89Zr-Labeled Multifunctional Liposomes Conjugate Chitosan for PET-Trackable Triple-Negative Breast Cancer Stem Cell Targeted Therapy

Int J Nanomedicine. 2020 Nov 17:15:9061-9074. doi: 10.2147/IJN.S262786. eCollection 2020.

Abstract

Purpose: Therapy for triple-negative breast cancer (TNBC) is a global problem due to lack of specific targets for treatment selection. Cancer stem cells (CSCs) are responsible for tumor formation and recurrence but also offer a promising target for TNBC-targeted therapy. Here, zirconium-89 (89Zr)-labelled multifunctional liposomes (MLPs) surface-decorated with chitosan (CS) were fabricated to specifically target and trace cluster of differentiation 44+ (CD44+) TNBC CSCs specifically.

Patients and methods: The biological basis of CS targeting CD44 for cancer therapy was investigated by detecting the expression of CD44 in TNBC CSCs and TNBC tissues. Molecular docking and dynamics simulations were performed to investigate the molecular basis of CS targeting CD44 for cancer therapy. Gambogic acid (GA)-loaded, 89Zr@CS-MLPs (89Zr-CS-GA-MLPs) were prepared, and their uptake and biodistribution were observed. The anti-tumor efficacy of 89Zr@CS-GA-MLPs was investigated in vivo.

Results: CD44 is overexpressed in TNBC CSCs and tissues. Molecular docking and dynamics simulations showed that CS could be stably docked into the active site of CD44 in a reasonable conformation. Furthermore, 89Zr@CS-GA-MLPs were able to bind specifically to CD44+ TNBC stem-like cells and accumulated in tumors of xenograft-bearing mice with excellent radiochemical stability. 89Zr@CS-GA-MLPs loaded with GA showed remarkable anti-tumor efficacy in vivo.

Conclusion: The GA-loaded, 89Zr-labelled, CS-decorated MLPs developed in this study represent a novel strategy for TNBC imaging and therapy.

Keywords: CD44; CS; PET; molecular docking; molecular dynamics simulation; radionuclide.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Cell Line, Tumor
  • Chitosan / chemistry
  • Female
  • Humans
  • Hyaluronan Receptors / chemistry
  • Hyaluronan Receptors / metabolism
  • Liposomes / chemistry*
  • Liposomes / pharmacokinetics
  • Mice, Nude
  • Middle Aged
  • Molecular Docking Simulation
  • Molecular Targeted Therapy / methods
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Positron-Emission Tomography / methods
  • Radioisotopes / chemistry*
  • Tissue Distribution
  • Triple Negative Breast Neoplasms / diagnostic imaging*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology
  • Xanthones / pharmacokinetics
  • Xenograft Model Antitumor Assays
  • Zirconium / chemistry*

Substances

  • Antineoplastic Agents
  • CD44 protein, human
  • Hyaluronan Receptors
  • Liposomes
  • Radioisotopes
  • Xanthones
  • gambogic acid
  • Chitosan
  • Zirconium
  • Zirconium-89

Grants and funding

The present study was supported by the high-level talents (333 Project) of Jiangsu Province (grant No. BRA2019024), National Natural Science Foundation of China (grant No. 81602728), Key Project Foundation of Jiangsu Health and Health Committee (grant No. H2018114), the China Postdoctoral Science Foundation Funded Project (grant No.2018M630605, 2017M611874), the Youth Talent’s Project of Jiangsu Province (grant No. QNRC2016164, QNRC2016169) and the Provincial Foundation of Jiangsu Province (grant No. BK20171148, BK20170209).