Abstract
We have previously evaluated and reported numerous classes of linear and cyclic peptides containing hydrophobic and hydrophilic segments for intracellular delivery of multiple molecular cargos. Herein, a combination of histidine and tryptophan amino acids were designed and evaluated for their efficiency in intracellular delivery of cell-impermeable phosphopeptides and the anti-HIV drug, emtricitabine. Two new decapeptides, with linear and cyclic natures, both containing alternate tryptophan and histidine residues, were synthesized using Fmoc/tBu solid-phase chemistry. The peptides were characterized and purified by using matrix-assisted laser desorption/ionization (MALDI) spectroscopy and high-performance liquid chromatography (HPLC), respectively. These peptides did not show significant toxicity up to 100 µM in ovarian cancer (SK-OV-3) and leukemia cancer (CCRF-CEM) cells. Furthermore, the cellular uptake of a fluorescence (F’)-labeled cell-impermeable phosphopeptide (F’-GpYEEI) was enhanced in the presence of linear (WH)5 and cyclic [WH]5 by 2- and 8-fold, respectively, compared to the uptake of the phosphopeptide alone. The cellular uptake was not significantly changed in the presence of endocytosis inhibitors. Furthermore, the intracellular uptake of the fluorescently-labeled anti-HIV drug, emtricitabine (F’-FTC), by linear (WH)5 and cyclic [WH]5 in SK-OV-3 cancer cell lines was found to be enhanced by 3.5- and 9-fold, respectively, compared to that of the drug alone. Fluorescent uptake experiments confirmed the localization of F’-GpYEEI-loaded cyclic [WH]5 intracellularly in the SK-OV-3 cancer cell line after 3 h of incubation. Thus, these data demonstrated that [WH]5 containing tryptophan and histidine enhanced the cellular uptake of F’-GpYEEI and emtricitabine.
Highlights
Peptide-based Drug Delivery Systems (PDDS) have been introduced as one of the prominent non-viral delivery tools of various types of cargo molecules [1]
PDDS for efficient transportation molecular cargos, we explored using a combination of alternate histidine and tryptophan amino acids in the structure of a short peptides containing tryptophan and histidine residues
Discussion report a new of decapeptides containing an alternative sequence of tryptophan and histidine amino acids as efficient intracellular carriers
Summary
Peptide-based Drug Delivery Systems (PDDS) have been introduced as one of the prominent non-viral delivery tools of various types of cargo molecules [1]. PDDS are capable of loading molecules with relatively low molecular weight, such as doxorubicin, lamivudine, and dasatinib [2,3], and molecules with relatively high molecular weight, such as siRNA, phosphopeptides, and DNA [4,5]. The majority of PDDS possess a fine balance of physicochemical properties based on their assigned tasks [6]. They can be categorized as amphipathic, hydrophobic, and cationic peptides [7]. Numerous PDDS, including Tat peptide, polyarginine, and penetratin, have been developed for the delivery of drugs [8].
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