A predictive microfluidic model of human glioblastoma to assess trafficking of blood–brain barrier-penetrant nanoparticles
Name
straehla-et-al-a-predictive-microfluidic-model-of-human-glioblastoma-to-assess-trafficking-of-blood-brain-barrier.pdf
Description
Published version
Size
3.31 MB
Format
Adobe PDF
Checksum (MD5)
e70476b8dd42475530ee413954610158
Author(s)
Straehla, Joelle P
Hajal, Cynthia
Safford, Hannah C
Offeddu, Giovanni S
Boehnke, Natalie
Dacoba, Tamara G
Wyckoff, Jeffrey
Kamm, Roger D
Hammond, Paula T
Date Issued
June 1, 2022
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Citation
J.P. Straehla,C. Hajal,H.C. Safford,G.S. Offeddu,N. Boehnke,T.G. Dacoba,J. Wyckoff,R.D. Kamm, & P.T. Hammond, A predictive microfluidic model of human glioblastoma to assess trafficking of blood–brain barrier-penetrant nanoparticles, Proc. Natl. Acad. Sci. U.S.A. 119 (23) e2118697119 (2022).
Version
Final published version
Abstract
The blood–brain barrier represents a significant challenge for the treatment of high-grade gliomas, and our understanding of drug transport across this critical biointerface remains limited. To advance preclinical therapeutic development for gliomas, there is an urgent need for predictive in vitro models with realistic blood–brain-barrier vasculature. Here, we report a vascularized human glioblastoma multiforme (GBM) model in a microfluidic device that accurately recapitulates brain tumor vasculature with self-assembled endothelial cells, astrocytes, and pericytes to investigate the transport of targeted nanotherapeutics across the blood–brain barrier and into GBM cells. Using modular layer-by-layer assembly, we functionalized the surface of nanoparticles with GBM-targeting motifs to improve trafficking to tumors. We directly compared nanoparticle transport in our in vitro platform with transport across mouse brain capillaries using intravital imaging, validating the ability of the platform to model in vivo blood–brain-barrier transport. We investigated the therapeutic potential of functionalized nanoparticles by encapsulating cisplatin and showed improved efficacy of these GBM-targeted nanoparticles both in vitro and in an in vivo orthotopic xenograft model. Our vascularized GBM model represents a significant biomaterials advance, enabling in-depth investigation of brain tumor vasculature and accelerating the development of targeted nanotherapeutics.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Mechanical Engineering
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
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Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
https://doi.org/10.1073/pnas.2118697119
