Design of Novel PEGylated Materials for Different Approaches to Cancer Immunotherapy

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  • Nagasaki Yukio
    Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Master's School of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Satellite Laboratory, International Center for Materials Nanoarchitectonics(WPI―MANA), National Institute for Materials Science(NIMS), University of Tsukuba, Tennoudai 1-1-1, Tsukuba 3058573, Japan

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  • がん免疫療法へのPEG化材料からのアプローチ
  • ガン メンエキ リョウホウ エ ノ PEGカ ザイリョウ カラ ノ アプローチ

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Abstract

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.

Journal

  • Drug Delivery System

    Drug Delivery System 31 (4), 320-330, 2016

    THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM

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