Nanoparticles like other colloidal carriers are rapidly taken up by cells of the reticulo-endothelial system (RES), also referred to as the mononuclear phagocytic system, and are then removed from the bloodstream [189, 199]. As a consequence, they do not remain long enough in the circulation to be able to reach the desired target site (unless of course the target site is the RES). One possibility to prolong the circulation time is the so-called "stealth" approach, the covalent attachment of PEG chains on the polymer. This process is called PEGylation (or pegylation) of the particles. The PEG chains are protruding from the nanoparticle surface into the aqueous environment yielding a hydrophilic shield around the particles and minimizing the adsorption of opsonins, compounds from the bloodstream that trigger the endocytotic uptake by macrophages and other cells of the RES.
The first nanoparticles that were pegylated were poly(lactide) nanoparticles [27, 200-205]. To obtain a coating that might prevent opsonization and subsequent recognition by the cells of the RES, PEG is attached to the particles using amphiphilic diblock copolymers, PEG-R, where R is the biodegradable polymer, that is, poly(lactic acid) or poly(lactic-co-glycolic acid) copolymer [27, 200, 201]. The PEG-R copolymers can be formed by the direct reaction of the terminal amino group from the monoamine monomethoxy PEG with the reactive carboxyl end group of the poly(lactic-co-glycolic acid). They can also be synthesized by the ring-opening polymerization at 114 °C of lac-tide and glycolide in the presence of monomethoxy PEG by the use of stannous octoate as a catalyst . Instead of poly(lactic acid) or poly(lactic-co-glycolic acid) poly(e-caprolactone) can be used [202-204]. The PEG-R polymers have amphiphilic properties where PEG due to its good water solubility represents the hydrophilic and R, being not water soluble but very soluble in organic phases, represents the hydrophobic part. For this reason, nanoparticles can easily be formed by the solvent evaporation method using methylene chloride or ethyl acetate  or by the solvent deposition or solvent displacement method using acetone . Due to its hydrophilicity the PEG part of the copolymer enriches on the polymer-water interface and after removal of the organic by evaporation  or solvent displacement  solid particles are formed. Therefore, with pegylated polymers generally no additional emulsifier is required. The production can easily be optimized and particles from 100 [27, 200, 201] up to 820 nm can be prepared with good reproducibility . Instead of diblock polymers, it is also possible to use PLA-PEG-PLA [PLA = poly(lactic acid)] using the salting-out process .
By a similar method sulfobutylated poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) nanoparticles using acetone and the solvent displacement method were produced especially for the delivery of proteins .
Poly(alkyl cyanoacrylates) belong to most rapidly biode-grading polymers and may be even more rapidly degrading then the poly(lactides) [25, 126]. For this reason also pegylated poly(alkyl cyanoycralate) nanoparticles were produced [28, 29, 208-212]. One method uses emulsion polymerization of isobutyl cyanoacrylate in the presence of methylated PEG (Me2PEG) as described in Section 4.1 . The authors claim that the PEG is covalently linked to the poly(isobutyl cyanoacrylate) by this method. Later poly(methoxy-polyethyleneglycol cyanoacrylate-co-hexadecyl cyanoacrylate) nanoparticles were produced [28, 29, 209212]. The methoxy-polyethyleneglycol cyanoacrylate-co-hexadecyl cyanoacrylate is amphiphilic like the pegylated poly(lactides). Consequently, as with the poly(lactides) nanoparticles can be produced by the solvent evaporation as well as by the nanoprecipitation methods .
In addition to these artificial polymers, PEG-modified albumin nanoparticles were prepared using albumin PEG
conjugates, poly(thioetheramido acid)-poly(ethylene glycol)-grafted human serum albumin and methoxy poly(ethylene glycol)-grafted human serum albumin [213-215]. The surface modified albumin nanoparticles released a model drug, rose bengal, in the presence of the enzyme trypsin much slower than similar unmodified albumin nanoparticles, suggesting the existence of a steric hydrophilic barrier by the PEG on the nanoparticle surface that made the digestion of the particles more difficult .
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