1. Academic Validation
  2. Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery

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

  • J Control Release. 2018 May 10;277:23-34. doi: 10.1016/j.jconrel.2018.02.037.
Shota Ichimizu 1 Hiroshi Watanabe 2 Hitoshi Maeda 1 Keisuke Hamasaki 1 Yuka Nakamura 1 Victor Tuan Giam Chuang 3 Ryo Kinoshita 1 Kento Nishida 1 Ryota Tanaka 1 Yuki Enoki 1 Yu Ishima 4 Akihiko Kuniyasu 5 Yoshihiro Kobashigawa 6 Hiroshi Morioka 6 Shiro Futaki 7 Masaki Otagiri 8 Toru Maruyama 9
Affiliations

Affiliations

  • 1 Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
  • 2 Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
  • 3 School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia.
  • 4 Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
  • 5 Department of Molecular Cell Pharmacology, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan.
  • 6 Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
  • 7 Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
  • 8 Faculty of Pharmaceutical Sciences, DDS Research Institute, Sojo University, 1-22-4 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
  • 9 Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. Electronic address: [email protected].
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.

Keywords

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

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