Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery

Shota Ichimizu, Hiroshi Watanabe, Hitoshi Maeda, Keisuke Hamasaki, Yuka Nakamura, Victor Tuan Giam Chuang, Ryo Kinoshita, Kento Nishida, Ryota Tanaka, Yuki Enoki, Yu Ishima, Akihiko Kuniyasu, Yoshihiro Kobashigawa, Hiroshi Morioka, Shiro Futaki, Masaki Otagiri, Toru Maruyama

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Human serum albumin (HSA) is a superior carrier for delivering extracellular drugs. However, the development of a cell-penetrating HSA remains a great challenge due to its low membrane permeability. We report herein on the design of a series of palmitoyl-poly-arginine peptides (CPPs) and an evaluation of their cell-penetrating effects after forming a complex with HSA for use in intracellular drug delivery. The palmitoyl CPPs forms a stable complex with HSA by anchoring itself to the high affinity palmitate binding sites of HSA. Among the CPPs evaluated, a cyclic polypeptide composed of D-dodecaarginines, palmitoyl-cyclic-(D-Arg)12 was the most effective for facilitating the cellular uptake of HSA by HeLa cells. Such a superior cell-penetrating capability is primarily mediated by macropinocytosis. The effect of the CPP on pharmacological activity was examined using three drugs loaded in HSA via three different methods: a) an HSA-paclitaxel complex, b) an HSA-doxorubicin covalent conjugate and c) an HSA-thioredoxin fusion protein. The results showed that cell-penetrating efficiency was increased with a corresponding and significant enhancement in pharmacological activity. In conclusion, palmitoyl-cyclic-(D-Arg)12/HSA is a versatile cell-penetrating drug delivery system with great potential for use as a nano-carrier for a wide diversity of pharmaceutical applications.

Original languageEnglish
Pages (from-to)23-34
Number of pages12
JournalJournal of Controlled Release
Volume277
DOIs
Publication statusPublished - 2018 May 10
Externally publishedYes

Keywords

  • Albumin fusion technology
  • Cell-penetrating peptide
  • Drug binding
  • Human serum albumin
  • Macropinocytosis
  • Palmitate high affinity binding site

ASJC Scopus subject areas

  • Pharmaceutical Science

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  • Cite this

    Ichimizu, S., Watanabe, H., Maeda, H., Hamasaki, K., Nakamura, Y., Chuang, V. T. G., Kinoshita, R., Nishida, K., Tanaka, R., Enoki, Y., Ishima, Y., Kuniyasu, A., Kobashigawa, Y., Morioka, H., Futaki, S., Otagiri, M., & Maruyama, T. (2018). Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery. Journal of Controlled Release, 277, 23-34. https://doi.org/10.1016/j.jconrel.2018.02.037