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

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

  • Eur J Med Chem. 2021 Mar 5:213:113050. doi: 10.1016/j.ejmech.2020.113050.
Xin Deng 1,  Ruiyao Mai 1,  Chenyu Zhang 2,  Dianbao Yu 3,  Yichang Ren 1,  Gang Li 4,  Binbin Cheng 1,  Ling Li 1,  Zhiqiang Yu 1,  Jianjun Chen 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, PR China.
  • 2 Department of Pharmacy, Guangzhou Chest Hospital, 62 Hengzhigang Road, Guangzhou 510095, PR China.
  • 3 Analytical Applications Center, Shimadzu (China) Co., Ltd. Guangzhou Branch, 230 Gaotang Road, Guangzhou 510656, PR China.
  • 4 Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Guangdong Institute of Applied Biological Resources, Guangdong Academy of Sciences, Guangzhou 510260, China.
  • 5 School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, PR China. Electronic address: jchen21@smu.edu.cn.
PMID: 33280896 DOI: 10.1016/j.ejmech.2020.113050
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.

Keywords

Antitumor; Cell penetrating peptide (CPP); Paclitaxel; Peptide-drug conjugate; Targeted delivery; Tumor targeting peptide (TTP).

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