ABSTRACT
The adsorption of serum proteins on the surface of nanoparticles (NPs) delivered into a biological environment has been known to alter NP surface properties and consequently their targeting efficiency. In this paper, we use random copolymer (p(HEMA- ran-GMA))-based NPs synthesized using 2-hydroxyethyl methacrylate (HEMA) and glycidyl methacrylate (GMA). We show that serum proteins bind to the NP and that functionalization with antibodies and peptides designed to facilitate NP passage across the blood-brain barrier (BBB) to bind specific cell types is ineffective. In particular, we use systematic in vitro and in vivo analyses to demonstrate that p(HEMA- ran-GMA) NPs functionalized with HIV-1 trans-activating transcriptor peptide (known to cross the BBB) and α neural/glial antigen 2 (NG2) (known for targeting oligodendrocyte precursor cells (OPCs)), individually and in combination, do not specifically target OPCs and are unable to cross the BBB, likely due to the serum protein binding to the NPs.
Subject(s)
Blood-Brain Barrier/metabolism , Nanoparticles/chemistry , Nanoparticles/metabolism , Animals , Biological Transport/physiology , Epoxy Compounds/chemistry , Female , Male , Methacrylates/chemistry , Microscopy, Confocal , Oligodendrocyte Precursor Cells/metabolism , Polymers/chemistry , RatsABSTRACT
Following injury to the central nervous system, secondary degeneration is mediated by Ca2+ imbalances and overproduction of reactive oxygen species from mitochondria, and is associated with myelin deficits and loss of function. Preventing intracellular Ca2+ influx at the acute phase of injury is a potential strategy for limiting these deficits and preserving function. The use of single ion channel inhibitors has had little success in attenuating morphological and functional deficits, potentially due to the many pathways by which calcium can traverse the cell membrane. Focus has shifted to the simultaneous administration of a combination of ion channel inhibitors: lomerizine, oxATP, and YM872. The combination has resulted in reductions in oxidative damage, as well as preservation of function and myelin ultrastructure, potentially due to the protection of oligodendrocytes and their progenitors. The use of multiple ion channel inhibitors is promising and suggests a reduction in total intracellular Ca2+ influx is necessary and sufficient for the protection of neurons and glia following neurotrauma. Optimization of treatment timing, inhibitor choice, and method of delivery will be required for translation of this strategy to the clinic.
