Enhancing Pre-Clinical Testing with 3D Cell Cultures Copy

Published by on March 11, 2024 | Leave a response

The pharmaceutical industry, driven by the new benchmarks in research and development from the COVID-19 pandemic, is surging forward with a variety of innovative and new technological methods for drug discovery, one of them being the use of 3-dimensional (3D) cell culture models (Nicholson, 2023). 3D cell culture models are in vitro multicellular structures designed to emulate tissue or organ-like properties to better mimic the in vivo micro-environment, producing improved drug screening data during preclinical testing (Bédard et al., 2020)

Like a normal cell culture, there are many components and steps to designing its 3D counterpart (de Dios Figueroa et al., 2021). The first is sourcing cells such as organoids and spheroids. Organoids are created from healthy or diseased adult and induced pluripotent stem cells; they are miniaturized versions of an organ in vitro, mimicking the structural, functional, and biological complexity of that organ (de Souza, 2018). Contrarily, spheroids are 3D cell aggregates that can mimic tissues and microtumors (Białkowska et al., 2020). Once the cell line has been selected, models can then be broken down into scaffold, scaffold-free or hybrid 3D cell cultures (Anthon and Valente, 2022). Popular scaffold methods include hydrogels, which are polymeric materials containing a network of crosslinked polymer chains that absorb water and allow cell growth. While, scaffold-free cell cultures rely on cells to self-assemble and include low attachment plates or hanging drops which induce cell aggregation (Figure 1) (Anthon and Valente, 2022).

Figure 1. Scheme of diverse 3D cell culture methods (scaffold-free, scaffold-based and hybrids). In monolayer cell cultures, cells grow attached to a plastic base. However, in 3D cell cultures, cells self-assemble or grow in structures that resemble the extracellular matrix. In scaffold-free systems, cells aggregate in natural processes of organogenesis. Scaffold-based systems use structures that mimic the extracellular matrix. Hybrids use a matrix to support scaffold-free systems (de Dios Figueroa et al., 2021).

In the context of drug discovery, recapitulating in vivo tissues in preclinical models is an essential part of accurately screening drug candidates for efficacy (Belfiore et al., 2021). For instance, tumour cells exist in vivo as a 3D mass with distinct proliferative and metabolic gradients that arise from their 3D structure (Langhans, 2018). Solid tumours exist within an extracellular matrix (ECM), compromising proteins, tumour-associated cells and soluble factors, which all contribute to the biology of the tumour and thus influence cellular response to drug treatments. In-vitro 3D cell culture models embedded within a 3D matrix have been found to better recapitulate the tumour microenvironment, allowing for cell-ECM interactions that mediate the morphology, cell behaviour and gene expression of tumours as observed in the body (Figure 2) (Langhans, 2018).

Figure 2. 3D Cell models for drug screening. 3D cell cultures better represent in vivo tissues and tumours by recapitulating in vivo structure and the presence of the extracellular matrix (ECM), which affects drug response (Belfiore et al., 2021).

Due to their similarity to in vivo tumours and tissues, there is growing evidence that 3D cell culture models can more accurately predict drug response and therapeutic efficacy compared to 2D cell cultures, accelerating the movement of efficacious therapeutics from preclinical studies to clinical trials (Fang, 2017). Certain cell types cultured in 2D have been found to be more sensitive to drug toxicity than when cultured in 3D, resulting in an optimized understanding of the physiological response of the cells when exposed to a certain drug dosage (Belfiore et al., 2021). Consequently, the integration of human cells and tissues in a 3D format in drug development programs may help to improve the predictive validity of toxicity testing (Figure 3).

Figure 3. Graphical abstract for drug discovery and development process for treatment of pulmonary infections. Currently, 2D cell culture models are used to emulate the in vivo physiologic environment; however, they hold great limitations due to the lack of correlation to in vivo cell organization, cell-to-cell interactions, and downstream processes. The use of organoid and spheroid 3D models allows for the monitoring of drug toxicity and shows potential for large-scale in vitro amplification, producing more personalized medicine (Shah et al., 2023).

