title: Design and evaluation of polyamidoamine dendrimer conjugate with PEG, α-cyclodextrin and lactose as a novel hepatocyte-selective gene carrier in vitro and in vivo.
abstract: To develop a novel hepatocyte-selective gene carrier, we prepared polyamidoamine starburst dendrimer (generation 3, G3) conjugates with three functional molecules, i.e. α-cyclodextrin, polyethylene glycol (PEG, molecular weight = 2170) and lactose (PEG-LαCs), and evaluated gene delivery efficiency of these conjugates in vitro and in vivo. PEG-LαC (G3, degrees of substitution of the PEG moiety (DSP) 2.1) showed higher gene transfer activity than other PEG-LαCs (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-LαC (G3, DSP2.1) was retained even in the presence of 50% serum, although the activity of α-cyclodextrin/lactosylated dendrimer (G3) conjugate (Lac-α-CDE (G3)), which is lacking a PEG moiety, was severely decreased in the presence of 20% serum. PEG-LαC (G3, DSP2.1) provided negligible cytotoxicity up to a charge ratio of 50 (carrier/pDNA) in HepG2 cells and less acute organ toxicity. PEG-LαC (G3, DSP2.1) showed selective gene transfer activity to hepatic parenchymal cells rather than hepatic non-parenchymal cells. These results suggest that PEG-LαC (G3, DSP2.1) is useful as a hepatocyte-selective gene carrier in vitro and in vivo.
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Mori
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
mesh_terms: D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000235:genetics; D001212:Asialoglycoproteins / Q000008:administration & dosage; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D060748:Fetuins / Q000008:administration & dosage; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006367:HeLa Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007785:Lactose / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011073:Polyamines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D047391:alpha-Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D050091:Dendrimers; D060748:Fetuins; C531249:Poly(amidoamine); D011073:Polyamines; D047391:alpha-Cyclodextrins; C017029:asialofetuin; D011092:Polyethylene Glycols; D007785:Lactose; C032613:alpha-cyclodextrin