximum efficacy at target tissue sites, with transport from tissue vasculature to the cellular environment being critical. Biological simulations, when coupled with in vitro approaches, can predict this exposure in a rapid and efficient manner. As a result, it becomes possible to predict drug biodistribution within single cells of live animal tissue without the need for animal studies. Here, we successfully utilized an in vitro assay and a computational fluid dynamic model to translate in vitro cell kinetics (accounting for cell-induced degradation) to whole-body simulations for multiple species as well as nanomaterial types to predict drug distribution into individual tissue cells. We expect this work to assist in refining, reducing, and replacing animal testing, while providing scientists with a new perspective during the drug development process.

Development of a multi-route physiologically based pharmacokinetic (PBPK) model for nanomaterials: a comparison between a traditional versus a new route-specific approach using gold nanoparticles in rats

“…The reason for the misestimation of the accumulated dose in lungs and GI tract is unknown, but it might be due to some organspecific cellular uptake and transport mechanisms of NPs in the lungs, or the presence of surfactants, that have not been accounted for in the model [49]. These results suggest that additional in vitro cellular uptake studies in major phagocytic cell types in major reticuloendothelial systems (e.g., liver, spleen, and lungs) are needed in the future to improve our understanding of the cellular uptake and transport mechanisms of NPs [50]. Also, the validation datasets did not have data on the HD of AuNPs, which plays an important role in the overall tissue distribution of AuNPs.…”

Integration of In Vitro and In Vivo Models to Predict Cellular and Tissue Dosimetry of Nanomaterials Using Physiologically Based Pharmacokinetic Modeling

“…The results of this in vitro work were applied to in vivo predictions of QD predisposition. 18 The mechanistic approach in the modeling resulted in a satisfactory agreement between predicted and observed in vivo data for multiple species. Interaction of silicon quantum dots (Si-QDs) with HUVEC cells resulted in near saturation of uptake by 6 h of exposure.…”

“…Unlike small molecules of which the IVIVE methodology is well-established, the IVIVE strategies for NPs remain to be developed. Currently, there are only a few studies that have attempted to perform IVIVE for NPs, with some studies showing IVIVE is feasible for NPs, , whereas another study suggests that direct IVIVE may produce suboptimal results for NPs and thus may require further optimization of the methodology . Additional studies are needed to develop and validate IVIVE methodology for NPs.…”

“…Finally, one of the reasons PBPK modeling is very useful in small molecular chemical risk assessment is its ability to extrapolate PK and toxicity data from animals to humans. Several NP PBPK models have attempted to conduct extrapolation from one species to another using the traditional approach for small molecules. ,,,, The study by Lin et al suggested that rats and pigs may be more suitable animal models for extrapolating the PK of AuNPs to humans. In addition, the PBPK model in mice by Aborig et al .…”

“…Several NP PBPK models have attempted to conduct extrapolation from one species to another using the traditional approach for small molecules. 12,18,35,140,141 The study by Lin et al 35 suggested that rats and pigs may be more suitable animal models for extrapolating the PK of AuNPs to humans. In addition, the PBPK model in mice by Aborig et al 140 was extrapolated to rats by adapting physiological parameters to represent rats, and the resulting rat model adequately simulated PK and tissue distribution data of citrated-capped AuNPs in rats.…”