Journal
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
Volume 14, Issue 2, Pages 317-325Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.nano.2017.11.004
Keywords
Cancer chemoprevention; Liver cancer; Kinase inhibitor; Epidermal growth factor; Nanoparticle
Funding
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science
- Program for advancing strategic international networks to accelerate the circulation of talented researchers
- U.S. NIH/NIDDK [DK099558]
- European Commission [ERC-2014-AdG-671231]
- Irma T. Hirschl Trust
- U.S. Department of Defense [W81XWH-16-1-0363]
- NATIONAL CANCER INSTITUTE [P30CA196521] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK099558] Funding Source: NIH RePORTER
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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.
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