Deep Tissue Translocation of Graphene Oxide Sheets in Human Glioblastoma 3D Spheroids and an Orthotopic Xenograft Model

Irene De Lázaro,Cansu Gurcan,Ahmet Ceylan,Kostas Kostarelos,Sandra Vranic,Yingxian Chen,Hadiseh Taheri,Thomas Kisby,Cyrill Bussy,Acelya Yilmazer,Maria Stylianou,Paul Sharp,Katharine Barr,Asuman Ozen

doi:10.1002/adtp.202000109

Abstract

AbstractIts anatomical localization, a highly heterogeneous and drug‐resistant tumor cell population and a “cold” immune microenvironment, all challenge the treatment of glioblastoma. Nanoscale drug delivery systems, including graphene oxide (GO) flakes, may circumvent some of these issues bypassing biological barriers, delivering multiple cargoes to impact several pathways simultaneously, or targeting the immune compartment. Here, the interactions of GO flakes with in vitro (U‐87 MG three‐dimensional spheroids, without stromal or immune compartments) and in vivo (U‐87 MG orthotopic xenograft) models of glioblastoma are investigated. In vitro, GO flakes translocated deeply into the spheroids with little internalization in tumor cells. In vivo, intracranially administered GO also show extensive distribution throughout the tumor and demonstrate no impact on tumor growth and progression for the duration of the study. Internalization within tumor cells is also scarce, with the majority of flakes preferentially taken up by microglia/macrophages. The results indicate that GO flakes could offer deep and homogenous distribution throughout glioblastoma tumors and a means to target their myeloid compartment. Further studies are warranted to investigate the mechanisms of GO flakes transport within the tumor mass and their capacity to deliver bioactive cargoes but, ultimately, this information could inform the development of immunotherapies against glioblastoma.

Highlights

Glioblastoma multiforme, which equates to grade IV glioma, is the most frequent form of cancer of the central nervous system and one of the most aggressive
To investigate the interactions of graphene oxide (GO) with glioblastoma cells, we first exposed 3D spheroids composed of human Uppsala 87 Malignant Glioma (U-87 MG) glioma cells to 10 or 100 μg mL−1 of GO flakes, dispersed in the cell culture medium, and measured spheroid growth for 12 d
Since we did not observe any significant increases in tumor volume in vivo following GO treatment, contrary to our observations in spheroids in vitro, we decided to investigate the deposition of extracellular matrix (ECM) in the tissue

Summary

Introduction

Glioblastoma multiforme, which equates to grade IV glioma, is the most frequent form of cancer of the central nervous system and one of the most aggressive. The current standard of care entails surgical resection followed by radiotherapy, plus concomitant and maintenance chemotherapy with temozolomide.[1] despite these interventions, the median overall survival (OS) after diagnosis does not surpass the 18-month threshold. Antiangiogenic therapy with the anti vascular endothelial growth factor (VEGF) antibody bevacizumab has only shown modest benefit in recurrent glioblastoma and does not significantly extend OS in newly diagnosed patients.[2]. Several challenges contribute to the difficulty in treating glioblastoma, which have been extensively reviewed by others.[3] First, the anatomical localization of the tumor into one of the body’s most vital organs sets hurdles to its complete surgical

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