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

Molecular Therapy: Oncolytics

Esther Revai Lechtich¹  Khalid Shah¹  Jordan J. Green²  Pranshu Bhardwaj²  Hannah J. Vaughan²  Camila G. Zamboni²  Nicholas P. Radant²  Laboni F. Hassan² 

[1] Center for Stem Cell Therapeutics and Imaging, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA;

关键词: gene therapy;    gene delivery;    TRAIL;    liver cancer;    nanoparticle;    bystander effect;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown