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Impact of polyplex micelles installed with cyclic RGD peptide as ligand on gene delivery to vascular lesions

Gene Therapy volume 19, pages 61–69 (2012)Cite this article

Abstract

Gene therapy is expected to open a new strategy for the treatment of refractory vascular diseases, so the development of appropriate gene vectors for vascular lesions is needed. To realize this requirement with a non-viral approach, cyclo(RGDfK) peptide (cRGD) was introduced to block copolymer, poly(ethylene glycol)-block-polycation carrying ethylenediamine units (PEG-PAsp(DET)). cRGD recognizes αvβ3 and αvβ5 integrins, which are abundantly expressed in vascular lesions. cRGD-conjugated PEG-PAsp(DET) (cRGD-PEG-PAsp(DET)) formed polyplex micelles through complexation with plasmid DNA (pDNA) and the cRGD-PEG-PAsp(DET) micelles achieved significantly more efficient gene expression and cellular uptake as compared with PEG-PAsp(DET) micelles in endothelial cells and vascular smooth muscle cells. Intracellular tracking of pDNA showed that cRGD-PEG-PAsp(DET) micelles were internalized via caveolae-mediated endocytosis, which is associated with a pathway avoiding lysosomal degradation and that, PEG-PAsp(DET) micelles were transported to acidic endosomes and lysosomes via clathrin-mediated endocytosis. Further, in vivo evaluation in rat carotid artery with a neointimal lesion revealed that cRGD-PEG-PAsp(DET) micelles realized sustained gene expression, whereas PEG-PAsp(DET) micelles facilitated rapid, but transient gene expression. These findings suggest that introduction of cRGD to polyplex micelles might create novel and useful functions for gene transfer and contribute to the establishment of efficient gene therapy for vascular diseases.

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Acknowledgements

This work was supported by Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and the Core Research Program for Educational Science and Technology (CREST) from the Japan Science and Technology Corporation (JST).

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Authors and Affiliations

  1. Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    H Kagaya & T Miyata

  2. Division of Tissue Engineering, The University of Tokyo, Tokyo, Japan

    H Kagaya, Y Miura, H Koyama, T Shimada & T Takato

  3. Department of Molecular Medicinal Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki-shi, Japan

    M Oba

  4. Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    T Ishii

  5. Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    K Kataoka

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Correspondence to H Koyama.

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Kagaya, H., Oba, M., Miura, Y. et al. Impact of polyplex micelles installed with cyclic RGD peptide as ligand on gene delivery to vascular lesions. Gene Ther 19, 61–69 (2012). https://doi.org/10.1038/gt.2011.74

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