Epidermal Growth Factor Receptor-Targeting Peptide Nanoparticles Simultaneously Deliver Gemcitabine and Olaparib to Treat Pancreatic Cancer with Breast Cancer 2 (BRCA2) Mutation

Chong Du, Yingqiu Qi, Yinlong Zhang, Yazhou Wang, Xiao Zhao, Huan Min, Xuexiang Han, Jiayan Lang, Hao Qin, Quanwei Shi, Zhengkui Zhang, Xiaodong Tian, Greg J. Anderson, Ying Zhao, Guangjun Nie, Yinmo Yang

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Pancreatic cancer (PCa) is one of the most lethal malignancies, with a 5 year survival rate of less than 8%. Current treatment regiments have a low response rate in unselected patients. However, the subgroup of PCa patients with BRCA mutations may benefit from poly-ADP-ribose polymerase inhibitors (PARPi) due to their biological properties in DNA repair. Dose-limiting toxicity in normal tissues is frequently observed when PARPi are combined with other chemotherapies, and the co-delivery of two drugs to tumor sites at an adequate concentration is challenging. To address this issue, we have engineered an epidermal growth factor receptor (EGFR) targeting (with GE11 peptide) self-assembly amphiphilic peptide nanoparticle (GENP) to co-deliver gemcitabine and the PARPi olaparib to treat BRCA mutant PCa. The GENP was relatively stable, exhibited high encapsulation efficiency, and could coordinately release the two drugs in tumor milieu. Gemcitabine and olaparib showed strong synergistic actions in optimized conditions in vitro. The nanoparticle prolonged the half-life of both drugs and resulted in their tumor accumulation at the optimal therapeutic ratio in vivo. The drug-loaded nanoparticles were able to significantly suppress tumor growth in a murine PCa model with minimal side effects. Drug co-delivery of DNA damaging agents and PARP inhibitors via the GENP represents a promising approach for treatment of pancreatic cancers with molecular defects in the DNA repair pathway.

Original languageEnglish (US)
Pages (from-to)10785-10796
Number of pages12
JournalACS Nano
Volume12
Issue number11
DOIs
StatePublished - Nov 27 2018

Keywords

  • BRCA2 mutation
  • drug co-delivery
  • pancreatic cancer
  • self-assembly peptide nanoparticle
  • synthetic lethality

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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