Journal
JOURNAL OF CONTROLLED RELEASE
Volume 98, Issue 3, Pages 437-446Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2004.05.013
Keywords
functional polyester; gene delivery; 4-hydroxy-L-proline; microsphere; non-viral vector
Funding
- NCI NIH HHS [CA74918] Funding Source: Medline
- NIAMS NIH HHS [AR45925] Funding Source: Medline
- NIDDK NIH HHS [DK44935] Funding Source: Medline
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Gene expression mediated by a non-viral vector usually lasts only a few days. The objective of this study was to synthesize and characterize a non-toxic, polymeric gene carrier, poly(D,L-lactide-co-4-hydroxy-L-proline) (PLHP) for sustained gene delivery. The copolymer was synthesized by ring-opening polymerization of D,L-lactide (DLLA) with N-cbz-4-hydroxy-L-proline (HP) in the presence of stannous octoate (Sn(Oct)(2)). The resulting copolymer was characterized by H-1 nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC). Degradation of PLHP was examined by monitoring the medium pH change and molecular weight (MW) of the remaining polymer. It showed a rapid initial degradation and followed by a slower degradation for about 30 days at 37 degreesC. The cytotoxicity of copolymer was significantly lower than polyethylenimine (PEI) and poly-L-lysine hydrochloride (PLL) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The plasmid DNA (pDNA)-loaded microspheres based on the copolymer were prepared by a water-oil-water (w/o/w) solvent evaporation emulsion method. The release profile of pDNA from PLHP microspheres showed an initial burst release, and then a slower and continuous release for about 18 days at 37 degreesC. Gene transfer efficiency of PLHP/pDNA delivery system showed a sustained activity (over a week) when compared with PEI and PLL, and can be further improved by the addition of cationic liposomes. The results suggest that PLHP is a promising candidate for long-term gene delivery with good biocompatibility and biodegradability. (C) 2004 Elsevier B.V. All rights reserved.
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