Modular <i>in vitro</i> evaluation of buparlisib-polymeric nanomedicines in 2D and 3D models of glioblastoma.

Overview

1. Department of Neuroregeneration, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czechia
2. Laboratory of Biomaterials and Tissue Engineering, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
3. Faculty of Science, Charles University, Prague, Czechia
4. Department of Biomedical Polymers, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czechia

Abstract

Introduction: In this study, we developed a modular in vitro platform that integrates advanced polymer–drug conjugation chemistry with stepwise cytotoxicity screening in both 2D (monolayer) and 3D (spheroids) glioblastoma (GBM) models. Buparlisib was selected as the model therapeutic agent due to its well-characterised mechanism of action, high blood–brain barrier permeability, and relevance to PI3K-targeted therapy.

Methods: Two mechanistically distinct conjugation strategies were explored using N-(2-hydroxypropyl)methacrylamide-based copolymers (pHPMA). The first strategy was based on a redox-sensitive disulphide linkage designed for intracellular glutathione-triggered release, whereas the second used an azide-bearing derivative compatible with strain-promoted azide–alkyne cycloaddition. Drug release was assessed by high-performance liquid chromatography. Biological activity was systematically evaluated in U87MG, U118MG, and T98G cells under 2D conditions using a resazurin-based metabolic activity assay. Subsequently, the more promising disulphide-based formulations were assessed in 3D spheroids by metabolic activity measurements and live-cell monitoring of spheroid growth dynamics.

Results: Free buparlisib showed the strongest inhibitory effect, while its modification and polymer conjugation reduced the apparent activity. Nevertheless, the disulphide-based derivative and polymer conjugate retained concentration-dependent activity, whereas the azide-based polymer conjugate showed minimal effects. Moreover, treatment responses differed between cell lines and between 2D and 3D models.

Discussion: Overall, linker chemistry, cell-line-specific behaviour, and model dimensionality strongly influenced the biological performance of the polymeric buparlisib formulations. The redox-sensitive polymer conjugate therefore represents the more promising strategy for further development.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• zenodo:19261011, at Zenodo; found in “Data availability statement”

Data availability statement

The datasets for this study can be found in the Zenodo at [doi.org/10.5281/zenodo.19261011] The repository includes all figures and raw and processed data used in this research.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Funding: added Ministerstvo Školství, Mládeže a Tělovýchovy: CZ.02, LM2023050, CZ.02.01.01/00/ 22_008/0004562, CZ.02.01; Grantová Agentura České Republiky: GA22-12483S, CZ.02.01.01, CZ.02.01, LM2023050, CZ.02.01.01/00/22_008/0004562

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 10 authors, 8 keywords, 44 references.

Cite

This paper

Havelkova, J., Petrenko, Y., Stehlikova, A., Marekova, D., Peskova, K., Pechar, M., Studenovsky, M., Etrych, T., Pola, R., & Jendelova, P. (2026). Modular <i>in vitro</i> evaluation of buparlisib-polymeric nanomedicines in 2D and 3D models of glioblastoma. Frontiers in toxicology, 8, 1783704. https://doi.org/10.3389/ftox.2026.1783704

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