TY - JOUR
T1 - Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery
AU - Ichimizu, Shota
AU - Watanabe, Hiroshi
AU - Maeda, Hitoshi
AU - Hamasaki, Keisuke
AU - Nakamura, Yuka
AU - Chuang, Victor Tuan Giam
AU - Kinoshita, Ryo
AU - Nishida, Kento
AU - Tanaka, Ryota
AU - Enoki, Yuki
AU - Ishima, Yu
AU - Kuniyasu, Akihiko
AU - Kobashigawa, Yoshihiro
AU - Morioka, Hiroshi
AU - Futaki, Shiro
AU - Otagiri, Masaki
AU - Maruyama, Toru
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid Scientific Research from the Japan Society for the Promotion of Science (JSPS) ( KAKENHI 15H04758 ) and the Research Foundation for Pharmaceutical Sciences, Japan .
PY - 2018/5/10
Y1 - 2018/5/10
N2 - 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.
AB - 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.
KW - Albumin fusion technology
KW - Cell-penetrating peptide
KW - Drug binding
KW - Human serum albumin
KW - Macropinocytosis
KW - Palmitate high affinity binding site
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U2 - 10.1016/j.jconrel.2018.02.037
DO - 10.1016/j.jconrel.2018.02.037
M3 - Article
C2 - 29530390
AN - SCOPUS:85043996259
VL - 277
SP - 23
EP - 34
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -