Journal
MOLECULAR THERAPY-ONCOLYTICS
Volume 21, Issue -, Pages 377-388Publisher
CELL PRESS
DOI: 10.1016/j.omto.2021.04.004
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Funding
- NIH [R01CA228133, P41EB028239, R01EB022148]
- Bloomberg~Kimmel Institute for Cancer Immunotherapy
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Researchers have developed poly(beta-amino ester) nanoparticles to locally deliver a secretable TRAIL protein to liver cancer cells, inducing apoptosis effectively. By combining NP treatment with histone deacetylase inhibitors, they achieved over 80% TRAIL-mediated cell death in target cancer cells. This approach offers a new potential strategy for cancer treatment by addressing multiple challenges associated with TRAIL therapy.
Despite initial promise, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based approaches to cancer treatment have yet to yield a clinically approved therapy, due to delivery challenges, a lack of potency, and drug resistance. To address these challenges, we have developed poly(beta-amino ester) (PBAE) nanoparticles (NPs), as well as an engineered cDNA sequence encoding a secretable TRAIL (sTRAIL) protein, to enable reprogramming of liver cancer cells to locally secrete TRAIL protein. We show that sTRAIL initiates apoptosis in transfected cells and has a bystander effect to non-transfected cells. To address TRAIL resistance, NP treatment is combined with histone deacetylase inhibitors, resulting in >80% TRAIL-mediated cell death in target cancer cells and significantly slowed xenograft tumor growth. This anti-cancer effect is specific to liver cancer cells, with up to 40-fold higher cell death in HepG2 cancer cells over human hepatocytes. By combining cancer-specific TRAIL NPs with small-molecule-sensitizing drugs, this strategy addresses multiple challenges associated with TRAIL therapy and offers a new potential approach for cancer treatment.
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