Bradykinin-Potentiating Peptide-Paclitaxel Conjugate Directed at Ectopically Expressed Angiotensin-Converting Enzyme in Triple-Negative Breast Cancer

Xuan Ming Guo, Maruti Balaso Yadav, Mahjabin Khan, Chao Wei Hao, Cheng Yuan Lin, Tao Huang*, Jiang Wu*, Bao Min Fan*, Zhao Xiang Bian*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer with poor prognosis. Here, we present a peptide-drug conjugate (PDC)─bradykinin-potentiating peptide-paclitaxel (BPP-PTX) conjugate─synthesized by conjugating BPP9a with PTX via a succinyl linker. BPP-PTX targets the angiotensin-converting enzyme (ACE) on TNBC cells. ACE was found to be ectopically expressed in two TNBC cell lines but was absent in both the receptor-positive breast cancer cell line and healthy kidney cell line. Overexpression, knockdown, and competitive inhibition experiments demonstrated ACE-mediated cytotoxicity of BPP-PTX. In vivo, ACE-positive tumors were enriched with BPP-PTX, with the PDC being better tolerated than plain PTX. Compared with plain PTX, BPP-PTX exhibited improved tumor-suppressive effects in MDA-MB-468 xenografted female nude mice. Meanwhile, BPP-PTX resulted in less body weight loss and white blood cell reduction toxicity. These results collectively imply the novelty, efficacy, and low-toxicity profile of BPP-PTX as a potential therapeutic for ACE-positive TNBC.

Original languageEnglish
Pages (from-to)17051-17062
Number of pages12
JournalJournal of Medicinal Chemistry
Volume64
Issue number23
Early online date26 Oct 2021
DOIs
Publication statusPublished - 9 Dec 2021

Scopus Subject Areas

  • Molecular Medicine
  • Drug Discovery

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