2. Academic Validation
  3. 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: tomaru@gpo.kumamoto-u.ac.jp.
PMID: 29530390 DOI: 10.1016/j.jconrel.2018.02.037
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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