TY - JOUR
T1 - Polymer-enhanced delivery increases adenoviral gene expression in an orthotopic model of bladder cancer
AU - Gosnell, Helen
AU - Kasman, Laura M.
AU - Potta, Thrimoorthy
AU - Vu, Lucas
AU - Garrett-Mayer, Elizabeth
AU - Rege, Kaushal
AU - Voelkel-Johnson, Christina
N1 - Funding Information:
This project was supported by grants from the National Institutes of Health (grant R21 CA143505 from the National Cancer Institute and grant R01GM093229 from the National Institute of General Medical Sciences to CVJ and KR). The work was also supported in part by institutional grants to MUSC and the Hollings Cancer Center from the National Center for Research Resources and the Office of the Direction of National Institute of Health ( C06 RR015455 ) and the National Cancer Institute ( P30 CA138313 ), respectively. The authors would like to thank D'Angelo Dinkins for the technical assistance with the toxicity assays and Dr. Rupak Mukherjee, director of the Multidisciplinary Murine Physiology Core in the Division of Cardiothoracic Surgery Research, for the assistance with analysis of heart function in NPGDE1,4 Bis treated mice.
PY - 2014/2/28
Y1 - 2014/2/28
N2 - Gene therapy has garnered significant attention as a therapeutic approach for bladder cancer but efficient delivery and gene expression remain major hurdles. The goal of this study was to determine if cationic polymers can enhance adenoviral gene expression in cells that are difficult to transduce in vitro and to subsequently investigate lead candidates for their capacity to increase adenoviral gene expression in an orthotopic in vivo model of bladder cancer. In vitro screening of linear polyamine-based and aminoglycoside-based polymer libraries identified several candidates that enhanced adenoviral reporter gene expression in vitro. The polyamine-based polymer NPGDE-1,4 Bis significantly enhanced adenoviral gene expression in the orthotopic model of bladder cancer but unfortunately further use of this polymer was limited by toxicity. In contrast, the aminoglycoside-based polymer paromomycin-BGDE, enhanced adenoviral gene expression within the bladder without adverse events. Our study demonstrates for the first time that cationic polymers can enhance adenoviral gene expression in an orthotopic model of bladder cancer, thereby providing the foundation for future studies to determine therapeutic benefits of polymer-adenovirus combination in bladder cancer gene therapy.
AB - Gene therapy has garnered significant attention as a therapeutic approach for bladder cancer but efficient delivery and gene expression remain major hurdles. The goal of this study was to determine if cationic polymers can enhance adenoviral gene expression in cells that are difficult to transduce in vitro and to subsequently investigate lead candidates for their capacity to increase adenoviral gene expression in an orthotopic in vivo model of bladder cancer. In vitro screening of linear polyamine-based and aminoglycoside-based polymer libraries identified several candidates that enhanced adenoviral reporter gene expression in vitro. The polyamine-based polymer NPGDE-1,4 Bis significantly enhanced adenoviral gene expression in the orthotopic model of bladder cancer but unfortunately further use of this polymer was limited by toxicity. In contrast, the aminoglycoside-based polymer paromomycin-BGDE, enhanced adenoviral gene expression within the bladder without adverse events. Our study demonstrates for the first time that cationic polymers can enhance adenoviral gene expression in an orthotopic model of bladder cancer, thereby providing the foundation for future studies to determine therapeutic benefits of polymer-adenovirus combination in bladder cancer gene therapy.
KW - Adenovirus
KW - Bladder cancer
KW - Cationic polymer
KW - Gene delivery
KW - Orthotopic
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U2 - 10.1016/j.jconrel.2013.12.012
DO - 10.1016/j.jconrel.2013.12.012
M3 - Article
C2 - 24370892
AN - SCOPUS:84892634747
SN - 0168-3659
VL - 176
SP - 35
EP - 43
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 1
ER -