Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid-coated Layer-by-Layer Nanoparticles.

Abstract

The oncogenic transcription factor STAT3 is aberrantly activated in 70% of breast cancers, including nearly all triple-negative breast cancers (TNBCs). Because STAT3 is difficult to target directly, we considered whether metabolic changes driven by activated STAT3 could provide a therapeutic opportunity. We found that STAT3 prominently modulated several lipid classes, with most profound effects on N-acyl taurine and arachidonic acid, both of which are involved in plasma membrane remodeling. To exploit these metabolic changes therapeutically, we screened a library of layer-by-layer (LbL) nanoparticles (NPs) differing in the surface layer that modulates interactivity with the cell membrane. We found that poly-l-glutamic acid (PLE)-coated NPs bind to STAT3-transformed breast cancer cells with 50% greater efficiency than to nontransformed cells, and the heightened PLE-NP binding to TNBC cells was attenuated by STAT3 inhibition. This effect was also observed in densely packed three-dimensional breast cancer organoids. As STAT3-transformed cells show greater resistance to cytotoxic agents, we evaluated whether enhanced targeted delivery via PLE-NPs would provide a therapeutic advantage. We found that cisplatin-loaded PLE-NPs induced apoptosis of STAT3-driven cells at lower doses compared with both unencapsulated cisplatin and cisplatin-loaded nontargeted NPs. In addition, because radiation is commonly used in breast cancer treatment, and may alter cellular lipid distribution, we analyzed its effect on PLE-NP-cell binding. Irradiation of cells enhanced the STAT3-targeting properties of PLE-NPs in a dose-dependent manner, suggesting potential synergies between these therapeutic modalities. These findings suggest that cellular lipid changes driven by activated STAT3 may be exploited therapeutically using unique LbL NPs.

• Authors: Isidora Tošić, Lisa N Heppler, Susana P Egusquiaguirre, Natalie Boehnke, Santiago Correa, Daniel F Costa, Elizabeth A Grossman Moore, Sharmistha Pal, Douglas S Richardson, Alexander R Ivanov, Daphne A Haas-Kogan, Daniel K Nomura, Paula T Hammond, David A Frank
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 20 Issue 4 Pg. 726-738 (04 2021) ISSN: 1538-8514 [Electronic] United States
• PMID: 33536189 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• STAT3 Transcription Factor
• STAT3 protein, human
• Glutamic Acid

Topics

• Drug Delivery Systems (methods)
• Glutamic Acid (pharmacology, therapeutic use)
• Humans
• Lipidomics (methods)
• Nanoparticles (metabolism)
• STAT3 Transcription Factor (metabolism)
• Triple Negative Breast Neoplasms (genetics, pathology)