Polypseudorotaxanes of pegylated α-cyclodextrin/polyamidoamine dendrimer conjugate with cyclodextrins as a sustained release system for DNA

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 4; pp. 1425 - 1433
• Main Authors: Motoyama, Keiichi, Hayashida, Kayoko, Higashi, Taishi, Arima, Hidetoshi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2012; Elsevier
• Subjects: administration & dosage; alpha-cyclodextrin; alpha-Cyclodextrins; alpha-Cyclodextrins - chemistry; alpha-Cyclodextrins - pharmacology; Animals; Biological and medical sciences; Cell Line, Tumor; chemical synthesis; chemistry; Crystallography, X-Ray; Cyclodextrin; Delayed-Action Preparations; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - chemistry; Delayed-Action Preparations - pharmacology; Dendrimer; Dendrimers; Dendrimers - chemistry; DNA; DNA - chemistry; Electrophoresis, Gel, Two-Dimensional; gene expression; genes; Injections, Intramuscular; intramuscular injection; Male; Medical sciences; Mice; Mice, Inbred BALB C; Molecular Structure; molecular weight; Particle Size; pharmacology; Pharmacology. Drug treatments; plasmids; Polyamines; Polyamines - chemistry; Polyamines - pharmacology; polyethylene glycol; Polyethylene Glycols; Polyethylene Glycols - chemistry; Polypseudorotaxane; Rotaxanes; Rotaxanes - chemical synthesis; Rotaxanes - chemistry; Sustained release; transfection; X-Ray Diffraction; Sustained release; Cyclodextrin; Dendrimer; DNA; Polypseudorotaxane; Branched polymer; Controlled release form; Amidoamine polymer; Ethylene oxide polymer; α-Cyclodextrin; Dosage form; Conjugated compound; Inclusion compound; Pegylated form; Dendritic structure; Rotaxane
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2011.12.060

Proposed scheme for gene transfer mechanism of PEG-α-CDE/γ-CyD PPRX suspension after intramuscular injection to mice. Nonviral gene delivery suffers from a number of limitations including short transgene expression times and low transfection efficiency. In this study, we examined whether polypseudorotaxanes (PPRXs) of polyethylene glycol (PEG, molecular weight: 2,000)-grafted α-cyclodextrin (α-CyD)/polyamidoamine dendrimer conjugate (PEG-α-CDE) with CyDs have the potential for the novel sustained release systems for plasmid DNA (pDNA). The PEG-α-CDE/pDNA complex formed PPRXs with α-CyD and γ-CyD solutions, but not with β-CyD solution. In the PEG-α-CDE/CyDs PPRX systems, 20.6mol of α-CyD and 11.8mol of γ-CyD were involved in the PPRXs formation with one PEG chain by α-CyD and γ-CyD, respectively, consistent with in the PEG-dendrimer/CyDs systems. PEG-α-CDE/pDNA/α-CyD PPRX and PEG-α-CDE/pDNA/γ-CyD PPRX formed hexagonal and tetragonal columnar channels in the crystalline phase, respectively. In addition, the CyDs PPRX provided the sustained release of pDNA from PEG-α-CDE complex with pDNA at least 72h in vitro. The release of pDNA from CyDs PPRX retarded as the volume of dissolution medium decreased. Furthermore, the PEG-α-CDE/γ-CyD PPRX system showed sustained transfection efficiency after intramuscular injection to mice at least for 14days. These results suggest that the PEG-α-CDE/CyD PPRX systems are useful for novel sustained DNA release systems.