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In Vitro and In Vivo Co-delivery of siRNA and Doxorubicin by Folate-PEG-Appended Dendrimer/Glucuronylglucosyl-β-Cyclodextrin Conjugate
Ist Teil von
The AAPS journal, 2019-07, Vol.21 (4), p.54, Article 54
Ort / Verlag
Cham: Springer International Publishing
Erscheinungsjahr
2019
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
We have previously reported the utility of folate-polyethylene glycol-appended dendrimer conjugate with glucuronylglucosyl-β-cyclodextrin (Fol-PEG-GUG-β-CDE) (generation 3) as a tumor-selective carrier for siRNA against polo-like kinase 1 (siPLK1)
in vitro
. In the present study, we evaluated the potential of Fol-PEG-GUG-β-CDE as a carrier for the low-molecular antitumor drug doxorubicin (DOX). Further, to fabricate advanced antitumor agents, we have prepared a ternary complex of Fol-PEG-GUG-β-CDE/DOX/siPLK1 and evaluated its antitumor activity both
in vitro
and
in vivo
. Fol-PEG-GUG-β-CDE released DOX in an acidic pH and enhanced the cellular accumulation and cytotoxic activity of DOX in folate receptor-α (FR-α)-overexpressing KB cells. Importantly, the Fol-PEG-GUG-β-CDE/DOX/siPLK1 ternary complex exhibited higher cytotoxic activity than a binary complex of Fol-PEG-GUG-β-CDE with DOX or siPLK1 in KB cells. In addition, the cytotoxic activity of the ternary complex was reduced by the addition of folic acid, a competitor against FR-α. Furthermore, the ternary complex showed a significant antitumor activity after intravenous administration to the tumor-bearing mice. These results suggest that Fol-PEG-GUG-β-CDE has the potential of a tumor-selective co-delivery carrier for DOX and siPLK1.