Design and evaluation of polyamidoamine dendrimer conjugate with PEG, alpha-cyclodextrin and lactose as a novel hepatocyte-selective gene carrier in vitro and in vivo

作者：Hayashi Yuya; Higashi Taishi; Motoyama Keiichi; Mori Yoshimasa; Jono Hirofumi; Ando Yukio; Arima Hidetoshi^*

来源：Journal of Drug Targeting, 2013, 21(5): 487-496.

DOI：10.3109/1061186X.2013.769105

• alpha-Cyclodextrin
• hepatocyte-selective gene delivery
• lactose
• non-viral vector
• polyamidoamine starburst dendrimer
• polyethylene glycol

To develop a novel hepatocyte-selective gene carrier, we prepared polyamidoamine starburst dendrimer (generation 3, G3) conjugates with three functional molecules, i.e. alpha-cyclodextrin, polyethylene glycol (PEG, molecular weight = 2170) and lactose (PEG-L alpha Cs), and evaluated gene delivery efficiency of these conjugates in vitro and in vivo. PEG-L alpha C (G3, degrees of substitution of the PEG moiety (DSP) 2.1) showed higher gene transfer activity than other PEG-L alpha Cs (G3, DSP4.0, 6.2) in HepG2 cells, expressing asialoglycoprotein receptor, and the activity decreased in HeLa cells, non-expressing the receptor and in the presence of asialofetuin. High gene transfer activity of PEG-L alpha C (G3, DSP2.1) was retained even in the presence of 50% serum, although the activity of alpha-cyclodextrin/lactosylated dendrimer (G3) conjugate (Lac-alpha-CDE (G3)), which is lacking a PEG moiety, was severely decreased in the presence of 20% serum. PEG-L alpha C (G3, DSP2.1) provided negligible cytotoxicity up to a charge ratio of 50 (carrier/pDNA) in HepG2 cells and less acute organ toxicity. PEG-L alpha C (G3, DSP2.1) showed selective gene transfer activity to hepatic parenchymal cells rather than hepatic non-parenchymal cells. These results suggest that PEG-L alpha C (G3, DSP2.1) is useful as a hepatocyte-selective gene carrier in vitro and in vivo.

• 出版日期2013-5