Optical blood-brain-tumor barrier modulation expands therapeutic options for glioblastoma treatment

Abstract

The treatment of glioblastoma has limited clinical progress over the past decade, partly due to the lack of effective drug delivery strategies across the blood-brain-tumor barrier. Moreover, discrepancies between preclinical and clinical outcomes demand a reliable translational platform that can precisely recapitulate the characteristics of human glioblastoma. Here we analyze the intratumoral blood-brain-tumor barrier heterogeneity in human glioblastoma and characterize two genetically engineered models in female mice that recapitulate two important glioma phenotypes, including the diffusely infiltrative tumor margin and angiogenic core. We show that pulsed laser excitation of vascular-targeted gold nanoparticles non-invasively and reversibly modulates the blood-brain-tumor barrier permeability (optoBBTB) and enhances the delivery of paclitaxel in these two models. The treatment reduces the tumor volume by 6 and 2.4-fold and prolongs the survival by 50% and 33%, respectively. Since paclitaxel does not penetrate the blood-brain-tumor barrier and is abandoned for glioblastoma treatment following its failure in early-phase clinical trials, our results raise the possibility of reevaluating a number of potent anticancer drugs by combining them with strategies to increase blood-brain-tumor barrier permeability. Our study reveals that optoBBTB significantly improves therapeutic delivery and has the potential to facilitate future drug evaluation for cancers in the central nervous system.

Glioblastoma Margin as a Diffusion Barrier Revealed by Photoactivation of Plasmonic Nanovesicles

“…The GEMMs contain the common mutations in human GBM, e.g., the loss of critical tumor suppressor genes (PTEN –/– and P53 –/– or PTEN –/– and INK4ab/Arf –/– ). We have characterized the heterogeneous vascular properties of the two GEMMs in the previous work . Here, we demonstrate the spatially cellular heterogenicity in these GEMMs, including the loss of neurons in the tumor core and the activation of astrocytes in the tumor margin.…”

“…We have characterized the heterogeneous vascular properties of the two GEMMs in the previous work. 18 Here, we demonstrate the spatially cellular heterogenicity in these GEMMs, including the loss of neurons in the tumor core and the activation of astrocytes in the tumor margin. Moreover, the de novo GEMM includes the mutations Braf V600Ef/+ , P53 f/f , and Pten f/f seen in both adult and pediatric high-grade GBM.…”

“…We then tested 73C GBM that carries mutations including Braf V600E , P53 –/– , and PTEN –/– , seen in both adult and pediatric high-grade gliomas, and is derived from conditional multiallele primary astrocytes. , 73C GBM is characterized by a clear boundary between the tumor core and margin (Figure e), resulting from a fast-growing angiogenic tumor with limited infiltration. We found that the diffusion coefficient in the tumor core is 2.1-fold higher than that in the tumor margin, and the tortuosity of ECS in the tumor core is around 71% of that in the tumor margin (Figure f,g, Figure S4).…”

“…Toward this, we present a novel technique utilizing the photoactivation of plasmonic nanovesicles (PANO) to measure the molecular diffusion in the GBM extracellular space, which includes all-optical activation and observation of fluorophore diffusion. We applied the PANO technique to investigate the heterogeneous GBM brains in three preclinical genetically engineered glioma mouse models (GEMM), which carry mutations common in both adult and pediatric high-grade gliomas. , The orthotopic xenografted PS5A1 and 73C GBM were characterized with a highly infiltrative margin and rapidly expanding core, respectively, which represent a reasonable facsimile of human GBM features. The third GEMM, de novo GBM, in a natural immune-proficient microenvironment, more closely mimics the histopathological features and the progress of human GBM.…”

Functionalized Nanomaterials Capable of Crossing the Blood–Brain Barrier

“…However, while often they are described as “leakier” than the BBB, some studies find the BBTB capable of expressing active efflux transporters and maintaining barrier integrity . Therefore, the leaky BBTB is highly heterogeneous with wide variability in permeation − and abnormal tumor angiogenesis. This typically leads to a highly disorganized vasculature characterized by increased fenestrations and wider intercellular gaps that enhance paracellular transport.…”