Poly(beta-amino ester) nanoparticles enable tumor-specific TRAIL secretion and a bystander effect to treat liver cancer

Hannah J. Vaughan, Camila G. Zamboni, Nicholas P. Radant, Pranshu Bhardwaj, Esther Revai Lechtich, Laboni F. Hassan, Khalid Shah, Jordan J. Green

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)377-388
Number of pages12
JournalMolecular Therapy - Oncolytics
Volume21
DOIs
StatePublished - 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)

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