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Mimicking Tumors: Toward More Predictive In Vitro Models for Peptide- and Protein-Conjugated Drugs
Dirk van den Brand1,2, Leon F Massuger2, Roland Brock1
1Department of Biochemistry, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
Abstract:
Macromolecular drug candidates and nanoparticles are typically tested in 2D cancer cell culture models, which are often directly followed by in vivo animal studies. The majority of these drug candidates, however, fail in vivo. In contrast to classical small-molecule drugs, multiple barriers exist for these larger molecules that two-dimensional approaches do not recapitulate. In order to provide better mechanistic insights into the parameters controlling success and failure and due to changing ethical perspectives on animal studies, there is a growing need for in vitro models with higher physiological relevance. This need is reflected by an increased interest in 3D tumor models, which during the past decade have evolved from relatively simple tumor cell aggregates to more complex models that incorporate additional tumor characteristics as well as patient-derived material. This review will address tissue culture models that implement critical features of the physiological tumor context such as 3D structure, extracellular matrix, interstitial flow, vascular extravasation, and the use of patient material. We will focus on specific examples, relating to peptide-and protein-conjugated drugs and other nanoparticles, and discuss the added value and limitations of the respective approaches.
Insights
Three-dimensional (3D) tumor models offer greater physiological relevance than 2D cultures for testing macromolecular drugs and nanoparticles, improving prediction of in vivo success.
Area of Science:
- Oncology
- Biomedical Engineering
- Drug Delivery
Background:
- Traditional 2D cancer cell cultures and subsequent animal studies often fail to predict the in vivo efficacy of macromolecular drugs and nanoparticles.
- 2D models do not recapitulate the complex barriers encountered by larger molecules within the tumor microenvironment.
- There is a growing need for more physiologically relevant in vitro models due to ethical considerations and the high failure rate of drug candidates.
Purpose of the Study:
- To review advanced in vitro 3D tumor models that incorporate key physiological features of the tumor microenvironment.
- To discuss the application of these models in evaluating peptide- and protein-conjugated drugs and nanoparticles.
- To highlight the added value and limitations of these complex 3D models for drug development.
Main Methods:
- Review of current literature on advanced 3D tumor models.
- Focus on models incorporating 3D structure, extracellular matrix, interstitial flow, and vascular extravasation.
- Inclusion of models utilizing patient-derived materials.
Main Results:
- 3D tumor models are evolving to include critical physiological aspects like matrix, flow, and vascularization.
- Patient-derived materials enhance the translational relevance of 3D models.
- These advanced models provide better mechanistic insights into drug candidate behavior.
Conclusions:
- 3D tumor models represent a significant advancement over 2D cultures for assessing macromolecular drugs and nanoparticles.
- Incorporating physiological complexity improves the predictive power of in vitro drug screening.
- These models are crucial for understanding drug efficacy and overcoming in vivo failure in cancer research.
