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

• DOI: 10.1016/j.ejmech.2020.113050
• Publication Date: 2020-11-27T07:24:43Z
• Authors: Xin Deng; Ruiyao Mai; Chenyu Zhang; Dianbao Yu; Yichang Ren; Gang Li; Binbin Cheng; Ling Li; Zhiqiang Yu; Jianjun Chen
• Keywords: 0301 basic medicine; Drug Carriers; Cell Membrane Permeability; Paclitaxel; Drug Compounding; Apoptosis; Cell-Penetrating Peptides; Neoplasms, Experimental; Antineoplastic Agents, Phytogenic; Hemolysis; 3. Good health; Drug Liberation; Mice; 03 medical and health sciences; Tubulin; MCF-7 Cells; Animals; Humans; Amino Acid Sequence; Molecular Targeted Therapy; Receptors, LHRH; Cell Proliferation

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.