PEGylation of Proteins and Liposomes: a Powerful and Flexible Strategy to Improve the Drug Delivery

Abstract

Abstract:PEGylation is one of the most successful strategies to improve the delivery of therapeutic molecules such as proteins, macromolecular carriers, small drugs, oligonucleotides, and other biomolecules. PEGylation increase the size and molecular weight of conjugated biomolecules and improves their pharmacokinetics and pharmacodinamics by increasing water solubility, protecting from enzymatic degradation, reducing renal clearance and limiting immunogenic and antigenic reactions. PEGylated molecules show increased half-life, decreased plasma clearance, and different biodistribution, in comparison with non-PEGylated counterparts. These features appear to be very useful for therapeutic proteins, since the high stability and very low immunogenicity of PEGylated proteins result in sustained clinical response with minimal dose and less frequent administration. PEGylation of liposomes improves not only the stability and circulation time, but also the 'passive' targeting ability on tumoral tissues, through a process known as the enhanced permeation retention effect, able to improve the therapeutic effects and reduce the toxicity of encapsulated drug.The molecular weight, shape, reactivity, specificity, and type of bond of PEG moiety are crucial in determining the effect on PEGylated molecules and, at present, researchers have the chance to select among tens of PEG derivatives and PEG conjugation technologies, in order to design the best PEGylation strategy for each particular application.The aim of the present review will be to elucidate the principles of PEGylation chemistry and to describe the already marketed PEGylated proteins and liposomes by focusing our attention to some enlightening examples of how this technology could dramatically influence the clinical application of therapeutic biomolecules.

Development of111In-Labeled Liposomes for Vulnerable Atherosclerotic Plaque Imaging

“…However, in atherosclerosis imaging, signals from the blood pool disturb the visualization of plaque in the vessel wall; thus, blood clearance of the imaging probe should ideally be not too slow, and excessive liver uptake makes it difficult to visualize the small atherosclerotic region in coronary arteries. In general, PEGylation of particles prolongs the blood clearance because of the avoidance from the reticuloendothelial system, and liver accumulation would be decreased by PEGylation (30). However, because the high liver accumulation can be explained by the liposome uptake into the Kupffer cells, which have characteristics similar to macrophages concerning phagocytosis, the too-low accumulation to the liver would cause the decreased uptake to the macrophages in atherosclerotic lesions.…”

Liposomes as nanomedical devices

“…G M1 decreases the blood proteins absorbed on the liposomal surface and improves the half-life of liposomes in the blood. 15,16 Similarly, the PEGylation of the liposomal carrier proved to extend the blood-circulation time while diminishing the uptake by the reticuloendothelial system (RES). Further, by modifying the PEG-molecule terminus, liposomes can be actively addressed with specific ligands or monoclonal antibodies (more details are reported in the section "Pharmacokinetics of liposomes").…”

Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

“…87 In addition, extended circulation in the blood by the addition of PEG on the surface of nanocarriers and an active targeting by grafting peptides or antibodies to the shell of nanocarriers result in sustained exposure to tumour cells and enhanced efficacy. 88,89 In 1998, Eli Lilly patented the synthesis of lipophilic gemcitabine. To protect against the deamination of gemcitabine, it was proposed to covalently link the amino group in position 4 with saturated and mono-unsaturated, long-chain C18 and C20.…”