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

doi:10.1016/j.omto.2021.04.004

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

Journal article

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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 and Jordan J. Green

Molecular therapy. Oncolytics, Vol.21, pp.377-388

06/25/2021

DOI: 10.1016/j.omto.2021.04.004

PMID: 34189258

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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. [Display omitted] Green and colleagues develop polymeric nanoparticles to program liver cancer cells to locally secrete tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). The authors show that the delivered sTRAIL initiates apoptosis in transfected liver cancer cells and has a bystander effect to non-transfected cancer cells, with potency enhanced by histone deacetylase inhibitors.

bystander effect

gene delivery

gene therapy

histone deacetylase inhibitors

liver cancer

nanoparticle

PBAE

polymer

TRAIL

Details

Title: Subtitle: Poly(beta-amino ester) nanoparticles enable tumor-specific TRAIL secretion and a bystander effect to treat liver cancer
Creators: Hannah J. Vaughan - Johns Hopkins University
Camila G. Zamboni - Johns Hopkins University
Nicholas P. Radant - Johns Hopkins University
Pranshu Bhardwaj - Johns Hopkins University
Esther Revai Lechtich - Brigham and Women's Hospital
Laboni F. Hassan - Johns Hopkins University
Khalid Shah - Brigham and Women's Hospital
Jordan J. Green - Johns Hopkins University
Resource Type: Journal article
Publication Details: Molecular therapy. Oncolytics, Vol.21, pp.377-388
DOI: 10.1016/j.omto.2021.04.004
PMID: 34189258
NLM abbreviation: Mol Ther Oncolytics
ISSN: 2372-7705
eISSN: 2372-7705
Publisher: Elsevier Inc
Number of pages: 12
Language: English
Date published: 06/25/2021
Academic Unit: Radiology
Record Identifier: 9985179850002771

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