Design and application of redox polymers for nanomedicine


Reactive oxygen species (ROS), such as superoxide and hydroxyl radicals, cause oxidative stress that strongly affects aging and various diseases. Although various antioxidants have been developed to eliminate ROS, they cause serious problems by destroying important redox reactions in normal cells. We designed redox polymers with antioxidants covalently bonded to them. These polymers, with a self-assembling property, form nanoparticles in aqueous media (redox nanoparticles; RNPs), suppress uptake into normal cells, accumulate at inflammation sites, and effectively prevent ROS-related diseases. As such, RNPs have been found to be effective in preventing diseases involving ROS, such as myocardial and cerebral ischemia-reperfusion injuries, ulcerative colitis, and cancer. Redox polymers have several other applications. We designed redox injectable gels (RIGs), which transform from flowable solution at ambient temperature to gel at body temperature under the physiological conditions. RIGs can be applied for suppression of local inflammation, such as periodontitis. RIGs can also be used in anti-tissue adhesion sprays applied after physical surgery. Redox polymers can also be used as a surface coating of biodevices to make them blood compatible. This review summarizes the synthesis and application of these redox polymers.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Scheme 1
Fig. 15


  1. 1.

    Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8:473–80.

    Article  CAS  Google Scholar 

  2. 2.

    Dancey J. Recent advances with molecular target agents in cancer: opportunities for imaging. Cancer Biol Ther. 2003;2:601–9.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Matsuoka T, Yashiro M. Recent advances in the HER2 targeted therapy of gastric cancer. World J Clin Cases. 2015;3:42–51.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Report of National Cancer Organization, Global cancer rates could increase by 50% to 15 million by 2020,

  5. 5.

    Yoshikawa T. "Emperor of Qin", Kodansha Academic Paperback (2002)

  6. 6.

    "Medicine of Oxidative Stress", Toshikazu Yoshikawa, Hirohito Naito, Shinya Toyokuni, Diagnosis and Treatment Co. Ltd.(2008)

  7. 7.

    Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. J Am Med Soc. 2007;297:842–57.

    CAS  Google Scholar 

  8. 8.

    Nagasaki Y. Nitroxide radicals and nanoparticles: a partnership for nanomedicine radical delivery. Ther Deliv. 2012;3:1–15.

    Article  CAS  Google Scholar 

  9. 9.

    Toru Y, Daisuke M, Yukio N. Design of core-shell-type nanoparticles carrying stable radicals in the core. Biomacromolecules. 2009;10:596–601.

    Article  CAS  Google Scholar 

  10. 10.

    Vong LB, Kobayashi M, Nagasaki Y. Evaluation of the toxicity and antioxidant activity of redox nanoparticles in Zebrafish (Danio rerio) embryos. Mol Pharm. 2016;13:3091–7.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Chonpathompikunlert P, Yoshitomi T, Long Binh V, Imaizumi N, Ozaki Y, Nagasaki Y. Recovery of cognitive dysfunction via orally administered redox-polymer nanotherapeutics in SAMP8 mice. PLoS ONE. 2015;10:e0126013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Abe C, Uto Y, Kawasaki A, Noguchi C, Tanaka R, Yoshitomi T, Nagasaki Y, Endo Y, Hori H. Evaluation of the in vivo antioxidative activity of redox nanoparticles by using a developing chicken egg as an alternative animal model. J Control Release. 2014;182:67–72.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Yoshitomi T, Nagasaki Y. ROS-scavenging nanomedicine for treatment of oxidative stress injuries. Adv Healthc Mater. 2014;3:1149–61.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Yoshitomi T, Hirayama A, Nagasaki Y. The ROS scavenging and renal protective effects of pH-responsive nitroxide radical-containing nanoparticles. Biomaterials. 2011;32:8021–8.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Yoshitomi T, Suzuki R, Mamiya T, Matsui H, Hirayama A, Nagasaki Y. pH-Sensitive radical-containing-nanoparticle (RNP) for the L-band-EPR imaging of low pH circumstances. Bioconjug Chem. 2009;20:1792–8.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Marushima A, Tsurusima H, Yoshitomi T, Toh K, Hirayama A, Nagasaki Y, Matumura A. Newly synthesized radical-containing nanoparticles (RNP) enhance neuroprotection after cerebral ischemia-reperfusion injury. Neurosurgery. 2011;68:1418–26.