Pharmaceutical companies are adopting 3D cell culture models to enhance drug response evaluation in preclinical testing and streamline drug discovery. The continued development of new technologies to generate 3D cell models that better represent the in vivo environment in a high-throughput way will help ensure that the right drug candidates are selected for further evaluation.

References

Anthon, S.G. and Valente, K.P., 2022. Vascularization Strategies in 3D Cell Culture Models: From Scaffold-Free Models to 3D Bioprinting. International Journal of Molecular Sciences, 23(23), p.14582. https://doi.org/10.3390/ijms232314582.

Bédard, P., Gauvin, S., Ferland, K., Caneparo, C., Pellerin, È., Chabaud, S. and Bolduc, S., 2020. Innovative Human Three-Dimensional Tissue-Engineered Models as an Alternative to Animal Testing. Bioengineering, 7(3), p.115. https://doi.org/10.3390/bioengineering7030115.

Belfiore, L., Aghaei, B., Law, A.M.K., Dobrowolski, J.C., Raftery, L.J., Tjandra, A.D., Yee, C., Piloni, A., Volkerling, A., Ferris, C.J. and Engel, M., 2021. Generation and analysis of 3D cell culture models for drug discovery. European Journal of Pharmaceutical Sciences, 163, p.105876. https://doi.org/10.1016/j.ejps.2021.105876.

Białkowska, K., Komorowski, P., Bryszewska, M. and Miłowska, K., 2020. Spheroids as a Type of Three-Dimensional Cell Cultures—Examples of Methods of Preparation and the Most Important Application. International Journal of Molecular Sciences, 21(17), p.6225. https://doi.org/10.3390/ijms21176225.

de Dios Figueroa, G., Aguilera-Marquez, J., Camacho-Villegas, T. and Lugo, P., 2021. biomedicines 3D Cell Culture Models in COVID-19 Times: A Review of 3D Technologies to Understand and Accelerate Therapeutic Drug Discovery. Biomedicines, 9. https://doi.org/10.3390/biomedicines9060602.

Fang, Y., 2017. Three-Dimensional Cell Cultures in Drug Discovery and Development – Ye Fang, Richard M. Eglen, 2017. [online] Available at: <https://journals.sagepub.com/doi/full/10.1177/1087057117696795> [Accessed 10 March 2024].

Langhans, S.A., 2018. Three-Dimensional in Vitro Cell Culture Models in Drug Discovery and Drug Repositioning. Frontiers in Pharmacology, [online] 9. https://doi.org/10.3389/fphar.2018.00006.

Nicholson, M., 2023. What are the latest developments in drug discovery in 2023? [online] Available at: <https://www.nesfircroft.com/resources/blog/what-are-the-latest-developments-in-drug-discovery-in-2023/> [Accessed 10 March 2024].

Shah, D.D., Raghani, N.R., Chorawala, M.R., Singh, S. and Prajapati, B.G., 2023. Harnessing three-dimensional (3D) cell culture models for pulmonary infections: State of the art and future directions. Naunyn-Schmiedeberg’s Archives of Pharmacology, 396(11), pp.2861–2880. https://doi.org/10.1007/s00210-023-02541-2.

de Souza, N., 2018. Organoids. Nature Methods, 15(1), pp.23–23. https://doi.org/10.1038/nmeth.4576.

Takeda, M., Miyagawa, S., Fukushima, S., Saito, A., Ito, E., Harada, A., Matsuura, R., Iseoka, H., Sougawa, N., Mochizuki-Oda, N., Matsusaki, M., Akashi, M. and Sawa, Y., 2018. Development of In Vitro Drug-Induced Cardiotoxicity Assay by Using Three-Dimensional Cardiac Tissues Derived from Human Induced Pluripotent Stem Cells. Tissue Engineering Part C: Methods, 24(1), pp.56–67. https://doi.org/10.1089/ten.tec.2017.0247.

Leave a Reply

You must be logged in to post a comment.