Glioblastoma immuno-endothelial multicellular microtissue as a 3D in vitro evaluation tool of anti-cancer nano-therapeutics

Authors and Affiliations:
Cláudia Martins^1,2,3, Catarina Pacheco^1,2,4, Catarina Moreira-Barbosa^1,2,3, Ângela Marques-Magalhães^1,2,3, Sofia Dias^1,2,3, Marco Araújo^1,2, Maria J. Oliveira^1,2,3, Bruno Sarmento^1,2,4*

¹i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal.

²INEB – Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal

³ICBAS – Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal ⁴CESPU – Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal

Abstract:

Despite being the most prevalent and lethal type of adult brain cancer, glioblastoma (GBM) remains intractable. Promising anti-GBM nanoparticle (NP) systems have been developed to improve the anti-cancer performance of difficult-to-deliver therapeutics, with particular emphasis on tumor targeting strategies. However, current disease modeling toolboxes lack close-to-native in vitro models that emulate GBM microenvironment and bioarchitecture, thus partially hindering translation due to poorly predicted clinical responses. Herein, human GBM heterotypic multicellular tumor microtissues (MCTMs) are generated through high-throughput 3D modeling of U-251 MG tumor cells, tissue differentiated macrophages isolated from peripheral monocytes, and brain microvascular primary endothelial cells. GBM MCTMs mimicked tumor spatial organization, extracellular matrix production and necrosis areas. The bioactivity of a model drug, docetaxel (DTX), and of tumor-targeted DTX-loaded polymeric NPs with a surface L-Histidine moiety (H-NPs), were assessed in the MCTMs. MCTMs cell uptake and anti-proliferative effect was 8- and 3-times higher for H-NPs, respectively, compared to the non-targeted NPs and to free DTX. H-NPs provided a decrease of MCTMs anti-inflammatory M2-macrophages, while increasing their pro-inflammatory M1 counterparts. Moreover, H-NPs showed a particular biomolecular signature through reduced secretion of an array of medium cytokines (IFN-γ, IL-1β, IL-1Ra, IL-6, IL-8, TGF-β). Overall, MCTMs provide an in vitro biomimetic model to recapitulate key cellular and structural features of GBM and improve in vivo drug response predictability, fostering future clinical translation of anti-GBM nano-therapeutic strategies.

Journal: Journal of Controlled Release

Link: https://www.sciencedirect.com/science/article/pii/S0168365922007684