Stealth Pegcoated Drug Carriers

To take advantage of the protein rejecting abilities of PEG, nanoparticles were coated with PEG mainly by polymer adsorption or by covalent grafting. Nondegradable polystyrene (PS) or poly(methyl methacrylate) nanospheres were coated by adsorption of amphiphilic copolymers such as Poloxamer™ and Poloxamine™, composed of hydrophobic poly propylene oxide (PPO) blocks that adsorb on the surface and of hydrophilic PEG blocks, which stick out of the surface [5, 31, 32]. An important reduction of liver accumulation attributed to the PEG coatings was observed [33].

This approach was adapted from model PS nanospheres to degradable PLGA nanospheres coated by adsorption of diblock PEG-PLA copolymers, which advantageously replaced the nonbiodegradable Poloxamer™ and Poloxam-ine™ surfactants [34].

However, it was emphasized that the adsorbed copolymers might desorb in vivo, due to replacement by blood components with a higher affinity for the particle surface, leading eventually to particle recognition by the MPS [35, 36]. Therefore, to obtain stable coatings, polymer grafting is a preferred alternative to polymer adsorption.

Poly(ethylene glycol) grafting on drug carriers was first achieved with liposomes [37, 38], micelles [39], and lately with model polystyrene nanospheres [40, 41] and cross-linked albumin nanospheres [42]. The use of preformed copolymers containing PEG blocks is a very convenient method to directly form PEG-coated nanoparticles. By this way, PEG-coated nanoparticles with biodegradable cores made of polyesters such as PLA [43], PLGA [9], poly(e-caprolactone) (PCL) [44], polyanhydride [44], and poly(alkyl cyanoacrylate) [45] were prepared. Figure 1 shows a nonex-haustive list of the structures of the most employed preformed block copolymers used for the manufacture of stealth nanoparticles. Diblock and triblock copolymers were synthesized since the early 1970s by anionic or ring-opening polymerization of monomers (lactide or e-caprolactone), initiated by the hydroxyl endgroups of PEG [46, 47]. Multiblock copolymers were prepared by coupling one end-group of PEG to polyester chains [48]. The development of surface-modified poly(alkyl cyanoacrylate) (PACA) nano-particles has been accelerated since the synthesis of a new PEG-containing PACA copolymer (poly(PEGcyanoacrylate-co-hexa decyl cyanoacrylate)), allowing the preparation of nanospheres by methods avoiding in-situ polymerization (i.e., nanoprecipitation or emulsification-solvent evaporation) [45]. In these nanospheres, PEG chains are grafted covalently to the surface by the means of PACA anchors forming the core of the particles.

Nanoparticles were formed with the block copolymers listed in Figure 1, mainly by using techniques such as nanoprecipitation, emulsification-solvent evaporation, double emulsion, or salting out.

CH,-O-(CH2-CH2-O)n-CH2-CH2-O-(C-CH-O)m-C-CH-OH PEG-PLA

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