Breast Cancer Cell Ablation Using Nanoparticle-Engineered Adipose-Derived Stem Cells
Ronnie L. Shammas, Jr., B.S.1, Bridget M. Crawford, B.S.2, Andrew M. Fales, PhD2, David A. Brown, M.D. PhD3, Tuan Vo-Dinh, PhD2, Gayathri R. Devi, PhD4, Scott T. Hollenbeck, M.D. FACS3.
1Duke University School of Medicine, Durham, NC, USA, 2Duke University, Department of Biomedical Engineering, Durham, NC, USA, 3Duke University, Division of Plastic, Maxillofacial, and Oral Surgery, Durham, NC, USA, 4Duke University, Department of Surgery, Durham, NC, USA.
Purpose: Inflammatory breast cancer (IBC) is an aggressive disease characterized by the formation of tumor emboli, rapid local invasion, and lymphatic dissemination. Furthermore, IBC rapidly develops therapeutic resistance and evades immune surveillance and attack. For these reasons, the treatment of inflammatory breast cancer is extremely challenging and new therapeutic approaches are needed. Numerous studies have shown that adipose derived stem cells (ASCs), which are abundant in breast tissue, are recruited to the tumor microenvironment where they influence tumor progression. We have previously demonstrated the feasibility of using nanoparticles in conjunction with ASCs in treatment-resistant breast cancer. In this study, we show that ASCs localize to IBC tumor emboli and can be used as a targeted delivery vehicle for cancer nanotherapeutics.
Methods: We tested the feasibility of this hypothesis by labeling ASCs with photothermal nanoparticles (GNS) and evaluating their ability to be delivered to 2D and 3D models of breast cancer cells for targeted tumor cell ablation. A panel of breast cancer cell lines [IBC (SUM149/SUM190), non-IBC (BT474M1/MD-MBA-231), and a drug-resistant isogenic variant (rSUM149)] were employed to evaluate: 1) The ability of GNSs to label tumor cells in 2D and 3D culture models of tumor emboli using multiphoton microscopy (MPM); 2) The migratory capacity of GNS-bearing ASCs toward tumor cells; and 3) The ability of GNS-labeled ASCs (GNS-ASCs) to target and ablate tumor cells and emboli after photothermal treatment. Overall, the effects of photothermal therapy on cell viability were assessed using various laser intensities and confirmed with a live/dead fluorescent stain. In addition, tumor emboli were sectioned and imaged with MPM to demonstrate GNS penetrance and distribution.
Results: In the cell lines tested, GNSs displayed rapid cellular uptake in both 2D culture and in 3D tumor emboli. Furthermore, GNS-labeled ASCs displayed robust migration toward cancer cells (Figure 1). Live/dead staining confirmed effective photothermal treatment in all cultures, including GNS-ASC co-cultures, with a clear zone of cellular death. For tumor emboli studies, GNSs and GNS-ASCs allowed for bright fluorescent monitoring of tumor emboli using MPM, and cross-sectional imaging demonstrated nanoparticle penetrance into the embolic core. GNS-labeled tumor emboli were successfully photothermally ablated following laser irradiation. Similar results were achieved with GNS-ASC and emboli co-cultures.
Conclusion: Taken together, these results highlight the ability of ASCs to effectively deliver nanoparticles (GNS) to inflammatory breast cancer emboli. This allows for the targeted
photothermal ablation of IBC tumors. These studies demonstrate our ongoing development of a novel approach to treat therapeutically resistant breast cancers.
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