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Cell type-specific pharmacological kinase inhibition for cancer chemoprevention

Deshmukh, M., Nakagawa, S., Higashi, T., Vincek, A., Venkatesh, A., Ruiz de Galarreta, M., Koh, A. P., Goossens, N., Hirschfield, H., Bian, C. B., Fujiwara, N., Ono, A., Hoshida, H., El-Abtah, M., Ahmad, N. B., Lujambio, A., Sanchez, R., Fuchs, B. C., Poelstra, K., Prakash, J. & Hoshida, Y., Feb-2018, In : Nanomedicine-Nanotechnology biology and medicine. 14, 2, p. 317-325 9 p.

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  • Cell type-specific pharmacological kinase inhibition

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DOI

  • Manjeet Deshmukh
  • Shigeki Nakagawa
  • Takaaki Higashi
  • Adam Vincek
  • Anu Venkatesh
  • Marina Ruiz de Galarreta
  • Anna P Koh
  • Nicolas Goossens
  • Hadassa Hirschfield
  • C Billie Bian
  • Naoto Fujiwara
  • Atsushi Ono
  • Hiroki Hoshida
  • Mohamed El-Abtah
  • Noor B Ahmad
  • Amaia Lujambio
  • Roberto Sanchez
  • Bryan C Fuchs
  • Klaas Poelstra
  • Jai Prakash
  • Yujin Hoshida

Safety is prerequisite for preventive medicine, but non-toxic agents are generally ineffective as clinical chemoprevention. Here we propose a strategy overcoming this challenge by delivering molecular-targeted agent specifically to the effector cell type to achieve sufficient potency, while circumventing toxicity in the context of cancer chemoprevention. Hepatic myofibroblasts drive progressive fibrosis that results in cirrhosis and liver cancer. In a rat model of cirrhosis-driven liver cancer, a small molecule epidermal growth factor receptor inhibitor, erlotinib, was delivered specifically to myofibroblasts by a versatile nanoparticle-based system, targeting platelet-derived growth factor receptor-beta uniquely expressed on their surface in the liver. With systemic administration of erlotinib, tumor burden was reduced to 31%, which was further improved to 21% by myofibroblast-targeted delivery even with reduced erlotinib dose (7.3-fold reduction with equivalent erlotinib dose) and less hepatocyte damage. These findings demonstrate a strategy, cell type-specific kinase inhibition, for more effective and safer precision cancer chemoprevention. (c) 2017 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)317-325
Number of pages9
JournalNanomedicine-Nanotechnology biology and medicine
Volume14
Issue number2
Publication statusPublished - Feb-2018

    Keywords

  • Cancer chemoprevention, Epidermal growth factor, Kinase inhibitor, Liver cancer, Nanoparticle, erlotinib, glutathione transferase, glypican 3, mesoporous silica nanoparticle, nanocarrier, platelet derived growth factor, platelet derived growth factor beta receptor, animal cell, animal experiment, animal model, animal tissue, article, cancer prevention, cell specificity, comparative study, conjugate, controlled study, enzyme inhibition, experimental liver neoplasm, fibrogenesis, fluorescence imaging, human, human cell, in vitro study, in vivo study, internalization, liver fibrosis, liver toxicity, male, molecular docking, mouse, myofibroblast, myofibroblast cell line, nanopharmaceutics, nonhuman, target cell

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