Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome
- Tel Aviv University, Israel
- Freie Universität Berlin, Germany
- Tel Aviv Sourasky Medical Center, Israel
- Northwestern University, United States
- University of Maryland, United States
Abstract
Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.
Article and author information
Author details
Ronit Satchi-Fainaro
Funding
H2020 European Research Council (617445)
- Ronit Satchi-Fainaro
Israel Science Foundation (918/14)
- Ronit Satchi-Fainaro
Israel Cancer Association (20150909)
- Ronit Satchi-Fainaro
Bundesministerium für Bildung und Forschung (13N11536)
- Rainer Haag
Bundesministerium für Bildung und Forschung (13N12561)
- Marcelo Calderón
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Charles L Sawyers, Memorial Sloan-Kettering Cancer Center, United States
Ethics
Animal experimentation: All animals were housed in the Tel Aviv University animal facility. The experiments were approved by the animal care and use committee (IACUC) of Tel Aviv University (approval no. 01-12-064, 01-12-065) and conducted in accordance with NIH guidelines.
Human subjects: Experiments involving human tissues were performed with the approval of the Institutional Review Board (IRB) and in compliance with all legal and ethical considerations for human subject research (approval no. 0735-13-TLV). Single human plasma was obtained from a healthy consented unmedicated donor according to German ethical guidelines.
Version history
- Received: January 23, 2017
- Accepted: October 3, 2017
- Accepted Manuscript published: October 4, 2017 (version 1)
- Version of Record published: October 17, 2017 (version 2)
- Version of Record updated: November 3, 2017 (version 3)
Copyright
© 2017, Ferber et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome
eLife 6:e25281.
https://doi.org/10.7554/eLife.25281
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