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 Prakash & 1 others Yujin 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

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Chemoprevention
Liver
Myofibroblasts
Phosphotransferases
Pharmacology
Fibrosis
Liver Neoplasms
Neoplasms
Platelets
Platelet-Derived Growth Factor beta Receptor
Preventive Medicine
Medicine
Toxicity
Rats
Tumors
Tumor Burden
Epidermal Growth Factor Receptor
Nanoparticles
Hepatocytes
Molecules

Keywords

  • UT-Hybrid-D

Cite this

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
Deshmukh, Manjeet ; Nakagawa, Shigeki ; Higashi, Takaaki ; Vincek, Adam ; Venkatesh, Anu ; De Galarreta, Marina Ruiz ; Koh, Anna P ; Goossens, Nicolas ; Hirschfield, Hadassa ; Bian, C Billie ; Fujiwara, Naoto ; Ono, Atsushi ; Hoshida, Hiroki ; El-abtah, Mohamed ; Ahmad, Noor B ; Lujambio, Amaia ; Sanchez, Roberto ; Fuchs, Bryan C ; Poelstra, Klaas ; Prakash, Jai ; Hoshida, Yujin. / Cell type-specific pharmacological kinase inhibition for cancer chemoprevention. In: Nanomedicine : nanotechnology, biology and medicine. 2018 ; Vol. 14, No. 2. pp. 317-325.
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Deshmukh, M, Nakagawa, S, Higashi, T, Vincek, A, Venkatesh, A, De Galarreta, MR, Koh, AP, Goossens, N, Hirschfield, H, Bian, CB, Fujiwara, N, Ono, A, Hoshida, H, El-abtah, M, Ahmad, NB, Lujambio, A, Sanchez, R, Fuchs, BC, Poelstra, K, Prakash, J & Hoshida, Y 2018, 'Cell type-specific pharmacological kinase inhibition for cancer chemoprevention' Nanomedicine : nanotechnology, biology and medicine, vol. 14, no. 2, pp. 317-325. https://doi.org/10.1016/j.nano.2017.11.004

Cell type-specific pharmacological kinase inhibition for cancer chemoprevention. / Deshmukh, Manjeet; Nakagawa, Shigeki; Higashi, Takaaki; Vincek, Adam; Venkatesh, Anu; De Galarreta, Marina Ruiz; Koh, Anna P; Goossens, Nicolas; Hirschfield, Hadassa; Bian, C Billie; Fujiwara, Naoto; Ono, Atsushi; Hoshida, Hiroki (Corresponding Author); El-abtah, Mohamed; Ahmad, Noor B; Lujambio, Amaia; Sanchez, Roberto; Fuchs, Bryan C; Poelstra, Klaas; Prakash, Jai; Hoshida, Yujin.

In: Nanomedicine : nanotechnology, biology and medicine, Vol. 14, No. 2, 01.02.2018, p. 317-325.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Cell type-specific pharmacological kinase inhibition for cancer chemoprevention

AU - Deshmukh, Manjeet

AU - Nakagawa, Shigeki

AU - Higashi, Takaaki

AU - Vincek, Adam

AU - Venkatesh, Anu

AU - De Galarreta, Marina Ruiz

AU - Koh, Anna P

AU - Goossens, Nicolas

AU - Hirschfield, Hadassa

AU - Bian, C Billie

AU - Fujiwara, Naoto

AU - Ono, Atsushi

AU - Hoshida, Hiroki

AU - El-abtah, Mohamed

AU - Ahmad, Noor B

AU - Lujambio, Amaia

AU - Sanchez, Roberto

AU - Fuchs, Bryan C

AU - Poelstra, Klaas

AU - Prakash, Jai

AU - Hoshida, Yujin

N1 - Elsevier deal

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

KW - UT-Hybrid-D

U2 - 10.1016/j.nano.2017.11.004

DO - 10.1016/j.nano.2017.11.004

M3 - Article

VL - 14

SP - 317

EP - 325

JO - Nanomedicine : nanotechnology, biology and medicine

JF - Nanomedicine : nanotechnology, biology and medicine

SN - 1549-9634

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