    Article  PubMed  Google Scholar 

  17. 17.

    Hiroshi A, Shoji S, Toru Y, Hideyuki S, Hiroyuki T, Madoka I, Yoshiro S, Hidezo M, Masanori A, Atsushi N, Masaru S, Yoshihiro A3, Tetsuo M, Seiji T, Yukio N, Masafumi K. Novel synthesized radical-containing nanoparticles limits infarct size following ischemia and reperfusion in canine hearts – Role of Nitric Oxide, Cardiovascular Drugs and Therapy, in press

  18. 18.

    Ueda T, Katada K, Iida T, Mizushima K, Dohi O, Okayama T, Yoshida N, Kamada K, Uchiyama K, Handa O, Ishikawa T, Naito Y, Nagasaki Y, Itoh Y. The protective effect of orally administered redox nanoparticle on intestinal ischemia-reperfusion injury in mice. Biochem Biophys Res Commun. 2018;495:2044–9.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474:307–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Vong LB, Tomita T, Yoshitomi T, Matsui H, Nagasaki Y. An orally administered redox nanoparticle that accumulates in the colonic mucosa and reduces colitis in mice. Gastroenterology. 2012;143:1027–36.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Okatani Y, Wakatsuki A, Reiter RJ, Miyahara Y. Melatonin reduces oxidative damage of neural lipids and proteins in senescence-accelerated mouse. Neurobiol Aging. 2002;23:639–44.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Danielle GS, Roberto C, Barnham KJ. The redox chemistry of the Alzheimer's disease amyloid beta peptide. Biochim Et Biophys Acta (BBA)-Biomembr. 2007;1768:1976–90.

    Article  CAS  Google Scholar 

  23. 23.

    Yagi H, Katoh S, Akiguchi I, Takeda T. Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse. Brain Res. 1988;474:86–93.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Hosoo H, Marushima A, Nagasaki Y, Hirayama A, Ito H, Puentes S, Mujagic A, Tsurushima H, Tsuruta W, Suzuki K, Matsui H, Matsumaru Y, Yamamoto T, Matsumura A. Nurovascular unit protection from cerebral ischemia-reperfusion injury by radical-containing nanoparticles in mice. Stroke. 2017;48:2238–47.

    Article  PubMed  Google Scholar 

  25. 25.

    Dunne AL, Price ME, Mothersill C, McKeown SR, Robson T, Hirst DG. Relationship between clonogenic radiosensitivity, radiation-induced apoptosis and DNA damage/repair in human colon cancer cells. Br J Cancer. 2003;89:2277–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Azzam EI, Jay-Gerin J-P, Pain D. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett. 2012;327:48–60.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Feliciano CP, Tsuboi K, Suzuki K, Kimura H, Nagasaki Y. Long-term bioavailability of redox nanoparticles effectively reduces organ dysfunctions. Biomaterials. 2017;129:68–82.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Jeong B, Bae YH, Lee DS, Kim SW. Biodegradable block copolymers as injectable drug-delivery systems. Nature. 1997;388:860–2.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Pua ML, Yoshitomi T, Chonpathompikunlert P, Hirayama A, Nagasaki Y. Redox-active injectable gel using thermo-responsive nanoscale polyion complex flower micelle for noninvasive treatment of local inflammation. J Control Release. 2013;172:914–20.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Ishii S, Kaneko J, Nagasaki Y. Dual stimuli-responsive redox-active injectable gel by polyion complex based flower micelles for biomedical applications. Macromolecules. 2015;48:3088–94.

    Article  CAS  Google Scholar 

  31. 31.

    Yu L, Zhang H, Ding J. A subtle end-group effect on macroscopic physical gelation of triblock copolymer aqueous solutions. Angew Chem, Int Ed. 2006;45:2232–5.

    Article  CAS  Google Scholar 

  32. 32.

