TY - JOUR
T1 - Delivery of TRAIL-expressing plasmid DNA to cancer cells
T2 - In vitro and in vivo using aminoglycoside-derived polymers
AU - Goklany, Sheba
AU - Lu, Ping
AU - Godeshala, Sudhakar
AU - Hall, Andrea
AU - Garrett-Mayer, Elizabeth
AU - Voelkel-Johnson, Christina
AU - Rege, Kaushal
N1 - Funding Information: We are grateful to the NIH/NIGMS (Grant 1R01GM093229-01A1) and the Arizona Biomedical Research Commission (ABRC; Grant 1009) for funding this study. We thank Dr Matthew Christensen and Dr Taraka Sai Pavan Grandhi for helpful technical discussions on studies reported in this manuscript. We are also thankful to Prof. Joshua LaBaer, Director of the Biodesign Institute at ASU and Mr Seron Eaton, Research Lab Manager at the Center for Personalized Diagnostics at ASU for access to the imager for Western Blots. We would also like to acknowledge help from Shanshan Yang, Manager-Bioinformatics CORE Facility Biodesign Institute at ASU, for help with the survival analysis. Publisher Copyright: © 2019 The Royal Society of Chemistry.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1039/c9tb01286a
DO - 10.1039/c9tb01286a
M3 - Article
C2 - 31633707
SN - 2050-750X
VL - 7
SP - 7014
EP - 7025
JO - Journal of Materials Chemistry B
JF - Journal of Materials Chemistry B
IS - 44
ER -