The attention of many researchers has been devoted to another challenge, the entrapment of macromolecules such as proteins into stealth nanoparticles. It was shown by using a model protein, human serum albumin (HSA), that protein-loaded PEG-coated nanospheres of about 200 nm could be obtained [97, 98] following a preparation method that was an adaptation of the double emulsion water-in-oil-in-water (w/o/w) method for the preparation of microspheres [99]. Microscopic and surface analysis techniques indicated that HSA was well entrapped inside the nanosphere core and that it was not adsorbed on its surface. The HSA loadings of 7-8 wt% was achieved, together with a sustained in vitro release, over two weeks [98]. More recently, bovine serum albumin was loaded in 200 nm PEG-PLGA nanospheres, following the double emulsion method, with an entrapment efficiency of about 50% [100]. The albumin half-life in rats was extended from 13.6 min (uncoated nanospheres) up to 4.5 h (PEG-coated nanospheres).

Protein C, a plasma inhibitor that regulates the mechanism of blood coagulation, was successfully entrapped in PEG-PLA nanospheres [101]. Tetanus toxoid (TT), a model antigen known to readily lose its activity during encapsulation and release from microspheres [102], was also efficiently entrapped within PEG-PLA and PLA nanospheres of less than 150 nm [103]. The PEG-coated nanospheres released a greater amount of active antigen than those made of PLA. Moreover, when the TT-loaded nanospheres were administered intranasally in mice, a significant enhancement of the TT concentration in the blood stream was obtained with the PEG-PLA nanospheres [103]. More recently, the potential of TT-loaded PEG-coated nanospheres for oral administration was evaluated [104]. The nanospheres did not degrade in significant amounts in digestive fluids during a 4-hour incubation period, so that the encapsulated TT remained associated to them. After oral administration to rats, the levels of radioactive TT in the blood stream and lymphatics were higher for PEG-coated nanospheres than for PLA nanospheres.

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