Quantification and localization of PEGylated polycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat

Abstract

Under healthy conditions, the blood-brain barrier (BBB) limits the passage of solutes and cells from the blood to the CNS. During neurological diseases, BBB permeability increases dramatically and it has been hypothesized that drug carrier systems such as polymeric nanoparticles could cross the BBB and penetrate into the CNS. PEGylated polyalkylcyanoacrylate nanoparticles (long-circulating carrier) are one such system and have been investigated during experimental allergic encephalomyelitis (EAE). Brain and spinal cord concentrations of [(14)C]-radiolabelled PEGylated polyalkylcyanoacrylate nanoparticles were compared with another blood long-circulating carrier (poloxamine 908-coated polyalkylcyanoacrylate nanoparticles) and with conventional non-long-circulating polyalkylcyanoacrylate nanoparticles. The microscopic localization of fluorescent nanoparticles in the CNS was also investigated in order to further understand the mechanism by which the particles penetrate the BBB. The results demonstrate that the concentration of PEGylated nanoparticles in the CNS, especially in white matter, is greatly increased in comparison to conventional non-PEGylated nanoparticles. In addition, this increase was significantly higher in pathological situations where BBB permeability is augmented and/or macrophages have infiltrated. Passive diffusion and macrophage uptake in inflammatory lesions seems to be the mechanism underlying such particles' brain penetration. Based on their long-circulating properties in blood and on their surface characteristics that allow cell interactions, PEGylated nanoparticles penetrated into CNS to a larger extent than all the other formulations tested. Thus, PEGylated polycyanoacrylate nanoparticles are proposed here as a new brain delivery system for neuroinflammatory diseases.

‘Stealth’ nanoparticles evade neural immune cells but also evade major brain cell populations: Implications for PEG-based neurotherapeutics

“…PEG-coated nanoparticles accumulate in brain tissue more effectively than non-PEG-coated nanoparticles, and those coated with high density PEG also display greater diffusion through brain parenchyma [4,16]. Of high relevance for clinical applications, PEG-coated nanoparticle accumulation is enhanced in pathological foci including gliosarcoma and Multiple Sclerosis models [17,18], possibly due to inflammation-induced BBB hyperpermeability -similar to enhanced nanoparticle permeability/retention (EPR effect) in brain tumors [19]. [20,21] exhibiting dramatically more rapid/extensive nanoparticle uptake than all other neural subtypes, in vitro [22] and in vivo [23].…”

Recent advances in nanotechnology based drug delivery to the brain

“…For instance, many growth factors and neuropeptides are effective when administrated into the ventricle, but lack efficiency for systemic application, explained by their failure in crossing the BBB. Now people have successfully delivered PEG-coated nanoparticles to brain and spinal cord in rat model of experimental allergic encephalomyelitis, for instance (Calvo et al 2002). It is believed that in the future more and more other brain diseases could be treated in similar manners.…”

Uses of Nanoparticles for Central Nervous System Imaging and Therapy

“…For instance, in one study that used a common brain inflammation model (experimental allergic encephalomyelitis), nanoparticle delivery was pronounced in areas where the BBB had been disrupted and in regions of macrophage infiltration. 18 However, most CNS uses of nanoparticles are intended for conditions in which the BBB is intact. In the experimental allergic encephalomyelitis study just cited, the concentration of PEGylated nanoparticles was found to be increased even in brain regions in which the BBB was intact compared with non-PEGylated nanoparticles, especially in white matter.…”