Journal
JOURNAL OF CONTROLLED RELEASE
Volume 277, Issue -, Pages 23-34Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2018.02.037
Keywords
Human serum albumin; Cell-penetrating peptide; Macropinocytosis; Drug binding; Albumin fusion technology; Palmitate high affinity binding site
Funding
- Japan Society for the Promotion of Science (JSPS) [KAKENHI 15H04758]
- Research Foundation for Pharmaceutical Sciences, Japan
- Grants-in-Aid for Scientific Research [17K08383, 15K14983] Funding Source: KAKEN
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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.
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