Efficient drug delivery and induction of apoptosis in colorectal tumors using a death receptor 5-targeted nanomedicine

Schmid, D. et al. (2014) Efficient drug delivery and induction of apoptosis in colorectal tumors using a death receptor 5-targeted nanomedicine. Molecular Therapy, 22(12), pp. 2083-2092. (doi: 10.1038/mt.2014.137)

Abstract

Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that is a potential therapeutic target in cancer. Despite the potency of DR5-targeting agents in preclinical models, the translation of these effects into the clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles. We describe the development of an optimized polymer-based nanotherapeutic incorporating both a functionalized polyethylene glycol (PEG) layer and targeting antibodies to limit premature phagocytic clearance whilst enabling targeting of DR5-expressing tumor cells. Using the HCT116 colorectal cancer model, we show that following binding to DR5, the nanoparticles activate caspase 8, enhancing the anti-tumor activity of the camptothecin payload both in vitro and in vivo. Importantly, the combination of nanoparticle-induced DR5 clustering with camptothecin delivery overcomes resistance to DR5-induced apoptosis caused by loss of BAX or overexpression of anti-apoptotic FLIP. This novel approach may improve the clinical activity of DR5-targeted therapeutics while increasing tumor-specific delivery of systemically toxic chemotherapeutics.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Riley, Dr Joel
• Authors: Schmid, D., Fay, F., Small, D. M., Jaworski, J., Riley, J. S., Tegazzini, D., Fenning, C., Jones, D. S., Johnston, P. G., Longley, D. B., and Scott, C. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Therapy
• Publisher: Nature Publishing Group
• ISSN: 1525-0016
• ISSN (Online): 1525-0024