Efficient Drug Delivery and Induction of Apoptosis in Colorectal Tumors Using a Death Receptor 5-Targeted Nanomedicine
Data(s) |
01/12/2014
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Resumo |
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.Molecular Therapy (2014); doi:10.1038/mt.2014.137. |
Formato |
application/pdf |
Identificador |
http://dx.doi.org/10.1038/mt.2014.137 http://pure.qub.ac.uk/ws/files/17395111/Schmid_et_al_final_molecular_therapy_clean_1_.pdf |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/openAccess |
Fonte |
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 & Scott , C J 2014 , ' Efficient Drug Delivery and Induction of Apoptosis in Colorectal Tumors Using a Death Receptor 5-Targeted Nanomedicine ' Molecular therapy : the journal of the American Society of Gene Therapy , vol 22 , no. 12 , pp. 2083-2092 . DOI: 10.1038/mt.2014.137 |
Tipo |
article |