Author: Hirofumi Jono ; Keiichi Motoyama ; Kaneto Uekama ; Hidetoshi Arima ; Fumitoshi Hirayama ; Shogo Yamashita ; Tomoko Takeuchi ; Yoshimasa Mori ; Yuya Hayashi ; Yukio Ando ; Kenjiro Hattori

The purpose of this study is to evaluate in vitro and in vivo gene delivery efficiency of polyamidoamine (PAMAM) starburst dendrimer (generation 2, G2) conjugates with alpha-cyclodextrin (alpha-CDE (G2)) bearing lactose (Lac-alpha-CDE) with various degrees of substitution of the lactose moiety (DSL) as a novel hepatocyte-selective carrier in hepatocytes. Lac-alpha-CDE (DSL 2.6) was found to have much higher gene transfer activity than dendrimer, alpha-CDE, Lac-alpha-CDE (DSL 1.2, 4.6, 6.2 and 10.2) and lactosylated dendrimer (Lac-dendrimer, DSL 2.4) in HepG2 cells, which are dependent on the expression of cell-surface asialoglycoprotein receptor (ASGP-R), reflecting the cellular association of the plasmid DNA (pDNA) complexes. The physicochemical properties of pDNA complex with Lac-alpha-CDE (DSL 2.6) were almost comparable to that with alpha-CDE. Lac-alpha-CDE (DSL 2.6) provided negligible cytotoxicity up to a charge ratio of 150 in HepG2 cells. Lac-alpha-CDE (DSL 2.6) provided gene transfer activity higher than jetPEI-Hepatocyte to hepatocytes with much less changes of blood chemistry values 12h after intravenous administration in mice. These results suggest the potential use of Lac-alpha-CDE (DSL 2.6) as a non-viral vector for gene delivery toward hepatocytes.

01 Aug 2008·Journal of Pharmaceutical SciencesQ3 · MEDICINE

Potential Use of Polyamidoamine Dendrimer/α-Cyclodextrin Conjugate (Generation 3, G3) as a Novel Carrier for Short Hairpin RNA-Expressing Plasmid DNA

Q3 · MEDICINE

Article

Author: Kaneto Uekama ; Hidetoshi Arima ; Toshihito Tsutsumi ; Fumitoshi Hirayama

The potential of starburst polyamidoamine dendrimer (dendrimer, generation 3, G3) conjugate with alpha-cyclodextrin (alpha-CyD) having an average degree of substitution of 2.4 (alpha-CDE) as a novel carrier of short hairpin RNA (shRNA) expressing plasmid DNA (shpDNA) was evaluated and the shpDNA transfer activity of alpha-CDE was compared with that of dendrimer (G3). Alpha-CDE formed a stable and condensed complex with shpDNA and induced a conformational transition of shpDNA in solution even in the low charge ratios. In addition, alpha-CDE markedly inhibited the enzymatic degradation of shpDNA by DNase I. The shpDNA complex with alpha-CDE at the charge ratio of 20/1 (alpha-CDE/shpDNA) elicited the most potent RNAi effects in cells transiently and stably expressing the GL3 and GL2 luciferase genes without cytotoxicity among the complexes with the various charge ratios. Besides, the RNAi effects were strikingly enhanced by the further addition of the adequate amounts of siRNA to the shpDNA complex with alpha-CDE. Taken together, the prominent RNAi effects of the shpDNA complex with alpha-CDE could be attributed to the stabilizing effect of alpha-CDE on enzymatic degradation of shpDNA and negligible cytotoxicity. These results suggest that alpha-CDE possesses the potential to be a novel carrier for shpDNA and siRNA.

01 Mar 2008·Nature ProtocolsQ1 · BIOLOGY

Preparation of magnetic resonance contrast agents activated by β-galactosidase

Q1 · BIOLOGY

Article

Author: L. M Lauren M Urbanczyk-Pearson ; Thomas J Meade

The preparation of beta-EgadMe and alpha-EgadMe, magnetic resonance (MR) contrast agents that can be used for in vivo detection of beta-galactosidase, is described. Diastereomerically pure beta-EgadMe can be synthesized by kinetically resolving the starting material as described in Step 1. The total time for the preparation of the racemic mixture of beta-EgadMe is about 8 d, and the total time for an diastereomerically resolved agent is about 9 d. The final metallated agent is stable at room temperature as a solid or in aqueous buffer (pH 5.5-10) indefinitely. Diastereomerically pure alpha-EgadMe can be prepared by beginning the synthesis with enantiomerically pure bromopropionic acid. The total time for the preparation of racemic alpha-EgadMe or diastereomerically pure alpha-EgadMe is about 8 d. The final metallated agent is stable at room temperature as a solid or in aqueous buffer (pH 5.5-10) indefinitely.

100 Deals associated with RPI-78M

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis	Phase 3	-	Nutra Pharma Corp.	-
Multiple Sclerosis	Phase 3	-	Centers for Disease Control & Prevention	-
Herpes Zoster	Discovery	United States	ReceptoPharm, Inc.	09 Jun 2010
Herpes Simplex	Discovery	United States	ReceptoPharm, Inc.	18 May 2010
Adrenoleukodystrophy	Discovery	United Kingdom	ReceptoPharm, Inc.	03 Jan 2007

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