Cell type-specific pharmacological kinase inhibition for cancer chemoprevention

• Published in: Nanomedicine 2018-02, Vol.14 (2), p.317-325
• Main Authors: Deshmukh, Manjeet, Nakagawa, Shigeki, Higashi, Takaaki, Vincek, Adam, Venkatesh, Anu, Ruiz de Galarreta, Marina, 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
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Cancer chemoprevention; Cell Proliferation - drug effects; Drug Delivery Systems; Epidermal growth factor; ErbB Receptors - antagonists & inhibitors; Erlotinib Hydrochloride - pharmacology; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Kinase inhibitor; Liver cancer; Liver Cirrhosis - complications; Liver Neoplasms, Experimental - etiology; Liver Neoplasms, Experimental - prevention & control; Male; Mice, Inbred C57BL; Myofibroblasts - cytology; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Nanoparticle; Protein Kinase Inhibitors - pharmacology; Rats; Rats, Wistar
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2017.11.004

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. Nanoparticle-based system for cell type-specific delivery of selective kinase inhibitor was developed. The system enabled specific inhibition of epidermal growth factor signaling in hepatic myofibroblasts, the major driver of liver cancer development, and elicited cancer chemoprevention effect with reduced drug dose and toxicities. [Display omitted]