Delivery of TRAIL-expressing plasmid DNA to cancer cells: In vitro and in vivo using aminoglycoside-derived polymers

Sheba Goklany, Ping Lu, Sudhakar Godeshala, Andrea Hall, Elizabeth Garrett-Mayer, Christina Voelkel-Johnson, Kaushal Rege

Research output: Contribution to journalArticle

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand that can preferentially induce apoptosis in cancer cells over normal cells. The transmembrane form of TRAIL has been shown to elicit much stronger activity than its soluble counterpart but delivery is a potential challenge. Here, we investigated the potential of aminoglycoside-derived polymers to enhance delivery of a plasmid (pEF-TRAIL) that expresses the transmembrane form of TRAIL in order to determine the effect on cell death in vitro and tumor growth in vivo. Transgene delivery efficacy and toxicity of aminoglycoside-derived polymers was first evaluated using a GFP-expressing plasmid (pEF-GFP) at different plasmid amounts and plasmid : polymer ratios in UMUC3 bladder cancer and HeLa cervical cancer cells. Delivery of the TRAIL plasmid using aminoglycoside-derived polymers resulted in up to 60% cell death in UMUC3 and HeLa cells; TRAIL protein expression was confirmed using Western blots. TRAIL plasmid delivery resulted in a decrease in cellular procaspase-8 and an increase in TRAIL receptor DR5 levels, suggesting a role for the death receptor and caspase cascade in TRAIL-mediated apoptosis. The TRAIL plasmid did not cause cell death in normal human or mouse fibroblasts. The in vivo delivery of the TRAIL plasmid using a paromomycin-derived polymer resulted in significant reduction in tumor burden and increased survival in tumor-bearing live mice.

Original languageEnglish (US)
Pages (from-to)7014-7025
Number of pages12
JournalJournal of Materials Chemistry B
Volume7
Issue number44
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Aminoglycosides
Cell death
Polymers
Plasmids
DNA
Cells
Tumors
Bearings (structural)
Apoptosis
Ligands
Paromomycin
TNF-Related Apoptosis-Inducing Ligand
Fibroblasts
TNF-Related Apoptosis-Inducing Ligand Receptors
Death Domain Receptors
Toxicity
Caspase 8
Caspases
Proteins
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Chemistry(all)
  • Biomedical Engineering
  • Materials Science(all)

Cite this

Delivery of TRAIL-expressing plasmid DNA to cancer cells : In vitro and in vivo using aminoglycoside-derived polymers. / Goklany, Sheba; Lu, Ping; Godeshala, Sudhakar; Hall, Andrea; Garrett-Mayer, Elizabeth; Voelkel-Johnson, Christina; Rege, Kaushal.

In: Journal of Materials Chemistry B, Vol. 7, No. 44, 01.01.2019, p. 7014-7025.

Research output: Contribution to journalArticle

Goklany, Sheba ; Lu, Ping ; Godeshala, Sudhakar ; Hall, Andrea ; Garrett-Mayer, Elizabeth ; Voelkel-Johnson, Christina ; Rege, Kaushal. / Delivery of TRAIL-expressing plasmid DNA to cancer cells : In vitro and in vivo using aminoglycoside-derived polymers. In: Journal of Materials Chemistry B. 2019 ; Vol. 7, No. 44. pp. 7014-7025.
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