Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.

Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

Endotoxin-induced systemic inflammation activates microglia: [¹¹C]PBR28 positron emission tomography in nonhuman primates.

UNLABELLED: Microglia play an essential role in many brain diseases. Microglia are activated by local tissue damage or inflammation, but systemic inflammation can also activate microglia. An important clinical question is whether the effects of systemic inflammation on microglia mediate the deleterious effects of systemic inflammation in diseases such as Alzheimer's dementia, multiple sclerosis, and stroke. Positron Emission Tomography (PET) imaging with ligands that bind to Translocator Protein (TSPO) can be used to detect activated microglia. The aim of this study was to evaluate whether the effect of systemic inflammation on microglia could be measured with PET imaging in nonhuman primates, using the TSPO ligand [(11)C]PBR28. METHODS: Six female baboons (Papio anubis) were scanned before and at 1h and/or 4h and/or 22 h after intravenous administration of E. coli lipopolysaccharide (LPS; 0.1mg/kg), which induces systemic inflammation. Regional time-activity data from regions of interest (ROIs) were fitted to the two-tissue compartmental model, using the metabolite-corrected arterial plasma curve as input function. Total volume of distribution (V(T)) of [(11)C]PBR28 was used as a measure of total ligand binding. The primary outcome was change in V(T) from baseline. Serum levels of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and interleukin-8 (IL-8) were used to assess correlations between systemic inflammation and microglial activation. In one baboon, immunohistochemistry was used to identify cells expressing TSPO. RESULTS: LPS administration increased [(11)C]PBR28 binding (F(3,6)=5.1, p=.043) with a 29 ± 16% increase at 1h (n=4) and a 62 ± 34% increase at 4h (n=3) post-LPS. There was a positive correlation between serum IL-1ß and IL-6 levels and the increase in [(11)C]PBR28 binding. TSPO immunoreactivity occurred almost exclusively in microglia and rarely in astrocytes. CONCLUSION: In the nonhuman-primate brain, LPS-induced systemic inflammation produces a robust increase in the level of TSPO that is readily detected with [(11)C]PBR28 PET. The effect of LPS on [(11)C]PBR28 binding is likely mediated by inflammatory cytokines. Activation of microglia may be a mechanism through which systemic inflammatory processes influence the course of diseases such as Alzheimer's, multiple sclerosis, and possibly depression.