Synthesis and Antiproliferative Activities of Conjugates of Paclitaxel and Camptothecin with a Cyclic Cell-Penetrating Peptide

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.

Biological behavior exploration of a paclitaxel-eluting poly-l-lactide-coated Mg–Zn–Y–Nd alloy intestinal stent in vivo

“…Paclitaxel reacts with b-tubulin in microtubule to induce microtubule polymerization, which leads to cell proliferation stopping at G2/M phase and nally result in tumor cell apoptosis. 46 Previous studies have shown that stent implantation can cause the formation of endothelialization in the surrounding tissue. [47][48][49] Although the time of stent implantation in intestinal tract is short, there may not be obvious tissue proliferation around the stent.…”

<p>Smart Targeting To Improve Cancer Therapeutics</p>

“…130 El-Sayed et al reported the conjugation of Paclitaxel and Camptothecin to a cyclic CPP containing tryptophan and arginine residues. 131 Results revealed that the antiproliferative activities of the CPP-drug conjugates were less than that of the free hydrophobic drugs in the breast cancer cell line MCF-7 after 72-hr incubation. Lastly, the modification of DDS with CPP (eg, RGD peptide) made NPs capable of penetrating deeper into tumor tissue, resulting in several-fold higher therapeutic efficacy indices.…”

Considerations on the Rational Design of Covalently Conjugated Cell-Penetrating Peptides (CPPs) for Intracellular Delivery of Proteins: A Guide to CPP Selection Using Glucarpidase as the Model Cargo Molecule

“…After excluding cyclic peptides and CPPs that had un-natural residues or amino acids with D-conformations, 1155 unique CPPs remained. Although some of the excluded CPPs—CPPs with unnatural or D-conformation residues and cyclic CPPs—have shown promising results in experimental studies [81,82,83], current computational web servers are unable to analyze these sequences. Mature CPG2 amino acid sequence from Pseudomonas sp.…”