Widespread gene transfer to malignant gliomas with In vitro-to-In vivo correlation

Abstract

Gene therapy of malignant gliomas has shown a lack of clinical success to date due in part to inability of conventional gene vectors to achieve widespread gene transfer throughout highly disseminated tumor areas within the brain. Here, we demonstrate that newly engineered polymerbased DNA-loaded nanoparticles (DNA-NP) possessing small particle diameters (~50 nm) and non-adhesive surface polyethylene glycol (PEG) coatings efficiently penetrate brain tumor tissue as well as healthy brain parenchyma. Specifically, this brain-penetrating nanoparticle (BPN), following intracranial administration via convection enhanced delivery (CED), provides widespread transgene expression in heathy rodent striatum and an aggressive brain tumor tissue established orthotopically in rats. The ability of BPN to efficiently traverse both tissues is of great

Magnetic nanoparticles: A new diagnostic and treatment platform for rheumatoid arthritis

“…Negron et al. have reported PEGylated PEI nanovectors carrying a reporter gene were able to transfect both healthy rat brain tissue and gliomas in vivo 42 …”

Recent Advances in the Use of Focused Ultrasound for Magnetic Resonance Image-Guided Therapeutic Nanoparticle Delivery to the Central Nervous System

“…Nevertheless, applying a dense PEG coat to nanoparticles has shown to be effective in producing biocompatible brain-penetrating nanoparticles upon FUS application without producing any significant signs of toxicity (Mastorakos et al, 2015; Mead et al, 2016; Suk et al, 2016; Mead et al, 2017) ( Figure 4 ). Further, increased PEGylation yields increased distribution within the target tissue (Mastorakos et al, 2015; Suk et al, 2016; Negron et al, 2019). For example, increasing the PEG density beyond conventional PEGylation ratios when designing PEGylated polyethylenimine (PEI) nanoparticles (i.e.…”

“…However, when densely coated with PEG, PEI nanoparticles do not exhibit significant toxic effects to cells (Huang et al, 2010; Mastorakos et al, 2015; Mead et al, 2017). When administered in vivo via convection enhanced delivery, PEGylated PEI nanovectors carrying a reporter gene were able to transfect both healthy rat brain tissue and gliomas (Negron et al, 2019). Increased PEGylation resulted in a larger volume of transgene expression and greater percentage of the tumor volume.…”

Augmented Therapeutic Potential of Glutaminase Inhibitor CB839 in Glioblastoma Stem Cells Using Gold Nanoparticle Delivery

“…Our tests reveal that treating the cells with AuPVA-CB839 NPs containing 1 µmol/L CB839 impaired tumor cell growth, as benchmarked to treatment with 1 µmol/L CB839 only ( Figure 6 ). The differences in the amount of reduction on CFE between the 2D (poly- d -lysine) vs. 3D (agarose) assay could be explained by the different susceptibly of the cells when grown in different conditions, whereby 3D more closely recapitulated the actual tumor physiology [ 32 ]. In addition, the variations in experimental handling sequence could result in different error introduction into the assays (pretreatment of cells for setting the Agarose assay, washing steps in 2D poly- d -lysine assay).…”

“…After a fast preparation of Au-Polymer-CB839 NPs without the need of additional linkers ( Figure 1 ), the efficacy of the CB839 inhibitor with and without the Au carriers was assessed in vitro using GBM neurospheres. These neurospheres are capable of reflecting the original tumor environment more closely due to their three-dimensional structure, compared to classical disease models using monolayer culturing technology [ 32 ]. For example, a hypoxic micro-environment could be formed in spheres from the outside to the inner core or the drug uptake can be slower for the inner cells than for the outlaying cells [ 33 ].…”