DR5 antibody conjugated lipid-based nanocarriers of gamma-secretase inhibitor for the treatment of triple negative breast cancer

Chem Phys Lipids. 2021 Mar:235:105033. doi: 10.1016/j.chemphyslip.2020.105033. Epub 2020 Dec 29.

Abstract

In the present study, Death receptor-5 (DR5) antibody conjugated solid lipid nanoparticles (DR5-DAPT-SLNs) has been formulated for effective intracellular of γ-secretase inhibitor, N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) to cancer cells. Emulsification-solvent evaporation, followed by EDC cross-linking methods, was employed to prepare DR5 targeted DAPT-SLNs (DR5-DAPT-SLNs). The formulation was characterized by its particle size, shape, and surface charge. The in vitro & in vivo anticancer efficacy was studied in MDA-MB231 triple negative breast cancer (TNBC) cells and DMBA induced breast cancer model in mice, respectively. The results show that thatDR5-DAPT-SLNs is found to be a spherical shape with an average particle size of 187 ± 0.98 nm and having an average surface charge of 23 ± 2.3 mV. DR5-DAPT-SLNs have higher cytotoxicity in MDA-MB231 cells compared to DAPT-SLNs (non-targeted) and the bulk drug. However, in DR5 negative HEK 293 noncancer cells, the formulation shows minimal cytotoxic effects. The above results, therefore, demonstrate DR5 mediated uptake is responsible for improved cytotoxicity of DAPT. In the in vivo anticancer study, DR5-DAPT-SLNs show greater tumor regression when compared to DAPT-SLNs and the bulk drug. In conclusion, the results of the present study demonstrate that the DR5-DAPT-SLNs selectively target cancer cells and potentiate the anticancer efficacy of DAPT against TNBC cells.

Keywords: Breast cancer stem cells; Metastasis; Notch signalling; Triple negative breast cancer; Tumor relapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Antibodies / chemistry*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Carriers / chemistry
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Lipids / chemistry*
  • Nanoparticles / chemistry
  • Particle Size
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / chemistry*
  • Surface Properties
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Cells, Cultured

Substances

  • Antibodies
  • Antineoplastic Agents
  • Drug Carriers
  • Enzyme Inhibitors
  • Lipids
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • Amyloid Precursor Protein Secretases