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Thymidine Kinase Gene Delivery Using Curcumin Loaded Peptide Micelles as a Combination Therapy for Glioblastoma

Abstract

Purpose

The effect of the combination therapy of curcumin and the herpes simplex virus thymidine kinase (HSVtk) gene using R7L10 as a carrier was evaluated in a glioblastoma animal model.

Methods

Curcumin was loaded into the cores of R7L10 peptide micelles using an oil-in-water emulsion/solvent evaporation method to generate curcumin loaded R7L10 micelles (R7L10-Cur), which were used as a carrier to deliver the HSVtk gene. The plasmid DNA (pDNA)/R7L10-Cur complex was confirmed by gel retardation, heparin competition, and dynamic light scattering analyses. Transfection efficiency and cytotoxicity were measured using luciferase, MTT, and TUNEL assays. Intracellular delivery of curcumin was determined by fluorescence and absorbance. In the glioblastoma animal model, the effects of the intratumoral delivery of curcumin and the HSVtk gene were evaluated according to tumor size, immunohistochemistry, and TUNEL assays.

Results

R7L10-Cur delivered pDNA into the cells more efficiently than PLL and R7L10. In addition, R7L10-Cur delivered curcumin into the cells more efficiently than curcumin alone. The pHSVtk/R7L10-Cur complex induced cell death efficiently both in vitro and in vivo. Likewise, the combination of curcumin and the HSVtk gene using the pHSVtk/R7L10-Cur complex reduced tumor size more efficiently than the pHSVtk/PEI and pHSVtk/R7L10 complexes in a glioblastoma animal model.

Conclusion

R7L10 is an efficient carrier for delivery of curcumin and the HSVtk gene, which may be a useful combination therapy for glioblastoma.

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was financially supported by a grant from the National Research Foundation of Korea, funded by the Ministry of Science, ICT and Future Planning (Grant number, 2013K000257 and NRF-2013R1A1A2059236) and a grant from the Ministry of Health and welfare in Korea (Grant number, HI12C-1210-010013).

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Correspondence to Minhyung Lee.

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Park, J.H., Han, J. & Lee, M. Thymidine Kinase Gene Delivery Using Curcumin Loaded Peptide Micelles as a Combination Therapy for Glioblastoma. Pharm Res 32, 528–537 (2015). https://doi.org/10.1007/s11095-014-1482-4

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  • DOI: https://doi.org/10.1007/s11095-014-1482-4

KEY WORDS

  • combination therapy
  • curcumin
  • gene therapy
  • glioblastoma
  • peptide micelles