The biodistribution of PLA and PEG-PLA nanospheres after intravenous administration was studied in rats [43]. The PLA nanospheres had a circulatory half-life of only 2 minutes, whereas the PEG-coated ones had a dramatically improved half-life (about 6 h). Autoradiography studies confirmed that after 6 hours, a high amount of nano-spheres were still in the blood compartment. However, it was observed that the uptake by MPS organs (essentially liver, spleen, and bone marrow) also took place. It was concluded that the phagocytosis of the PEG-PLA nanospheres was delayed due to their PEG coating, but that the final destination of the particles was always the MPS. More recently, the toxicity of these nanospheres after intravenous administration was investigated in rats [105]. In the case of PLA nanospheres, no toxicity was found at low doses, but at the highest doses investigated (220 and 440 mg/kg), a marked toxicity was observed, together with hematological and biochemical changes. Oppositely, even at these highest doses, no lethality and no clinical changes were observed in the case of PEG-PLA nanospheres.

The blood half-life of PEG-PLGA nanospheres in mice [9] was found to increase with the molecular weight of the coating PEG layer. In parallel, liver uptake was significantly reduced by increasing the PEG molecular weight. Gamma scintigraphy confirmed the dramatic body distribution differences between the long-circulating PEG-PLGA and the PLGA nanospheres, which were sequestered rapidly in liver and spleen. It was shown that both blood clearance and MPS uptake of the PLGA nanospheres were dose-dependent [106]. As this clearance decreased with the increase of the administered dose, it was suggested that MPS saturation occurred. Oppositely, it was shown that blood clearance and MPS uptake of the PEG-PLGA nanospheres were independent of dose.

Cyanoacrylate nanospheres coated with PEG were shown to circulate longer in mice than the uncoated ones [104]. The accumulation of these nanospheres in the liver, bone marrow, and lungs was reduced, whereas 10% of the injected dose reached the spleen 3 hours after injection [107]. Thus, these nanospheres also represent interesting colloidal systems for the targeting of active molecules to the spleen.

All the studies reviewed previously clearly prove the potential of PEG-coated nanoparticles by opposition to the uncoated ones: (i) to increase the blood half-lives, (ii) to reduce MPS accumulation, (iii) to reduce the toxicity, and (iv) to achieve dose-independent pharmacokinetics.

In certain pathological situations, the permeability of the vascular endothelium is dramatically increased because of the inflammatory response resulting from cancers, infections, or autoimmune diseases. This particular histological situation offers interesting perspectives for the targeting of these inflamed tissues with PEG-decorated nanoparticles, since their long circulating properties are believed to increase their chances to extravasate selectively through these leaky vasculatures. Very exciting applications were considered very recently for brain-tissue targeting. Indeed, under healthy conditions, the blood-brain barrier (BBB) limits the passage of solutes and cells from the blood to the central nervous system (CNS). During neurological diseases, BBB permeability, however, increases dramatically, and it has been hypothesized that drug carrier systems such as polymeric nanoparticles could cross the BBB and penetrate into the CNS. In this view, PEGylated polyalkylcyanocry-late nanoparticles (long-circulating carrier) have been investigated during experimental allergic encephalomyelitis [108]. Brain and spinal cord concentrations of [14C]-radiolabeled PEGylated polyalkylcyanoacrylate nanoparticles were compared with poloxamine 908-coated polyalkylcyanoacrylate nanoparticles, another blood long-circulating carrier and with conventional non-long-circulating polyalkylcyanoacry-late nanoparticles. The microscopic localization of fluorescent nanoparticles in the CNS also was investigated to further understand the mechanism by which the particles penetrate the BBB. The results demonstrated that the concentration of PEGylated nanoparticles in the CNS, especially in the white matter, was greatly increased in comparison to conventional non-PEGylated nanoparticles [108]. In addition, this increase was significantly higher in pathological situations where BBB permeability was augmented and/or macrophages were infiltrated. Passive diffusion and macrophage uptake in inflammatory lesions seem to be the mechanisms underlying such particle 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.

By the same way, the vasculature of brain glioma, like that of other solid tumors, may also present some peculiarities that form the basis of increased microvascular permeability. Some of these peculiarities include open endothelial gaps (interendothelial junctions and transendothelial channels; diameter of about 0.3 /¿m), fenestrations (maximum channel width of 5.5 nm), as well as cytoplasmic vesicles like caveolae (diameter of 50-70 nm) and vesicular vacuolar organelles (diameter of 108 nm ± 32). An increase in vessel-wall thickness also has been reported, which was attributed to endothelial cell hyperplasia, reflecting an increase in non-selective transendothelial transport. All these characteristics, which may be due in major part to the secretion of the vascular permeability factor VEGF and which can lead to a loss of BBB function in the case of cerebral malignances, would be beneficial for transvascular transport of drugs with the aid of blood long-circulating nanoparticles. This approach has been tested with radiolabeled long-circulating PEG-coated hexadecylcyanoacrylate nanospheres comparatively to non-PEG-coated hexadecylcyanoacrylate nano-spheres, after intravenous injection in Fischer rats bearing intracerebrally well-established 9L gliosarcoma [109]. Both types of nanospheres showed an accumulation with a retention effect in the 9L tumor. However, long-circulating nano-spheres concentrated 3.1 times higher in the gliosarcoma in comparison with non-PEG-coated nanospheres. The tumor-to-brain ratio of pegylated nanospheres was found to be 11. In addition, a 4- to 8-fold higher accumulation of the PEG-coated carriers was observed in normal brain regions, when compared to control nanospheres. By using a simplified pharmacokinetic model, two different mechanisms were proposed to explain this higher concentration of PEG-coated nanospheres in a tumoral brain: (i) in the 9L tumor, the preferential accumulation of pegylated nanospheres was attributable to their slower plasma clearance, relative to control nanospheres; diffusion or convection was the proposed mechanism for extravasation of the nanospheres in the 9L interstitium, across the altered blood brain barrier: (ii) in addition, PEG-coated nanospheres displayed an affinity with the brain endothelial cells (normal brain region), which may not be considered as the result of a simple diffusion or convection process [109].

In another study [110], PEGylated PHDCA nano-particles were proposed as a potential efficient drug carrier for the delivery of active therapeutic molecules to the brain of animals with prion experimental diseases. Again, due to the brain inflammatory process and based on their long-circulating characteristics, these PEGylated particles, indeed, showed comparatively to conventional non-PEGylated nanoparticles, a higher uptake by the brain.

These examples illustrate the potential of core corona PEG-co-hexadecylcyanoacrylate nanoparticles for the targeting of diseased brain tissues.

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