The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

Abstract

Gene and nucleic acid therapy is expected to play a major role in the next generation of agents for cancer treatment. We have recently developed a multifunctional envelope-type nano device (MEND) for use as a novel nonviral gene delivery system. The modification of polyethyleneglycol (PEG), i.e., PEGylation, is a useful method for achieving a longer circulation time for the delivery of MEND to a tumor via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity of the delivery system. For successful nucleic acid delivery for cancer treatment, the crucial problem associated with the use of PEG, i.e., the "PEG dilemma" must be resolved. In this review, we describe the development and applications of MEND and discuss various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release. To increase cellular uptake, target ligands including proteins, peptides, antibodies and aptamers that recognize molecules specifically expressed on tumors are first introduced. Second, cleavable PEG systems are described. The cleavage of PEG from carriers was achieved in response to the intracellular environment as well as the tumor microenvironment, which improvs cellular uptake and endosomal escape. Then, endosomal fusogenic peptides are discussed. Finally, pH-sensitive liposomes using pH-sensitive lipids are described.

Topology of Surface Ligands on Liposomes: Characterization Based on the Terms, Incorporation Ratio, Surface Anchor Density, and Reaction Yield

“…5,6,10) For active targeting, specific ligands for bioactive molecules such as nucleic acids, peptides, proteins, and antibodies are attached to the surface of nanoparticles via a PEG spacer.…”

“…5,6,10) For active targeting, specific ligands for bioactive molecules such as nucleic acids, peptides, proteins, and antibodies are attached to the surface of nanoparticles via a PEG spacer. 11) Many attempts have been made to develop various types of specific ligands for use in active targeting, which is critical for targeting non-fenestrated tissues such as the brain, lung and related tissues.…”

“…It is possible to accurately characterize various PEG and ligand densities and to define the surface topologies. In conclusion, this quantitative methodology can standardize the liposome preparation process and qualify the modified liposomal surfaces.Key words active targeting; surface ligand density; incorporation ratio; surface anchor density; reaction yield; surface topology Nanotechnology has the capability to deliver drugs to specific cell types, but it is important to maximize therapeutic effects and minimize unexpected adverse effects, for this technology to be effectively used.1-4) In using nanoparticles for specific drug delivery, they need to have both a stealth function to prevent non-specific recognition by the reticuloendothelial system (RES), 5,6) and an active targeting function to allow them to bind to the specific cell type of interest. …”

“…1-4) In using nanoparticles for specific drug delivery, they need to have both a stealth function to prevent non-specific recognition by the reticuloendothelial system (RES), 5,6) and an active targeting function to allow them to bind to the specific cell type of interest.…”

Influence of Physicochemical Properties and PEG Modification of Magnetic Liposomes on Their Interaction with Intestinal Epithelial Caco-2 Cells

“…26) PEG provides nanoparticles with several advantages, such as water solubility, increased stability, resistance to enzymatic degradation and opsonization. However, PEGylation of nanoparticles has been reported to reduce the uptake efficiency of nanoparticles into cells because of steric hindrance, 27) assuming that PEG modification strongly influences the cellular internalization process of magnetic liposomes.…”