Peptide-Amphiphile Containing Arginine and Fatty Acyl Chains as Molecular Transporters

Authors

Amir Nasrolahi Shirazi, University of Rhode Island
Donghoon Oh, University of Rhode Island
Rakesh Kumar Tiwari, University of Rhode Island
Brian Sullivan, University of Rhode Island
Anju Gupta
Geoffrey D. Bothun, University of Rhode IslandFollow
Keykavous Parang, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

10-29-2013

Department

Biomedical and Pharmaceutical Sciences

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 length, 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(C₁₆)-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 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 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 appropriate sequence of amino acids, chain length, charge, and hydrophobicity can be used as cellular delivery tools for transporting drugs and biomolecules.

Citation/Publisher Attribution

Shirazi, A. N., 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. doi: 10.1021/mp400539r

Available at: http://dx.doi.org/10.1021/mp400539r

Comment

Geoffrey D. Bothun is affiliated with the Department of Chemical Engineering.

Amir Nasrolahi, Donghoon Oh, Rakesh Kumar Tiwari, Brian Sullivan and Keykavous Parang are affiliated with the Department of Biomedical and Pharmaceutical Sciences.