Nanotoxicity comparison of four amphiphilic polymeric micelles with similar hydrophilic or hydrophobic structure

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Nanocarriers represent an attractive means of drug delivery, but their biosafety must be established before their use in clinical research.</jats:p> </jats:sec> <jats:sec> <jats:title>Objectives</jats:title> <jats:p>Four kinds of amphiphilic polymeric (PEG-PG-PCL, PEEP-PCL, PEG-PCL and PEG-DSPE) micelles with similar hydrophilic or hydrophobic structure were prepared and their <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> safety were evaluated and compared.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p> <jats:italic>In vitro</jats:italic> nanotoxicity evaluations included assessments of cell morphology, cell volume, inflammatory effects, cytotoxicity, apoptosis and membrane fluidity. An umbilical vein cell line (Eahy.926) and a kind of macrophages (J774.A1) were used as cell models considering that intravenous route is dominant for micelle delivery systems. <jats:italic>In vivo</jats:italic> analyses included complete blood count, lymphocyte subset analysis, detection of plasma inflammatory factors and histological observations of major organs after intravenous administration to KM mice.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>All the micelles enhanced inflammatory molecules in J774.A1 cells, likely resulting from the increased ROS levels. PEG-PG-PCL and PEEP-PCL micelles were found to increase the J774.A1 cell volume. This likely correlated with the size of PEG-PG-PCL micelles and the polyphosphoester structure in PEEP-PCL. PEG-DSPE micelles inhibited the growth of Eahy.926 cells via inducing apoptosis. This might relate to the structure of DSPE, which is a type of phospholipid and has good affinity with cell membrane. No evidence was found for cell membrane changes after treatment with these micelles for 24 h. In the <jats:italic>in vivo</jats:italic> study, during 8 days of 4 time injection, each of the four nanocarriers altered the hematic phase differently without changes in inflammatory factors or pathological changes in target organs.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These results demonstrate that the micelles investigated exhibit diverse nanotoxicity correlated with their structures, their biosafety is different in different cell model, and there is no <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> correlation found. We believe that this study will certainly provide more scientific understandings on the nanotoxicity of amphiphilic polymeric micelles.</jats:p> </jats:sec>