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

Mol Ther. 2014 Dec;22(12):2083-2092. doi: 10.1038/mt.2014.137. Epub 2014 Jul 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / immunology
  • Adenomatous Polyposis Coli / therapy*
  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / immunology
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis
  • Camptothecin / administration & dosage*
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Female
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Targeted Therapy
  • Nanomedicine
  • Nanoparticles / administration & dosage*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Antineoplastic Agents, Phytogenic
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Camptothecin

Supplementary concepts

  • Polyposis Syndrome, Hereditary Mixed, 1