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

Abstract

The colloidal stability, in vitro toxicity, cell association, and in vivo pharmacokinetic behavior of liposomes decorated with monomethoxy-poly­(ethylene glycol)-lipids (mPEG-lipids) with different chemical features were comparatively investigated. Structural differences of the mPEG-lipids used in the study included: (a) surface-anchoring moiety [1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), cholesterol (Chol), and cholane (Chln)]; (b) mPEG molecular weight (2 kDa mPEG45 and 5 kDa mPEG114); and (c) mPEG shape (linear and branched PEG). In vitro results demonstrated that branched (mPEG114)2-DSPE confers the highest stealth properties to liposomes (∼31-fold lower cell association than naked liposomes) with respect to all PEGylating agents tested. However, the pharmacokinetic studies showed that the use of cholesterol as anchoring group yields PEGylated liposomes with longer permeance in the circulation and higher systemic bioavailability among the tested formulations. Liposomes decorated with mPEG114-Chol had 3.2- and ∼2.1-fold higher area under curve (AUC) than naked liposomes and branched (mPEG114)2-DSPE-coated liposomes, respectively, which reflects the high stability of this coating agent. By comparing the PEGylating agents with same size, namely, linear 5 kDa PEG derivatives, linear mPEG114-DSPE yielded coated liposomes with the best in vitro stealth performance. Nevertheless, the in vivo AUC of liposomes decorated with linear mPEG114-DSPE was lower than that obtained with liposomes decorated with linear mPEG114-Chol. Computational molecular dynamics modeling provided additional insights that complement the experimental results.

Molecular Simulations of PEGylated Biomolecules, Liposomes, and Nanoparticles for Drug Delivery Applications

“…Their simulations also captured the insertion of hydrophobic drug or light-sensitizing molecules (e.g., porphyrins, indocyanine green, itraconazole, and piroxicam) to the PEG layer and the hydrophobic region of the bilayer ( Figure 6 ) [ 154 , 155 , 156 , 157 , 158 ]. Recently, they simulated linear and branched PEG chains grafted on lipid bilayers, showing that the architecture and length of PEG–lipid conjugates influence the structure and dynamics of membranes, in agreement with experimental results [ 159 ].…”

In Vivo Assessment of Thermosensitive Liposomes for the Treatment of Port Wine Stains by Antifibrinolytic Site-Specific Pharmaco-Laser Therapy

“…These formulations are DPPC:DSPE-PEG (96:4) and DPPC:MPPC:DSPE-PEG (86:10:4); i.e., formulations 3 and 6 in Figure 2 . DPPC:DSPE-PEG liposomes are sufficiently PEGylated [ 41 , 42 ] and properly sized [ 28 , 43 ] to prevent rapid clearance from the circulation, have a relatively high TA:lipid ratio and E eff that translate to a favorable C TA , and release nearly all TA cargo during a short period of exposure to mild hyperthermia but not near body temperature (37.0 °C) [ 16 ]. The MPPC-containing variant represents a formulation with accelerated release kinetics at the expense of C TA , serving as a back-up formulation for the DPPC:DSPE-PEG liposomes in case these do not pass attrition.…”

Mechanistic Understanding From Molecular Dynamics Simulation in Pharmaceutical Research 1: Drug Delivery

“…Since this time the methodology has been used to study the effect of exchanging PEG with two different poly-oxazolines, polyethoxazoline (PEOZ) and poly-methoxazoline (PMOZ), with the result indicating that several properties of PEG are highly specific and related to its amphiphilic nature and the ease with which it acts as a polymer electrolyte (Magarkar et al, 2017). We also simulated the effect of change in PEG length, branched structures, and functionalizing PEG to the cholesterol or cholane in the membrane rather than phospholipids and our results complemented both in vivo and in vitro experiments carried out on these novel liposome based delivery systems (Mastrotto et al, 2020).…”