Overall these data show that the stealth behaviour of long circulating nanocarriers is a very complex mechanism and it cannot be reduced to the simple opsonin repulsion underlining some additional

and relevant effects operated by the steric coating on the nanocarrier surface. 2.4.1. PEG Induced Complement Activation PEG coating on one side reduces the opsonisation process, while on the other can induce the complement Inhibitors,research,lifescience,medical activation that is involved in the nanoparticle removal. Liposomes are a typical example of the double effect of particle PEGylation. Liposomes with low surface charge obtained with saturated phospholipids and high cholesterol content, which endows rigid and uniform bilayer without surface defects, are poorly prone to opsonisation and structural destabilisation by C3 adsorption [121, 128, 131, 132]. On the contrary, negatively charged and flexible liposomes undergo rapid opsonisation and phagocytosis. Inhibitors,research,lifescience,medical The incorporation of 5–7.5mol% of PEG 2kDa-DSPE into the bilayer of anionic Inhibitors,research,lifescience,medical liposomes formed by egg phosphatidyl-choline, cholesterol, and cardiolipin (35:45:20 mole ratio) was found to dramatically

reduce the complement activation of these vesicles. However, the degree of complement activation also depended on the liposomes concentration. Indeed, in vitro studies showed that 15mM PEGylated liposomes concentration induced 40% complement consumption [133]. Studies carried out with Doxil showed that 0.4mg/mL of PEGylated liposomes elicited the rapid complement activation and generate the soluble terminal complement complex (SC5b-9) in 7 out of 10 human sera [134]. These results underline the individual effect of PEGylated liposomes on the complement Inhibitors,research,lifescience,medical activation. The complement activation by PEGylated liposomes was found to be Vandetanib order responsible for several side effects. In pigs Doxil was demonstrated

to activate the complement through both the C1q-dependent Inhibitors,research,lifescience,medical classical and the alternative complement activation pathways [135], which was responsible for the cardiopulmonary distress [136]. In few cases, a transient in vivo response was Dichloromethane dehalogenase observed in rabbits as a drop in the systemic arterial pressure at 10min after liposome injection which is typical of the complement activation [137]. On the contrary, no complement activation after PEGylated liposome administration was evidenced by the in vitro assay. These evidences highlight that in vitro complement activation tests should be carefully evaluated for what concerns their sensitivity and response threshold in order to obtain results that can be correlated with the in vivo data. Studies performed with PEGylated polymeric nanoparticles confirmed that PEG-coated systems can induce the complement activation regardless of the PEG chain length and surface density.