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 (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.
Significance Statement The blood-brain barrier represents a major therapeutic challenge for the treatment of glioblastoma, and there is an unmet need for in vitro models that recapitulate human biology and are predictive of in vivo response. Here we present a new microfluidic model of vascularized glioblastoma featuring a tumor spheroid in direct contact with self-assembled vascular networks comprised of human endothelial cells, astrocytes, and pericytes. This model was designed to accelerate the development of targeted nanotherapeutics, and enabled rigorous assessment of a panel of surface-functionalized nanoparticles designed to exploit a receptor overexpressed in tumor-associated vasculature. Trafficking and efficacy data in the in vitro model compared favorably to parallel in vivo data, highlighting the utility of the vascularized glioblastoma model for therapeutic development.
Competing Interest Statement
RDK is a co-founder of AIM Biotech that markets microfluidic systems for 3-dimensional culture and receives research funding from Amgen and Biogen. PTH is a co-founder and member of the board of LayerBio, a member of the Board of Alector, a member of the Scientific Advisory Board of Moderna, and receives research funding from Shepherd Pharmaceuticals, Novartis, and SecuraBio, all for work unrelated to this manuscript. All other authors report no competing interests.
Footnotes
↵‡ These authors jointly supervised this work
Competing Interest Statement: RDK is a co-founder of AIM Biotech that markets microfluidic systems for 3-dimensional culture and receives research funding from Amgen and Biogen. PTH is a co-founder and member of the board of LayerBio, a member of the Board of Alector, a member of the Scientific Advisory Board of Moderna, and receives research funding from Shepherd Pharmaceuticals, Novartis, and SecuraBio, all for work unrelated to this manuscript. All other authors report no competing interests.
