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Nanotheranostics 2024; 8(1):1-11. doi:10.7150/ntno.85439 This issue Cite

Research Paper

Three-dimensional in vitro model of bone metastases of neuroblastoma as a tool for pharmacological evaluations

Sanja Aveic^1,2,✉,#, Max Seidelmann^1,#, Roswitha Davtalab¹, Diana Corallo², Michael Vogt³, Stephan Rütten⁴, Horst Fischer¹

1. Department of Dental Materials and Biomaterials Research, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany.
2. Laboratory of Target Discovery and Biology of Neuroblastoma, Istituto di Ricerca Pediatrica Fondazione Città della Speranza, Corso Stati Uniti 4, 35127 Padova, Italy.
3. Interdisciplinary Center for Clinical Research, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany.
4. Electron Microscopy Facility, Institute of Pathology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany.
#: equally contributing authors

✉ Corresponding author: Dr. Sanja Aveic. Email: saveicde.

Abstract

In vitro metastatic models are foreseen to introduce a breakthrough in the field of preclinical screening of more functional small-molecule pharmaceuticals and biologics. To achieve this goal, the complexity of current in vitro systems requests an appropriate upgrade to approach the three-dimensional (3D) in vivo metastatic disease. Here, we explored the potential of our 3D β-tricalcium phosphate (β-TCP) model of neuroblastoma bone metastasis for drug toxicity assessment. Tailor-made scaffolds with interconnected channels were produced by combining 3D printing and slip casting method. The organization of neuroblastoma cells into a mesenchymal stromal cell (MSC) network, cultured under bioactive conditions provided by β-TCP, was monitored by two-photon microscopy. Deposition of extracellular matrix protein Collagen I by MSCs and persistent growth of tumor cells confirmed the cell-supportive performance of our 3D model. When different neuroblastoma cells were treated with conventional chemotherapeutics, the β-TCP model provided the necessary reproducibility and accuracy of experimental readouts. Drug efficacy evaluation was done for 3D and 2D cell cultures, highlighting the need for a higher dose of chemotherapeutics under 3D conditions to achieve the expected cytotoxicity in tumor cells. Our results confirm the importance of 3D geometry in driving native connectivity between nonmalignant and tumor cells and sustain β-TCP scaffolds as a reliable and affordable drug screening platform for use in the early stages of drug discovery.

Keywords: 3D geometry, bone metastatic niche, drug screening, neuroblastoma

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