A predictive microfluidic model of human glioblastoma to assess trafficking of blood–brain barrier-penetrant nanoparticles

Joelle P. Straehla, Cynthia Hajal, Hannah C. Safford, Giovanni S. Offeddu, Natalie Boehnke, Tamara G. Dacoba, Jeffrey Wyckoff, Roger D. Kamm, Paula T. Hammond

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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.

Original languageEnglish (US)
Article numbere2118697119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number23
DOIs
StatePublished - Jun 7 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2022 the Author(s).

Keywords

  • blood–brain barrier
  • drug delivery
  • glioblastoma
  • microfluidic
  • nanoparticle

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