Document Detail


Potential use of folate-polyethylene glycol (PEG)-appended dendrimer (G3) conjugate with α-cyclodextrin as DNA carriers to tumor cells.
MedLine Citation:
PMID:  22402627     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
We previously reported that polyamidoamine STARBURST dendrimer (generation 3, G3) (dendrimer) conjugate with α-cyclodextrin (α-CyD) having an average degree of substitution of 2.4 of α-CyD (α-CDE) provided remarkable aspects as novel carriers for DNA and small-interfering RNA. To develop novel α-CDE derivatives with tumor cell specificity, we prepared folate-appended α-CDEs (Fol-α-CDEs) and folate-polyethylene glycol (PEG)-appended α-CDEs (Fol-PαCs) with the various degrees of substitution of folate (DSF), and evaluated in vitro and in vivo gene transfer activity, cytotoxicity, cellular association and physicochemical properties. In vitro gene transfer activity of Fol-α-CDEs (G3, DSF 2, 5 or 7) was lower than that of α-CDE (G3) in KB cells, folate receptor (FR)-overexpressing cancer cells. Of the three Fol-PαCs (G3, DSF 2, 5 or 7), Fol-PαC (G3, DSF 5) had the highest gene transfer activity in KB cells. The activity of Fol-PαC (G3, DSF 5) was significantly higher than that of α-CDE (G3) in KB cells, but not in A549 cells, FR-negative cells. Negligible cytotoxicity of the plasmid DNA (pDNA) complex with Fol-PαC (G3, DSF 5) was observed in KB cells or A549 cells up to a charge ratio of 100/1 (carrier/pDNA). The cellular association of the pDNA complex with Fol-PαC (G3, DSF 5) could be mediated by FR on KB cells, resulting in its efficient cellular uptake. Fol-PαC (G3, DSF 5) had a higher binding affinity with folate-binding protein than α-CDE (G3), although the physicochemical properties of pDNA complex with Fol-PαC (G3, DSF 5) were almost comparable to that with α-CDE (G3), although the onset charge ratio and the compaction ability of Fol-PαC (G3, DSF 5) were slightly different. Fol-PαC (G3, DSF 5) tended to show a higher gene transfer activity than α-CDE (G3) 12 h after intratumoral administration in mice. These results suggest that Fol-PαC (G3, DSF 5), not Fol-α-CDEs, could be potentially used as a FR-overexpressing cancer cell-selective DNA carrier.Cancer Gene Therapy advance online publication, 9 March 2012; doi:10.1038/cgt.2012.9.
Authors:
H Arima; M Arizono; T Higashi; A Yoshimatsu; H Ikeda; K Motoyama; K Hattori; T Takeuchi; F Hirayama; K Uekama
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-09
Journal Detail:
Title:  Cancer gene therapy     Volume:  -     ISSN:  1476-5500     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9432230     Medline TA:  Cancer Gene Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
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