    Saita M, Kaneko J, Sato T, Takahashi S-s, Wada-Takahashi S, Kawamata R, Sakura T, Masaichi-Chang-il L, Hamada N, Kimoto K, Nagasaki Y. Novel antioxidative nanotherapeutics in a rat periodontitis model: reactive oxygen species scavenging by redox injectable gel suppresses alveolar bone resorption. Biomaterials. 2016;76:292–301.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Ishii S, Kaneko J, Nagasaki Y. Development of a long-acting, protein-loaded, redox-active, injectable gel formed by a polyion complex for local protein therapeutics. Biomaterials. 2016;84:210–8.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Nagasaki Y, Mizukoshi Y, Gao Z, Feliciano CP, Chang K, Sekiyama H, Kimura H. Development of a local anesthetic lidocaine-loaded redox-active injectable gel for postoperative pain management. Acta Biomater. 2017;57:127–35.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Nakagawa H, Matsumoto Y, Matsumoto Y, Miwa Y, Nagasaki Y. Design of high-performance anti-adhesion agent using injectable gel with an anti-oxidative stress function. Biomaterials. 2015;69:165–173.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Masakane I, Nakai S, Ogata S, Kimata N, Hanafusa N, Hamano T, Wakai K, Wada A, Nitta K. An overview of regular dialysis treatment in Japan. Ther Apher Dial. 2015;19:540–74.

    Article  CAS  Google Scholar 

  37. 37.

    Brown MC, Simpson K, Kerssens JJ, Mactier RA. Encapsulating peritoneal sclerosis in the New Millennium: a national cohort study. Clin J Am Soc Nephrol. 2009;4:1222–9.

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Hossain AM, Ikeda Y, Nagasaki Y. Novel biocompatible nanoreactor for silica/gold hybrid nanoparticles preparation. Colloids Surf B: Biointerfaces. 2013;102:778–82.

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Nagasaki Y, Yaguchi T, Matsumura T, Yoshitomi T, Ikeda Y, Ueda A, Hirayama A. Design and use of silica-containing redox nanoparticles, siRNP for high-performance peritoneal dialysis. Biomater Sci. 2014;2:522–9.

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Vong LB, Kimura S, Nagasaki Y. Newly designed silica-containing redox nanoparticles for oral delivery of novel TOP2 catalytic inhibitor for treating colon cancer. Adv Healthc Mater. 2017;6:1700428.

    Article  CAS  Google Scholar 

  41. 41.

    Yoshitomi T, Yamaguchi Y, Kikuchi A, Nagasaki Y. Creation of a blood-compatible surface: a novel strategy for suppressing blood activation and coagulation using nitroxide radical-containing polymer with reactive oxygen species scavenging activity. Acta Biomater. 2012;8:1323–9.

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Chen S, Li L, Zhao C, Zheng J. Surface hydration: principles and applications toward low-fouling/nonfouling biomaterials. Polymer. 2010;51:5283–93.

    Article  CAS  Google Scholar 

  43. 43.

    Reiners JJ Jr., Mathieu P, Okafor C, Putt DA, Lash LH. Depletion of cellular glutathione by conditions used for the passaging of adherent cultured cells. Toxicol Lett. 2000;115:153–63.

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Ikeda Y, Yoshinari T, Nagasaki Y. A novel biointerface that suppresses cell morphological changes by scavenging excess reactive oxygen species. J Biomed Mater Res, Part A. 2015;103:2815–22.

    Article  CAS  Google Scholar 

  45. 45.

    Ikeda Y, Yoshinari T, Miyoshi H, Nagasaki Y. Design of antioxidative biointerface for separation of hematopoietic stem cells with high maintenance of undifferentiated phenotype. J Biomed Mater Res: Part A. 2016;104A:2080–5.

    Article  CAS  Google Scholar 

Download references


This article is a contribution of the author, who was awarded the Award of the Society of Polymer Science, Japan (2017). The author would like to express his sincere gratitude to the Society of Polymer Science and to all the associated people. The data described here are the findings of studies conducted in collaboration with his students and colleagues in his laboratory at the University of Tsukuba, as well as with many other collaborators, including medical doctors. The author also thanks them for their continuous support. Most of the work described here was supported by a Grant-in-Aid for Scientific Research S (25220203), the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

Author information



Corresponding author

Correspondence to Yukio Nagasaki.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nagasaki, Y. Design and application of redox polymers for nanomedicine. Polym J 50, 821–836 (2018).

Download citation

Further reading


Quick links