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

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.

Core material and surface chemistry of Layer-by-Layer (LbL) nanoparticles independently direct uptake, transport, and trafficking in preclinical blood-brain barrier (BBB) models

“…As LbL films cover the surface of each core NP, we hypothesize that differences can be primarily attributed to the stiffness and deformability of the core material. This improved performance of softer nanomaterial transport is consistent with studies of nanogels in static hCMEC/D3 systems 35 , while limited studies in systems with fluid flow have not yet reached consensus on the relationship between particle stiffness and BBB transport 17,19,36 . By comparing surface chemistries, we once again saw that LbL functionalization improved monolayer association (Figure 4d) for most formulations, though the differences were less stark than those observed by flow cytometry.…”

“…Each combination of these factors offers its own advantages for inter-lab consistency, ease of handling, and/or recapitulation of the physical environment of the brain capillaries 16 . For example, there are several 3D microfluidic models currently under development for screening of therapeutics or material libraries [17][18][19] . However, these remain difficult to standardize across labs and to scale for high-throughput studies.…”

BBB-on-a-chip with Integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer’s disease

“…Recently, this nanosystem demonstrated be helpful for AD diagnosis through the detection of Aβ by computerized tomography and Aβ disaggregation in mice [38]. However, despite the great potential of nanotechnology, few works have used BBB-oC for the evaluation of nanoparticles permeability [39][40][41], but to our knowledge, none has yet tested any therapeutic nanoparticle as a potential treatment against NDDs.…”

BBB-on-a-chip with Integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer’s disease

“…Recently, this nanosystem demonstrated be helpful for AD diagnosis through the detection of Aβ by computerized tomography and Aβ disaggregation in mice [38]. However, despite the great potential of nanotechnology, few works have used BBB-oC for the evaluation of nanoparticles permeability [39–41], but to our knowledge, none has yet tested any therapeutic nanoparticle as a potential treatment against NDDs.…”

“…However, despite the great potential of nanotechnology, few works have used BBB-oC for the evaluation of nanoparticles permeability [39][40][41], but to our knowledge, none has yet tested any therapeutic nanoparticle as a potential treatment against NDDs.…”