PEGylation refers to the covalent attachment of poly(ethylene glycol) to molecules. PEGylation of the molecule results in the reduction of the immunogenicity and the extended time in blood circulation. PEGylation is recognized as a promising method to increase the therapeutic efficacy of medicines in clinical settings. The main advantages of PEGylation are (1) increase in the size of drug molecule, resulting in reduced filtration by kidneys, (2) increase in solubility, and (3) protection from enzymatic digestion and recognition by antibodies. A variety of molecules, such as small molecules, peptides, proteins, enzymes, antibodies and their fragments, and nanoparticles have been modified with PEG. Several PEGylated drugs have been approved by the Food and Drug Administration (FDA) and several more are being tested in clinical settings.

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Liposome is known as one of drug delivery system carriers. The most important factor of liposome for exerting a targeting effect is to have long circulation time in blood stream. For avoiding liposomes from immune system, it is generally used poly(ethylene glycol) (PEG)-lipid which makes aqueous layer around liposomal membrane. In this review, it was summarized our study on some characters of liposome with unique PEG modification, it is focused the relation between fixed aqueous layer thickness (FALT) around liposome and antitumor effect by changing molecular weight of PEG or combination various PEGs.

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We have extensively developed polymeric micelles by engineering functional block copolymers that are mainly composed of poly(ethylene glycol) (PEG) and poly(amino acid) segments, directed toward smart drug and nucleic acid delivery. Polymeric micelles have a basic structure of drug-loaded hydrophobic core and biocompatible PEG shell, associated with a size of less than 100 nm and narrow size distribution. These properties allow the polymeric micelles for stable circulation in the bloodstream and preferential tumor accumulation through the enhanced permeability and retention (EPR) effect. Moreover, fine-tuning of chemical structures of block copolymers can further functionalize the polymeric micelles for enhanced stability, programmed drug release, and active targeting. This article aims to facilitate understanding of basic characteristics of polymeric micelles and their recent progress, mainly by reviewing our studies.

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Gene and nucleic acid therapy are expected to play a major role in the next generation of medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel non-viral gene delivery system. PEGylation is a useful method for achieving a longer circulation time for delivery of the MEND to a tumor via the EPR effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results significant loss of activity for the delivery system. For successful gene delivery for cancer treatment, the crucial issue associated with the use of PEG, the "PEG dilemma" must be solved. Here, we describe the development and applications of MEND, and discuss strategies for overcoming the PEG dilemma, based on the manipulation of intracellular trafficking using functional devices such as cleavable PEG systems, endosomal fusogenic peptides, and pH-sensitive lipids.

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Modification with PEG(poly(ethylene glycol)), so-called PEGylation, is a golden standard to increase stability of biological medicine. However, PEGylated materials cause anti-PEG antibody after first injection. Then, the anti-PEG antibody induce the accelerated blood clearance(ABC) phenomenon of subsequent dose of PEGylated materials. So far, it has been reported that anti-PEG antibody production occurs not only in experimental animals, but also in human. In addition, characteristics of anti-PEG antibody induced by one PEGylated material differ from that of anti-PEG antibody induced by other PEGylated materials. In order to preserve the merit of PEGylation technology, it is important to understand the correct characteristics of anti-PEG immune response and develop strategy for escaping the immune response. In this review, we show the characteristics, evaluation and suppression of anti-PEG antibody.

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Recently, nanomaterials constructed by molecular self-assembly have gathered much attention to develop nano-devices incorporated with many types of drugs. Particularly, hollow capsules are one of promising materials, and recently, we have developed polyion complex vesicles, PICsomes, as novel polymeric vesicles. The most advantageous feature of PICsomes is its simple preparation process: Typically, they can be prepared by simple mixing of oppositely charged block copolymers consisting of poly(ethylene glycol) (PEG) and charged poly(amino acid)s in an aqueous medium. Moreover, many other unique properties of PICsomes have been reported, such as facile tuning of vesicle sizes ranging from 100-400 nm while keeping monodispersed size distribution, semipermeable vesicle membrane, facile loading of various water-dispersed materials, long blood circulation after crosslinking, excellent tumor accumulation based on the enhanced permeability and retention (EPR) effect, and so on. The present review article describes basic design and synthetic strategy of PICsomes, fundamental properties of PICsomes, and recent applications of PICsomes to drug delivery system.

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Cancer immunotherapies are attracting much attention as one of emerging cancer treatments. Because immunotherapy is based on the stimulation of a patient's own immune system, it is believed to be patient friendly. However, there are several hurdles in developing living cells and bioactive proteins for immunotherapy because of the several serious issues such as long-term cultivation, stability and systemic toxicities, called “immune-related adverse events”, caused by their conventional injection formulations. Increasing costs are also one of other serious issues. To overcome these issues, we designed new local protein delivery system by using a protein-loaded, redox-active, injectable gel (RIG), which is formed by a polyion complex (PIC) comprising three components, viz., cationic polyamine-poly(ethylene glycol)-polyamine triblock copolymer possessing ROS-scavenging moieties as side chains; anionic poly(acrylic acid); and a protein. The mixture formed the protein-loaded PIC flower micelles at room temperature, which immediately converted to a gel with high mechanical strength upon exposure to physiological conditions. Because the protein electrostatically interacts with the PIC gel network, RIG provided a sustained release of the protein without a significant initial burst, regardless of the types of proteins in vitro, and much longer retention of the protein at the local injection site in mice than that of the naked protein. Subcutaneous injections of IL12@RIG in the vicinity of tumor tissue showed remarkable tumor growth inhibition in tumor-bearing mice, compared to that observed with injection of IL-12 alone, suppressing adverse events caused by IL-12induced ROS. Another approach is to deliver arginine to macrophages in tumor environment by our original PIC micelle composed of PEG-b-poly(L-arginine) block copolymer coupled with chondroitin sulfate. After a phagocytosis of this PIC micelle by the macrophages, it hydrolyzed to arginine followed by nitric oxide by iNOS expressed in the activated macrophages to result in suppression of tumor growth. These approaches are different from conventional antitumor immunotherapies but promising as emerging technique from PEGylated materials.

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