In Vitro and in Vivo Behavior of Liposomes Decorated with PEGs with Different Chemical Features

Abstract

The colloidal stability, in vitro\ntoxicity, cell association, and\nin vivo pharmacokinetic behavior of liposomes decorated with monomethoxy-poly­(ethylene\nglycol)-lipids (mPEG-lipids) with different chemical features were\ncomparatively investigated. Structural differences of the mPEG-lipids\nused in the study included: (a) surface-anchoring moiety [1,2-distearoyl-<i>sn</i>-glycero-3-phosphoethanolamine (DSPE), cholesterol (Chol),\nand cholane (Chln)]; (b) mPEG molecular weight (2 kDa mPEG<sub>45</sub> and 5 kDa mPEG<sub>114</sub>); and (c) mPEG shape (linear and branched\nPEG). In vitro results demonstrated that branched (mPEG<sub>114</sub>)<sub>2</sub>-DSPE confers the highest stealth properties to liposomes\n(∼31-fold lower cell association than naked liposomes) with\nrespect to all PEGylating agents tested. However, the pharmacokinetic\nstudies showed that the use of cholesterol as anchoring group yields\nPEGylated liposomes with longer permeance in the circulation and higher\nsystemic bioavailability among the tested formulations. Liposomes\ndecorated with mPEG<sub>114</sub>-Chol had 3.2- and ∼2.1-fold\nhigher area under curve (AUC) than naked liposomes and branched (mPEG<sub>114</sub>)<sub>2</sub>-DSPE-coated liposomes, respectively, which\nreflects the high stability of this coating agent. By comparing the\nPEGylating agents with same size, namely, linear 5 kDa PEG derivatives,\nlinear mPEG<sub>114</sub>-DSPE yielded coated liposomes with the best\nin vitro stealth performance. Nevertheless, the in vivo AUC of liposomes\ndecorated with linear mPEG<sub>114</sub>-DSPE was lower than that\nobtained with liposomes decorated with linear mPEG<sub>114</sub>-Chol.\nComputational molecular dynamics modeling provided additional insights\nthat complement the experimental results.

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