Abstract
Cell-penetrating peptide [WR]5 has been previously shown to be an efficient molecular transporter for various hydrophilic and hydrophobic molecules. The peptide was synthesized using Fmoc/tBu solid-phase chemistry, and one arginine was replaced with one lysine to enable the conjugation with the anticancer drugs. Paclitaxel (PTX) was functionalized with an esterification reaction at the C2′ hydroxyl group of PTX with glutaric anhydride and conjugated with the cyclic peptide [W(WR)4K(βAla)] in DMF to obtain the peptide-drug conjugate PTX1. Furthermore, camptothecin (CPT) was modified at the C(20)-hydroxyl group through the reaction with triphosgene. Then, it was conjugated with two functionalized cyclic peptides through a formyl linker affording two different conjugates, namely CPT1 and CPT2. All the conjugates showed better water solubility as compared to the parent drug. The cytotoxicity assay of the drugs and their conjugates with the peptides were evaluated in the human breast cancer MCF-7 cell line. PTX inhibited cell proliferation by 39% while the PTX-peptide conjugate inhibited the proliferation by ~18% after 72 h incubation. On the other hand, CPT, CPT1, and CPT2 reduced the cell proliferation by 68%, 39%, and 62%, respectively, in the MCF-7 cell lines at 5 µM concentration after 72 h incubation.
Highlights
Intensive efforts have been exerted for the development of an intracellular stimuli-responsive drug delivery system that is stable under normal physiological conditions but able to release its payload in the tumor site in a selective and efficient manner [1]
The physicochemical profile, self-assembly, receptor recognition, and stimuli-responsive properties of amphipathic com/journal/moleculesCell-penetrating peptides (CPPs) can be engineered by selecting the proper amino acid sequences and peptide secondary structures, which are stabilized by hydrophobic–hydrophilic side chain interactions [14]
In continuation of our efforts to design CPP-drug conjugates based on the CPPs containing tryptophan and arginine residues, we report the conjugation of PTX and CPT to the [W(RW)4 K]
Summary
Intensive efforts have been exerted for the development of an intracellular stimuli-responsive drug delivery system that is stable under normal physiological conditions (e.g., in blood circulation) but able to release its payload in the tumor site in a selective and efficient manner [1]. Some CPPs have shown attractive therapeutic and biomedical potential due to their biocompatibility and high level of tissue selectivity through binding to specific cell receptors [8,9,10,11,12]. Due to their peptide-based nature, they have poor in vitro and in vivo stability, which may demote their bioactivity [13]. The physicochemical profile, self-assembly, receptor recognition, and stimuli-responsive properties of amphipathic CPPs can be engineered by selecting the proper amino acid sequences and peptide secondary structures, which are stabilized by hydrophobic–hydrophilic side chain interactions [14]. Rational functionalization of side chains with acid labile, redox sensitive bonds (ester bond and disulfide bridge), and tumor homing peptide motif, e.g., IKVAV, PEG, KGGVG, and RGD, confer remarkable properties to CPPs, such as peptide stability, control over the rate, and site of cargo release [15,16,17]
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