Improvement of gene delivery mediated by mannosylated dendrimer/alpha-cyclodextrin conjugates.
The purpose of this study is to evaluate in vitro and in vivo gene delivery efficiency of polyamidoamine (PAMAM) starburst dendrimer (generation 2, G2) conjugate with alpha-cyclodextrin (alpha-CDE conjugate (G2)) bearing mannose (Man-alpha-CDE conjugates) with the various degrees of substitution of the mannose moiety (DSM) as a novel non-viral vector in a variety of cells. Man-alpha-CDE conjugates (DSM 3.3 and 4.9) were found to have much higher gene transfer activity than dendrimer, alpha-CDE conjugate and Man-alpha-CDE conjugates (DSM 1.1 and 8.3) in various cells, which are independent of the expression of cell surface mannose receptors. Cellular association of pDNA complexes with dendrimer, alpha-CDE conjugate and Man-alpha-CDE conjugate (DSM 3.3) and their cytotoxic effects differed only very slightly. Surface plasmon resonance study demonstrated that the specific binding activity of Man-alpha-CDE conjugates to concanavalin A was not very strong. Much more conjugation of the mannose moiety to alpha-CDE conjugates provided unfavorable physicochemical properties of pDNA complexes for gene transfer, e.g. the low interaction with pDNA, the low enzymatic stability of pDNA and the lack of pDNA compaction. Man-alpha-CDE conjugate (DSM 3.3) provided gene transfer activity higher than dendrimer and alpha-CDE conjugate in kidney 12 h after intravenous injection in mice. These results suggest the potential use of Man-alpha-CDE conjugate (DSM 3.3) as a non-viral vector.
Wada
Koki
K
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Arima
Hidetoshi
H
Tsutsumi
Toshihito
T
Chihara
Yuko
Y
Hattori
Kenjiro
K
Hirayama
Fumitoshi
F
Uekama
Kaneto
K
D000818:Animals; D050091:Dendrimers; D004285:Dogs; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008358:Mannose; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D011073:Polyamines / Q000008:administration & dosage*; D047391:alpha-Cyclodextrins / Q000008:administration & dosage*
D050091:Dendrimers; C104700:PAMAM Starburst; D011073:Polyamines; D047391:alpha-Cyclodextrins; D008358:Mannose; C032613:alpha-cyclodextrin