Engineering Controlled Peritumoral Inflammation to Constrain Brain Tumor Growth

Abstract

Brain tumors remain a great clinical challenge, in part due to their capacity to invade into eloquent, inoperable regions of the brain. In contrast, inflammation in the central nervous system (CNS) due to injuries activates microglia and astrocytes culminating in an astroglial scar that typically “walls‐off” the injury site. Here, the hypothesis is tested that targeting peritumoral cells surrounding tumors to activate them via an inflammatory stimulus that recapitulates the sequelae of a traumatic CNS injury, could generate an environment that would wall‐off and contain invasive tumors in the brain. Gold nanoparticles coated with inflammatory polypeptides to target stromal cells in close vicinity to glioblastoma (GBM) tumors, in order to activate these cells and stimulate stromal CNS inflammation, are engineered. It is reported that this approach significantly contains tumors in rodent models of GBM relative to control treatments (reduction in tumor volume by over 300% in comparison to controls), by the activation of the innate and adaptive immune response, and by triggering pathways related to cell clustering. Overall, this report outlines an approach to contain invasive tumors that can complement adjuvant interventions for invasive GBM such as radiation and chemotherapy.

Targeting glioblastoma through nano- and micro-particle-mediated immune modulation

“…9d). 148 Overall these results suggest that generation of a physical barrier through upregulated inflammation may be able to reduce GBM invasiveness. Further understanding of targeting mechanisms to ensure scar tissue development is limited to the tumour periphery would be required before translation to human trials.…”

“…147 One unusual approach to tackling this problem was to hijack the natural formation of glial scar tissue in response to injury in order to 'wall-in' tumour cells, whereby the presence of chondroitin sulfate proteoglycans (CSPGs) within scar tissue repels tumour cells from passing through it. 148 By functionalising the surface of gold nanoparticles with poly(ethylene glycol) (PEG) and peptides derived from zymosan, a known stimulant of reactive gliosis and glial scarring, Saxena et al, were able to generate a pro-inflammatory nanoparticle capable of stimulating glial scarring. 148,149 Additionally, when nanoparticles were delivered intravenously to tumour-bearing rats, scar tissue developed around the tumour site, with tumours found to be significantly smaller with reduced growth (Fig.…”

“…148 By functionalising the surface of gold nanoparticles with poly(ethylene glycol) (PEG) and peptides derived from zymosan, a known stimulant of reactive gliosis and glial scarring, Saxena et al, were able to generate a pro-inflammatory nanoparticle capable of stimulating glial scarring. 148,149 Additionally, when nanoparticles were delivered intravenously to tumour-bearing rats, scar tissue developed around the tumour site, with tumours found to be significantly smaller with reduced growth (Fig. 9d).…”

Nanomedicine Revisited: Next Generation Therapies for Brain Cancer

“…Groups have also had success in leveraging toll‐like receptor‐mediated innate immune activation in GBM (Figure 4‐4). [ 121,182,183 ] In a study conducted by Shibata et al. intravenous delivery of liposomal nanoparticle formulations containing the agent, phospholipid‐conjugated indocyanine green, in combination with near infrared light irradiation (LP‐iDOPE‐NIR) was shown to directly recruit immune cells including T cells and microglia to produce a significant immune‐mediated anti‐tumor response in a rat GBM model on histological analysis.…”

“…When administered intravenously, these nanoparticles decreased tumor growth and spread beyond the inoculation site. [ 183 ]…”