Cell type-specific pharmacological kinase inhibition for cancer chemoprevention

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 (Corresponding Author), Mohamed El-abtah, Noor B Ahmad, Amaia Lujambio, Roberto Sanchez, Bryan C Fuchs, Klaas Poelstra, Jai PrakashYujin Hoshida

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Abstract

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.
Original languageEnglish
Pages (from-to)317-325
Number of pages9
JournalNanomedicine : nanotechnology, biology and medicine
Volume14
Issue number2
Early online date20 Nov 2017
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • UT-Hybrid-D

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    Deshmukh, M., Nakagawa, S., Higashi, T., Vincek, A., Venkatesh, A., De Galarreta, M. R., ... Hoshida, Y. (2018). Cell type-specific pharmacological kinase inhibition for cancer chemoprevention. Nanomedicine : nanotechnology, biology and medicine, 14(2), 317-325. https://doi.org/10.1016/j.nano.2017.11.004