Potential use of glucuronylglucosyl-β-cyclodextrin/dendrimer conjugate (G2) as a DNA carrier in vitro and in vivo.
In this study, we evaluated the polyamidoamine starburst dendrimer (dendrimer, generation 2: G2) conjugate with 6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-β-cyclodextrin (GUG-β-CDE (G2)) as a gene transfer carrier. The in vitro gene transfer activity of GUG-β-CDE (G2, degree of substitution (DS) of cyclodextrin (CyD) 1.8) was remarkably higher than that of dendrimer (G2) conjugate with α-CyD (α-CDE (G2, DS 1.2)) and that with β-CyD(β-CDE (G2, DS 1.3)) in A549 and RAW264.7 cells. The particle size, ζ-potential, DNase I-catalyzed degradation, and cellular association of plasmid DNA (pDNA) complex with GUG-β-CDE (G2, DS 1.8) were almost the same as those of the other CDEs. Fluorescent-labeled GUG-β-CDE (G2, DS 1.8) localized in the nucleus 6 h after transfection of its pDNA complex in A549 cells, suggesting that nuclear localization of pDNA complex with GUG-β-CDE (G2, DS 1.8), at least in part, contributes to its high gene transfer activity. GUG-β-CDE (G2, DS 1.8) provided higher gene transfer activity than α-CDE (G2, DS 1.2) and β-CDE (G2, DS 1.3) in kidney with negligible changes in blood chemistry values 12 h after intravenous injection of pDNA complexes with GUG-β-CDE (G2, DS 1.8) in mice. In conclusion, the present findings suggest that GUG-β-CDE (G2, DS 1.8) has the potential for a novel polymeric pDNA carrier in vitro and in vivo.
Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Takayuki
T
Anno
Taishi
T
Higashi
Keiichi
K
Motoyama
Fumitoshi
F
Hirayama
Kaneto
K
Uekama
Hidetoshi
H
Arima
D000230:Adenocarcinoma / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001692:Biological Transport; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D055598:Chemical Phenomena; D050091:Dendrimers / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D018014:Gene Transfer Techniques / Q000009:adverse effects; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000009:adverse effects* / Q000737:chemistry; D010316:Particle Size; D013499:Surface Properties; D014018:Tissue Distribution; D047392:beta-Cyclodextrins / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics
D050091:Dendrimers; D047392:beta-Cyclodextrins