Poly(ethylene glycol)-Coated Hexadecylcyanoacrylate Nanospheres Display a Combined Effect for Brain Tumor Targeting

Abstract

The aim of the present study was to evaluate the tumor accumulation of radiolabeled long-circulating poly(ethylene glycol) (PEG)-coated hexadecylcyanoacrylate nanospheres and non-PEG-coated hexadecylcyanoacrylate nanospheres (used as control), after intravenous injection in Fischer rats bearing intracerebrally well established 9L gliosarcoma. Both types of nanospheres showed an accumulation with a retention effect in the 9L tumor. However, long-circulating nanospheres concentrated 3.1 times higher in the gliosarcoma, compared with non-PEG-coated nanospheres. The tumor-to-brain ratio of pegylated nanospheres was found to be 11, which was in accordance with the ratios reported for other carriers tested for brain tumor targeting such as long-circulating liposomes or labels for magnetic resonance imaging. In addition, a 4-to 8-fold higher accumulation of the PEG-coated carriers was observed in normal brain regions, when compared with control nanospheres.Using a simplified pharmacokinetic model, two different mechanisms were proposed to explain this higher concentration of PEG-coated nanospheres in a tumoral brain. 1) in the 9L tumor, the preferential accumulation of pegylated nanospheres was attributable to their slower plasma clearance, relative to control nanospheres. Diffusion/convection was the proposed mechanism for extravasation of the nanospheres in the 9L interstitium, across the altered blood-brain barrier. 2) In addition, PEGcoated nanospheres displayed an affinity with the brain endothelial cells (normal brain region), which may not be considered as the result of a simple diffusion/convection process. The exact underlying mechanism of such affinity deserves further investigation, since it was observed to be as important as specific interactions described for immunoliposomes with the blood-brain barrier.

‘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

“…The first would be targeting brain tumors with therapeutic drugs given that most tumor blood vessels are more permeable and ''leaky'' in comparison to well built vessels in normal tissues. Conceivably the nanoparticles carrying antineoplastic drugs would reach brain tumors, and PEG-coated nanoparticles were found to be with more than 10 times of efficiency in delivery tested by accumulation in tumor tissues when compared to routine delivery through circulation (Brigger et al 2002;Feng et al 2004). Also, the polysorbate coated nanoparticles that can be taken up by brain endothelial cells have been shown to target tumor tissues efficiently (Alyautdin et al 1997).…”

Nanoparticle-Based Brain Targeted Delivery Systems

“…PEGylatingliposome vectors that target the brain's insulin receptor shows promising results for gene therapies [7], as studies in human and rat glioma cells have shown that targeting the insulin receptor yields 100-200 fold higher levels of gene expression as compared to targeting the human epidermal growth factor receptor (EGFR) or the rat transferrin receptor [8]. In addition, hexadecylcyanoacrylate nanoparticles coated with PEG were shown to target rat gliosarcoma cells and accumulate within the cells [9]. PEGylated micelles were shown to accumulate into rat brain glioma models [10].Furthermore, PEG-complexed nanoparticles were shown to permeate the BBB to therapeutically effect models of multiple sclerosis [3,11] and Parkinson's disease [12] among other diseases.…”