Discovery of novel cell-penetrating and tumor-targeting peptide-drug conjugate (PDC) for programmable delivery of paclitaxel and cancer treatment.

Abstract

To ameliorate the deficiencies (e.g. solubility, membrane permeability and non-selective cytotoxicity) of paclitaxel (PTX), we synthesized a "smart" PDC (peptide-drug conjugate), by linking PTX with a multifunctional peptide consisting of a tumor targeting peptide (TTP) and a cell penetrating peptide (CPP), to construct the TTP-CPP-PTX conjugate, LTP-1. LTP-1 could intelligently deliver PTX into LHRH receptor-overexpressed MCF-7 cells, showing 2 times higher cellular uptake than PTX, and enhanced cytotoxicity with IC50 of 3.8 nM (vs 6.6 nM for PTX). LTP-1 exhibited less cytotoxicity to normal cells and the ability to overcome PTX-resistance. Furthermore, LTP-1 had higher in vivo antitumor efficacy than PTX (TGI of 83.4% and 65.7% for LTP-1 and PTX, respectively, at 12 mmol/kg) without apparent toxicities. In summary, we proposed and testified the concept of constructing a novel PDC molecule, which can potentially conquer the drawbacks of PTX. LTP-1 represents a new class of antitumor PDC deserving further investigation.

• Authors: Xin Deng, Ruiyao Mai, Chenyu Zhang, Dianbao Yu, Yichang Ren, Gang Li, Binbin Cheng, Ling Li, Zhiqiang Yu, Jianjun Chen
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 213 Pg. 113050 (Mar 05 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33280896 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Cell-Penetrating Peptides
• Drug Carriers
• Receptors, LHRH
• Tubulin
• Paclitaxel

Topics

• Amino Acid Sequence
• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Membrane Permeability
• Cell Proliferation (drug effects)
• Cell-Penetrating Peptides (chemistry)
• Drug Carriers (chemistry)
• Drug Compounding
• Drug Liberation
• Hemolysis (drug effects)
• Humans
• MCF-7 Cells
• Mice
• Molecular Targeted Therapy
• Neoplasms, Experimental
• Paclitaxel (chemistry, pharmacology)
• Receptors, LHRH (metabolism)
• Tubulin (metabolism)