Journal
JOURNAL OF CONTROLLED RELEASE
Volume 324, Issue -, Pages 610-619Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2020.05.046
Keywords
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Funding
- Medical Research Council UK (MRC) [MC_PC_15013, 1598124]
- US-Ireland R&D Partnership - HSCNI [STL/5010/14]
- NIH/NCI [R01CA198096, R21CA234775]
- NIH/National Center for Advancing Translational Sciences [UL1TR001412]
- Comprehensive Cancer Center Support grant [NIH/NCI P30CA016056]
- BBSRC [BB/F013647/1] Funding Source: UKRI
- MRC [MC_PC_15013] Funding Source: UKRI
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Pancreatic cancer is usually advanced and drug resistant at diagnosis. A potential therapeutic approach outlined here uses nanoparticle (NP)-based drug carriers, which have unique properties that enhance intra-tumor drug exposure and reduce systemic toxicity of encapsulated drugs. Here we report that patients whose pancreatic cancers express elevated levels of Death Receptor 5 (DR5) and its downstream regulators/effectors FLIP, Caspase-8, and FADD had particularly poor prognoses. To take advantage of elevated expression of this pathway, we designed drug-loaded NPs with a surface-conjugated alpha DR5 antibody (AMG 655). Binding and clustering of the DR5 is a prerequisite for efficient apoptosis initiation, and the alpha DR5-NPs were indeed found to activate apoptosis in multiple pancreatic cancer models, whereas the free antibody did not. The extent of apoptosis induced by alpha DR5-NPs was enhanced by down-regulating FLIP, a key modulator of death receptor mediated activation of caspase-8. Moreover, the DNA topoisomerase-1 inhibitor camptothecin (CPT) down-regulated FLIP in pancreatic cancer models and enhanced apoptosis induced by alpha DR5-NPs. CPT-loaded alpha DR5-NPs significantly increased apoptosis and decreased cell viability in vitro in a caspase-8-and FADD-dependent manner consistent with their expected mechanism-of-action. Importantly, CPT-loaded alpha DR5-NPs markedly reduced tumor growth rates in vivo in established pancreatic tumor models, inducing regressions in one model. These proof-of-concept studies indicate that alpha DR5-NPs loaded with agents that downregulate or inhibit FLIP are promising candidate agents for the treatment of pancreatic cancer.
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