Abstract 6418: Targeting STAT3-driven breast cancer cells using layer-by-layer nanoparticles
Authors: Isidora Tošić, Lisa N. Heppler, Susana P. Egusquiaguirre, Natalie Boehnke, Santiago Correa, Daniel Costa, Daphne A. Haas-Kogan, Paula T. Hammond, David A. Frank
Journal: Cancer Research (2020)

Abstract Inappropriate activation of the oncogenic transcription factor STAT3 is a common finding in breast cancer, in which it is constitutively activated in 70% of all cases and almost all triple negative breast cancers (TNBC). We investigated exploiting this feature of breast cancer for the development of tumor-targeting therapy using a novel drug delivery system, layer-by-layer (LbL) nanoparticles (NP). We found that the cellular lipid profile, likely including the plasma membrane, is modulated by the level of STAT3 transcriptional activity. To explore the potential of utilizing this property to specifically target STAT3-driven cancer cells, we screened a library of LbL NPs differing in their surface layer, which modifies their interactivity and cellular internalization. We found that poly-L-glutamic acid (PLE)-coated NPs were taken up by STAT3-transformed mammary epithelial cells to a 50% greater extent than non-transformed cells. This did not reflect a non-specific effect of neoplastic transformation, as LbL NPs coated with other modifications, such as dextran sulfate, showed no difference in uptake. Furthermore, TNBC cell lines, such as MDA-MB-231 and SUM159-PT showed rapid uptake of PLE NPs, which was attenuated by inhibition of STAT3 by RNA interference. We also characterized NP uptake in three-dimensional breast cancer organoids, which may better model behavior in tumor systems. We found that STAT3-transformed organoids grew in structures of notably higher cellular density, yet they were penetrated by PLE NPs more effectively than non-transformed ones. To evaluate the translational potential of these findings, we tested the effect of PLE-coated NPs incorporating the cytotoxic agent cisplatin (CDDP), as platinum agents are used clinically in TNBC. Breast cancer cells characterized by high STAT3 activity, including TNBC, showed significantly less survival when treated with CDDP-loaded PLE NPs, and this effect was lost when STAT3 expression was abrogated. This did not reflect a general increased sensitivity to cell killing, as these cells were more resistant to the effects of free CDDP. Since radiation therapy is widely used in breast cancer treatment, and is known to further alter the plasma membrane lipid composition, we evaluated the effect of radiation on the uptake of PLE NPs. We found that gamma radiation, in a dose-dependent manner, led to enhanced NP uptake in STAT3-driven cancer cells compared to non-transformed counterparts. LbL nanoparticles with a terminal poly-L-glutamic acid layer represent a new class of drug carriers that are preferentially taken up by STAT3-transformed mammary epithelial cells, and may be used synergistically with radiation therapy. These findings provide a promising starting point for the development of targeted approaches to triple negative breast cancers, which currently lack such therapeutic options. Citation Format: Isidora Tošić, Lisa N. Heppler, Susana P. Egusquiaguirre, Natalie Boehnke, Santiago Correa, Daniel Costa, Daphne A. Haas-Kogan, Paula T. Hammond, David A. Frank. Targeting STAT3-driven breast cancer cells using layer-by-layer nanoparticles [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6418.