Peptide amphiphile containing arginine and fatty acyl chains as molecular transporters

Amir Nasrolahi Shirazi, Donghoon Oh, Rakesh Kumar Tiwari, Brian Sullivan, Anju Gupta, Geoffrey D. Bothun, Keykavous Parang

Research output: Contribution to journalArticle

Abstract

Peptide amphiphiles (PAs) are promising tools for the intracellular delivery of numerous drugs. PAs are known to be biodegradable systems. Here, four PA derivatives containing arginine and lysine conjugated with fatty acyl groups with different chain lengths, namely, PA1: R-K(C14)-R, PA2: R-K(C16)-R, PA3: K(C14)-R-K(C14), and PA4: K(C16)-R-K(C16), where C16 = palmitic acid and C14 = myristic acid, were synthesized through Fmoc chemistry. Flow cytometry studies showed that, among all synthesized PAs, only K(C 16)-R-K(C16), PA4 was able to enhance the cellular uptake of a fluorescence-labeled anti-HIV drug 2′,3′-dideoxy-3′- thiacythidine (F'-3TC, F' = fluorescein) and a biologically important phosphopeptide (F'-PEpYLGLD) in human leukemia cells (CCRF-CEM) after 2 h incubation. For example, the cellular uptake of F'-3TC and F'-PEpYLGLD was enhanced approximately 7.1- and 12.6-fold in the presence of the PA4 compared to those of the drugs alone. Confocal microscopy of F'-3TC and F'-PEpYLGLD loaded PA4 in live cells showed significantly higher intracellular localization than the drug alone in human ovarian cells (SK-OV-3) after 2 h incubation. The high-performance liquid chromatography (HPLC) results showed that loading of Dox by the peptide amphiphile was 56% after 24 h. The loaded Dox was released (34%) within 48 h intracellularly. The circular dichrosim (CD) results exhibited that the secondary structure of the peptide was changed upon interactions with Dox. Mechanistic studies revealed that endocytosis is the major pathway of the internalization. These studies suggest that PAs containing the appropriate sequence of amino acids, chain length, charge, and hydrophobicity can be used as cellular delivery tools for transporting drugs and biomolecules.

Original languageEnglish (US)
Pages (from-to)4717-4727
Number of pages11
JournalMolecular Pharmaceutics
Volume10
Issue number12
DOIs
StatePublished - Dec 2 2013
Externally publishedYes

Keywords

  • cellular uptake
  • drug delivery
  • nuclear targeting
  • peptide amphiphiles

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Nasrolahi Shirazi, A., Oh, D., Tiwari, R. K., Sullivan, B., Gupta, A., Bothun, G. D., & Parang, K. (2013). Peptide amphiphile containing arginine and fatty acyl chains as molecular transporters. Molecular Pharmaceutics, 10(12), 4717-4727. https://doi.org/10.1021/mp400539r