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Multifunctional polyion complex micelle featuring enhanced stability, targetability, and endosome escapability for systemic siRNA delivery to subcutaneous model of lung cancer

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Abstract

For systemic small interfering RNA (siRNA) delivery to tumor mass, a multifunctional polyion complex micelle was constructed with a block copolymer bearing a targeting ligand and a micelle-stabilizing moiety as well as an endosome-disrupting cationic unit. The block copolymer was comprised of poly(ethylene glycol) (PEG) and a polyaspartamide derivative with flanking cationic tetraethylenepentamine (TEP) moiety (PAsp(TEP)), in which the distal ends of PEG and PAsp(TEP) were further installed with cyclic RGD (cRGD) peptide ligand and cholesteryl (Chol) moiety, respectively. The resulting polymer was confirmed to form siRNA-loaded micelle with a diameter of sub 50 nm and a narrow size distribution. In the stability assays with fluorescently labeled siRNA, the terminal Chol moiety significantly suppressed both the rapid dissociation of the micelles in the serum-containing medium and their rapid elimination from the bloodstream, presumably due to its hydrophobic interactions in the micellar core. Moreover, the targeting cRGD ligand, associated with the stabilizing moiety, significantly enhanced the accumulation of siRNA-loaded micelle in a subcutaneous lung (A549) tumor, compared to a non-targeted control, after systemic administration. Ultimately, significant tumor growth inhibition was achieved by systemic administration of the targeted/stabilized micelle incorporating polo-like kinase 1 (Plk1) siRNA with negligible liver toxicity, consistent with the significant sequence-specific gene silencing of Plk1 in the tumor tissue. These results demonstrated the therapeutic potential of cRGD-PEG-PAsp(TEP)-Chol/siRNA micelle for systemic siRNA delivery toward cancer therapy.

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Acknowledgments

This work was supported by the Core Research Program for Evolutional Science and Technology (CREST) of the Japan Science and Technology Corporation (JST), the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) from the Japan Society for the Promotion of Science (JSPS), Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest

Every author declares that he has no conflict of interest.

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Authors and Affiliations

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

    Hyun Jin Kim & Kazunori Kataoka

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

    Takehiko Ishii & Kazunori Kataoka

  3. Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Meng Zheng, Sumiyo Watanabe, Kazuko Toh, Yu Matsumoto, Nobuhiro Nishiyama, Kanjiro Miyata & Kazunori Kataoka

  4. Department of Internal Medicine, School of Medicine, Teikyo University, Tokyo, Japan

    Sumiyo Watanabe

  5. Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Yu Matsumoto

  6. Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, Tokyo, Japan

    Nobuhiro Nishiyama

  7. Center for NanoBio Integration, The University of Tokyo, Tokyo, Japan

    Kazunori Kataoka

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  1. Hyun Jin Kim
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  2. Takehiko Ishii
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Correspondence to Kanjiro Miyata or Kazunori Kataoka.

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Kim, H.J., Ishii, T., Zheng, M. et al. Multifunctional polyion complex micelle featuring enhanced stability, targetability, and endosome escapability for systemic siRNA delivery to subcutaneous model of lung cancer. Drug Deliv. and Transl. Res. 4, 50–60 (2014). https://doi.org/10.1007/s13346-013-0175-6

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  • DOI: https://doi.org/10.1007/s13346-013-0175-6

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