On the synthesis of mucus permeating nanocarriers.

Abstract The synthesis of nanocarriers with “slippery” surface (i.e., poly(lactide-co-glycolide)–polyethylene glycol (PLGA–PEG) nanoparticles (NPs) and polyelectrolyte complexes (PECs) of polyacrylic acid (PAA) with poly- l -lysine (PLL) and/or polyarginine (PArg)) and of nanocarriers (i.e., PLGA NPs, PLGA–PEG NPs, liposomes) containing a mucolytic agent (i.e., 4-mercaptobenzoic acid (4MBA)) is presented. Depending on the molecular weight (MW) of PEG (i.e., 2, 5 kDa), PLGA–PEG NPs with a “brush” or “dense brush” PEG configuration were prepared. The PLGA–PEG NPs exhibited increased mucus permeability in comparison with non-pegylated PLGA NPs when tested in fresh porcine intestinal mucus. The NPs that were prepared using PEG with a MW equal to 5 kDa and had a “dense brush” PEG configuration, were found to exhibit the highest mucus permeability. The average size and the surface charge of PECs could be effectively tuned by varying the PAA/polycation charge ratio, thus resulting in the synthesis of neutral as well as positively and negatively charged PECs. The PECs with negative surface charges were found to exhibit the highest mucus permeability followed by the neutral and finally the positively charged PECs. Depending on the initial concentration of the mucolytic agent, 4MBA loadings up to 13.65, 13.1 and 18.43 wt% were achieved for PLGA NPs, PLGA–PEG NPs and liposomes, respectively. PLGA and PLGA–PEG NPs were characterized by a rapid release of the mucolytic agent (i.e., >80 wt% of 4MBA was released in 20 min) whereas, its encapsulation in liposomes allowed a more controlled release (i.e., up to 30 wt% of 4MBA was released in 45 min). 4MBA loaded liposomes were found to exhibit increased mucus permeability depending on the composition of the phospholipid bilayer.