Abstract
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.
Original language | English (US) |
---|---|
Pages (from-to) | 377-388 |
Number of pages | 12 |
Journal | Molecular Therapy Oncolytics |
Volume | 21 |
DOIs | |
State | Published - Jun 25 2021 |
Keywords
- PBAE
- TRAIL
- bystander effect
- gene delivery
- gene therapy
- histone deacetylase inhibitors
- liver cancer
- nanoparticle
- polymer
ASJC Scopus subject areas
- Molecular Medicine
- Oncology
- Cancer Research
- Pharmacology (medical)