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Controlled Gene Delivery System Based on Thermosensitive Biodegradable Hydrogel

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Abstract

Purpose. Currently, most pDNA delivery systems based on synthetic polymers are either nonbiodegradable or not sensitive to the release environment. The primary objective of this study was to develop and evaluate an aqueous-based, thermosensitive, biodegradable and biocompatible triblock copolymer to control pDNA delivery in vitro and in vivo.

Methods. The triblock copolymers, poly[ethylene glycol-b-(D, L-lactic acid-co-glycol acid)-b-ethylene glycol] (PEG-PLGA-PEG), were synthesized as previously described. The molecular weight and polydispersity of PEG-PLGA-PEG were monitored by gel permeation chromatography (GPC). The cytotoxicity of PEG-PLGA-PEG was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra- zolium bromide assay. The release of 32P-labeled pDNA entrapped in aqueous dispersion of PEG-PLGA-PEG in 0.1 mol/L sodium phosphate buffer solution (pH 7.4) was studied at 37°C under agitation. Gene transfection efficiency was evaluated in a skin wound model in CD-1 mice.

Results. The aqueous dispersion of PEG-PLGA-PEG flows freely at room temperature but form a gel at 37°C body temperature. The in vitro degradation of PEG-PLGA-PEG lasted for more than 30 days. The cytotoxicity of PEG-PLGA-PEG evaluated in HEK 293 cells was significantly lower than that of poly-L-lysine hydrochloride. The release profile of supercoiled pDNA from the polymer followed the zero-order kinetics up to 12 days. Maximal gene expression of luciferase was at 24 h in the skin wound of CD-1 mice and by 72 h, the expression dropped by nearly 94%.

Conclusions. These results suggest hydrogel formed by PEG-PLGA-PEG could be a promising platform for delivery of pDNA, which represents a novel strategy that may serve as a non-viral vector for gene therapy in wound healing.

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Authors and Affiliations

  1. Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213

    Zhenhua Li, Pui-Yan Lee, Pradeep Tyagi & Leaf Huang

  2. Division of Pulmonary, Allergy & Critical Care Medicine, UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213

    Wen Ning & Augustine Choi

  3. Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261

    Jumei Wang

Authors
  1. Zhenhua Li
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  2. Wen Ning
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  3. Jumei Wang
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  4. Augustine Choi
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  5. Pui-Yan Lee
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  6. Pradeep Tyagi
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  7. Leaf Huang
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Correspondence to Leaf Huang.

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Li, Z., Ning, W., Wang, J. et al. Controlled Gene Delivery System Based on Thermosensitive Biodegradable Hydrogel. Pharm Res 20, 884–888 (2003). https://doi.org/10.1023/A:1023887203111

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