Abstract
The possibility of using gene therapy for the treatment of prostate cancer is limited by the lack of intravenously administered delivery systems able to safely and selectively deliver therapeutic genes to tumors. Given that lactoferrin (Lf) receptors are overexpressed on prostate cancer cells, we hypothesized that the conjugation of Lf to generation 3-diaminobutyric polypropylenimine dendrimer would improve its transfection and therapeutic efficacy in prostate cancer cells. In this study, we demonstrated that the intravenous administration of Lf-bearing DAB dendriplexes encoding TNFα resulted in the complete suppression of 70% of PC-3 and 50% of DU145 tumors over one month. Treatment with DAB-Lf dendriplex encoding TRAIL led to tumor suppression of 40% of PC-3 tumors and 20% of DU145 tumors. The treatment was well tolerated by the animals. Lf-bearing generation 3-polypropylenimine dendrimer is therefore a highly promising delivery system for non-viral gene therapy of prostate cancer.
Highlights
Prostate cancer is the fourth most widespread cancer in the world, the second most common cancer in men, and the first in Europe and North America (Ferlay et al, 2015)
In order to remediate this issue, we propose to conjugate the iron-carrier lactoferrin (Lf), whose receptors are overexpressed on prostate cancer cell lines (Barresi & Tuccari, 1984; Tuccari & Barresi, 2011), to the surface of generation 3-diaminobutyric polypropylenimine (DAB) dendrimer carrying plasmids encoding for TNFa, TRAIL, or IL-12, and evaluate if these Lf-bearing dendriplexes could lead to an enhanced therapeutic efficacy on prostate cancer following intravenous administration
In DU145 cells, transfection efficacy of DAB-Lf dendriplex was lower than that observed in PC3 cells, but was still significantly higher than that observed with DAB dendriplex (1.26 Â 10À3 ± 0.17 Â 10À3)
Summary
Prostate cancer is the fourth most widespread cancer in the world, the second most common cancer in men, and the first in Europe and North America (Ferlay et al, 2015). It is responsible of the death of 300 000 patients per year worldwide and its incidence kept on increasing during the last two decades (Saman et al, 2014). Gene therapy would be highly promising for the treatment of prostate cancer, but its use is currently limited by the lack of delivery systems able to selectively deliver the therapeutic genes to the tumors following intravenous administration, without creating secondary effects to healthy tissues. In order to remediate this issue, we propose to conjugate the iron-carrier lactoferrin (Lf), whose receptors are overexpressed on prostate cancer cell lines (Barresi & Tuccari, 1984; Tuccari & Barresi, 2011), to the surface of generation 3-diaminobutyric polypropylenimine (DAB) dendrimer carrying plasmids encoding for TNFa, TRAIL, or IL-12, and evaluate if these Lf-bearing dendriplexes could lead to an enhanced therapeutic efficacy on prostate cancer following intravenous administration
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