2 research outputs found
'Stealth' nanoparticles evade neural immune cells but also evade major brain cell populations: Implications for PEG-based neurotherapeutics
Surface engineering to control cell behavior is of high interest across the chemical engineering, drug delivery and biomaterial communities. Defined chemical strategies are necessary to tailor nanoscale protein interactions/adsorption, enabling control of cell behaviors for development of novel therapeutic strategies. Nanoparticle-based therapies benefit from such strategies but particle targeting to sites of neurological injury remains challenging due to circulatory immune clearance. As a strategy to overcome this barrier, the use of stealth coatings can reduce immune clearance and prolong circulatory times, thereby enhancing therapeutic capacity. Polyethylene glycol (PEG) is the most widely-used stealth coating and facilitates particle accumulation in the brain. However, once within the brain, the mode of handling of PEGylated particles by the resident immune cells of the brain itself (the ‘microglia’) is unknown. This is a critical question as it is well established that microglia avidly sequester nanoparticles, limiting their bioavailability and posing a major translational barrier. If PEGylation can be proved to promote evasion of microglia, then this information will be of high value in developing tailored nanoparticle-based therapies for neurological applications. Here, we have conducted the first comparative study of uptake of PEGylated particles by all the major (immune and non-immune) brain cell types. We prove for the first time that PEGylated nanoparticles evade major brain cell populations — a phenomenon which will enhance extracellular bioavailability. We demonstrate changes in protein coronas around these particles within biological media, and discuss how surface chemistry presentation may affect this process and subsequent cellular interactions
Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy
Corticosteroid
(CS) therapy is used widely in the treatment of a range of pathologies,
but can delay production of myelin, the insulating sheath around central
nervous system nerve fibers. The cellular targets of CS action are
not fully understood, that is, “direct” action on cells
involved in myelin genesis [oligodendrocytes and their progenitors
the oligodendrocyte precursor cells (OPCs)] versus “indirect”
action on other neural cells. We evaluated the effects of the widely
used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes,
employing complementary histological and transcriptional analyses.
Histological assessments showed no DEX effects on OPC proliferation
or oligodendrocyte genesis/maturation (key processes underpinning
myelin genesis). Immunostaining and RT-PCR analyses show that both
cell types express glucocorticoid receptor (GR; the target for DEX
action), ruling out receptor expression as a causal factor in the
lack of DEX-responsiveness. GRs function as ligand-activated transcription
factors, so we simultaneously analyzed DEX-induced transcriptional
responses using microarray analyses; these substantiated the histological
findings, with limited gene expression changes in DEX-treated OPCs
and oligodendrocytes. With identical treatment, microglial cells showed
profound and global changes <i>post</i>-DEX addition; an
unexpected finding was the identification of the transcription factor <i>Olig1</i>, a master regulator of myelination, as a DEX responsive
gene in microglia. Our data indicate that CS-induced myelination delays
are unlikely to be due to direct drug action on OPCs or oligodendrocytes,
and may occur secondary to alterations in other neural cells, such
as the immune component. To the best of our knowledge, this is the
first comparative molecular and cellular analysis of CS effects in
glial cells, to investigate the targets of this major class of anti-inflammatory
drugs as a basis for myelination deficits