Molecularly engineered tumor acidity-responsive plant toxin gelonin for safe and efficient cancer therapy

Guo Bin Ding, Chenchen Zhu, Qian Wang, Huiyan Cao, Bin Chun Li, Peng Yang, Roland H. Stauber, Guangjun Nie, Zhuoyu Li

Research output: Contribution to journalArticlepeer-review

Abstract

Due to the unsatisfactory therapeutic efficacy and inexorable side effects of small molecule antineoplastic agents, extensive efforts have been devoted to the development of more potent macromolecular agents with high specificity. Gelonin is a plant-derived protein toxin that exhibits robust antitumor effect via inactivating ribosomes and inhibiting protein synthesis. Nonetheless, its poor internalization ability to tumor cells has compromised the therapeutic promise of gelonin. In this study, a tumor acidity-responsive intracellular protein delivery system ─ functional gelonin (Trx-pHLIP-Gelonin, TpG) composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP) and gelonin, was designed and obtained by genetic recombination technique for the first time. TpG could effectively enter into tumor cells under weakly acidic conditions and markedly suppress tumor cell proliferation via triggering cell apoptosis and inhibiting protein synthesis. Most importantly, treatment by intravenous injection into subcutaneous SKOV3 solid tumors in a mouse model showed that TpG was much more effective than gelonin in curtailing tumor growth rates with negligible toxicity. Collectively, our present work suggests that the tumor acidity-targeted delivery manner endowed by pHLIP offers a new avenue for efficient delivery of other bioactive substances to acidic diseased tissues.

Original languageEnglish (US)
Pages (from-to)42-55
Number of pages14
JournalBioactive Materials
Volume18
DOIs
StatePublished - Dec 2022

Keywords

  • Apoptosis
  • Biosynthesis
  • Cancer therapy
  • Gelonin
  • Tumor-acidity responsive
  • pHLIP

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Biomedical Engineering

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