LHRH-Targeted Redox-Responsive Crosslinked Micelles Impart Selective Drug Delivery and Effective Chemotherapy in Triple-Negative Breast Cancer

Kai Xiao, Qiangqiang Liu, Nell Suby, Wenwu Xiao, Rinki Agrawal, Michael Vu, Hongyong Zhang, Yan Luo, Yuanpei Li, Kit S. Lam

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Systemic chemotherapy is efficacious against triple-negative breast cancer (TNBC), but it is often associated with serious side effects. Here, a luteinizing hormone-releasing hormone (LHRH) receptor-targeted and tumor microenvironment-responsive nanoparticle system to selectively deliver chemotherapeutic drugs to TNBC cells, is reported. This delivery system (termed “LHRH-DCMs”) contains poly(ethylene glycol) and dendritic cholic acid as a micellar carrier, reversible intra-micellar disulfide bond as a redox-responsive crosslink, and synthetic high-affinity (D-Lys)-LHRH peptide as a targeting moiety. LHRH-DCMs exhibit high drug loading efficiency, optimal particle size, good colloidal stability, and glutathione-responsive drug release. As expected, LHRH-DCMs are more efficiently internalized into human TNBC cells through receptor-mediated endocytosis, resulting in stronger cytotoxicity against these cancer cells than the non-targeted counterpart when encapsulated with paclitaxel (PTX). Furthermore, near-infrared fluorescence and magnetic resonance imaging demonstrate that LHRH-DCMs facilitate the tumor distribution and penetration of payloads in three different animal models of breast cancer, including cell line-derived xenograft (CDX), patient-derived xenograft (PDX), and transgenic mammary carcinoma. Finally, in vivo therapeutic studies show that PTX-LHRH-DCMs outperform both the corresponding nontargeted PTX-DCMs and the current clinical formulation (Taxol) in an orthotopic TNBC model. These results provide new insights into approaches for precise drug delivery of TNBC.

Original languageEnglish (US)
JournalAdvanced Healthcare Materials
DOIs
StateAccepted/In press - 2020

Keywords

  • breast cancer
  • disulfide crosslinkers
  • LHRH
  • micelles
  • paclitaxel
  • redox-responsive micelles
  • targeted delivery

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science

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