Peptide Amphiphile Containing Arginine and Fatty Acyl Chains as Molecular Transporters

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.

When cationic cell‐penetrating peptides meet hydrocarbons to enhance in‐cell cargo delivery

“…(A) The lipopeptide stearyl‐tetraarginine has been studied by Burlina et al for the covalent delivery of small cationic peptides . (B) Short cationic LPA containing one arginine and two lysines conjugated with palmitic acid were developed by Shirazi et al . (C) Oh et al prepared a cyclic dodecanoyl‐[Arg6] LPA for the non‐covalent delivery of small anionic phosphopeptides .…”

“…They showed that an LPA containing one arginine and two lysines acylated by two palmitoyl acyl chains was able deliver into the cytoplasm a fluorescently labeled drug and a phosphopeptide. The endocytotic traffic was hypothesized to be the major internalization pathway .…”

Cyclic Peptide–Selenium Nanoparticles as Drug Transporters

“…The loading efficiency experiment was conducted as described previosuly. 42 Aqueous solution of Dox (100 μL of 200 μM) was mixed with the solution of [W 5 R 4 C]–SeNPs in water (400 μL of 500 μM) to maintain a 1 to 10 molar ratio. After 24 h of incubation, the free Dox was collected by using the dialysis method.…”

“…Furthermore, the entrapment of the drugs was also carried out by using our previously reported procedure. 42 All assays were conducted in triplicate assays.…”

Efficient Intracellular Delivery of Cell-Impermeable Cargo Molecules by Peptides Containing Tryptophan and Histidine

“…It was discovered that the presence of both arginine and tryptophan amino acids were critical to the function of the carrier system. Further investigations showed that, although the number of amino acids was important to maximize the transporting ability of the peptide, an optimized balance between electrostatic and hydrophobic forces are crucial for their high yield of intracellular uptake into cells [ 2 , 6 , 12 , 13 , 14 , 15 , 16 , 17 ].…”