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Photodynamic therapy as an effective therapeutic approach in MAME models of inflammatory breast cancer

  • Preclinical study
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Abstract

Photodynamic therapy (PDT) is a minimally invasive, FDA-approved therapy for treatment of endobronchial and esophageal cancers that are accessible to light. Inflammatory breast cancer (IBC) is an aggressive and highly metastatic form of breast cancer that spreads to dermal lymphatics, a site that would be accessible to light. IBC patients have a relatively poor survival rate due to lack of targeted therapies. The use of PDT is underexplored for breast cancers but has been proposed for treatment of subtypes for which a targeted therapy is unavailable. We optimized and used a 3D mammary architecture and microenvironment engineering (MAME) model of IBC to examine the effects of PDT using two treatment protocols. The first protocol used benzoporphyrin derivative monoacid A (BPD) activated at doses ranging from 45 to 540 mJ/cm2. The second PDT protocol used two photosensitizers: mono-l-aspartyl chlorin e6 (NPe6) and BPD that were sequentially activated. Photokilling by PDT was assessed by live–dead assays. Using a MAME model of IBC, we have shown a significant dose–response in photokilling by BPD–PDT. Sequential activation of NPe6 followed by BPD is more effective in photokilling of tumor cells than BPD alone. Sequential activation at light doses of 45 mJ/cm2 for each agent resulted in >90 % cell death, a response only achieved by BPD–PDT at a dose of 360 mJ/cm2. Our data also show that effects of PDT on a volumetric measurement of 3D MAME structures reflect efficacy of PDT treatment. Our study is the first to demonstrate the potential of PDT for treating IBC.

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Abbreviations

IBC:

Inflammatory breast cancer

ECM:

Extracellular matrix

rBM:

Reconstituted basement membrane

2D:

2-dimensional

3D:

3-dimensional

PDT:

Photodynamic therapy

BPD:

Benzoporphyrin derivative monoacid A

NPe6:

N-aspartyl chlorin e6

MAME:

Mammary architecture and microenvironment engineering

MEGM:

Mammary epithelial cell growth medium

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Acknowledgments

We thank Dr. Kamiar Moin and the Microscopy, Imaging and Cytometry Resources Core at Wayne State University School for consultation and training on the use of confocal microscopes.

Authors’ Contributions

NA carried out the experiments. AMS provided technical support with experiments. NA, DK, and BFS made substantial contributions to concept and design of experiments as well as drafting and/or revising the manuscript.

Funding

This work was supported by National Institute of Health R01 CA131990 to BFS and CA23378 to DK. Imaging was performed in the Microscopy, Imaging and Cytometry Resources Core of Wayne State University, which was supported in part by NIH Center grant P30CA22453 to the Karmanos Cancer Institute and by the Perinatology Branch of the National Institute of Child Health and Development.

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Authors and Affiliations

  1. Department of Physiology, Wayne State University School of Medicine, 540 East Canfield, Detroit, MI, 48201, USA

    Neha Aggarwal

  2. Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield, Detroit, MI, 48201, USA

    Ann Marie Santiago, David Kessel & Bonnie F. Sloane

  3. Department of Oncology, Wayne State University School of Medicine, 540 East Canfield, Detroit, MI, 48201, USA

    Bonnie F. Sloane

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  1. Neha Aggarwal
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Correspondence to Neha Aggarwal.

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10549_2015_3618_MOESM1_ESM.pptx

Supplemental Fig. 1 BPD-PDT induces dose-dependent photokilling of MAME structures of Hs578T cells. Tiled 16-panel images and z-stacks through the depth of structures were captured and reconstructed in 3D to show an en face view (a). Images show live cells (green, calcein AM) and dead cells (red, ethidium homodimer-1) and were taken 24 h after PDT with 1.5 µM BPD and for non-treated dark control; scale bar equals 700 microns. Intensities of red (dead) and green (live) fluorescence were used to calculate viability that is plotted against PDT dose (b). Significance was calculated by one-way ANOVA, p-value < 0.0001; n = 6, mean ± SD. Supplemental Fig. 2 Combination PDT results in a dose-dependent decrease in viability. SUM149 cells were grown in MAME cultures for 8 days followed by combination PDT. Live/Dead assay was performed 24 h after PDT, 16 panel z-stack images were captured (shown in Fig. 2) and intensities of red and green fluorescence were used to calculate viability and plotted against treatment. Significance was calculated by one-way ANOVA followed by Tukey’s post hoc analysis: * p-value < 0.05, ** p-value < 0.01, *** p-value < 0.001, **** p-value < 0.0001; n = 6-8, mean ± SD. Supplemental Fig. 3 Photokilling induced by sequential PDT protocol is comparable at one and two days post PDT. Optical sections through the depth of 3D structures were captured for 16 contiguous fields and reconstructed in 3D. Images were taken on day 1 (a-c) and day 2 (a’-c’) after combination PDT for 22.5 mJ/cm2 each with 1.5 µM BPD and 40 µM NPe6 and show live cells (green, calcein AM) and dead cells (red, ethidium homodimer-1) for untreated dark control (a, a’); sequential light irradiation targeting mitochondria then lysosomes (b, b’); and sequential light irradiation targeting lysosomes then mitochondria (c, c’); scale bars equal 40 microns. Intensities of red and green fluorescence were used to calculate viability and plotted against days post-PDT (d); Significance was calculated by ANOVA followed by Tukey’s post hoc analysis: **** p-value < 0.0001, n = 8-10, mean ± SD. (PPTX 3331 kb)

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Aggarwal, N., Santiago, A.M., Kessel, D. et al. Photodynamic therapy as an effective therapeutic approach in MAME models of inflammatory breast cancer. Breast Cancer Res Treat 154, 251–262 (2015). https://doi.org/10.1007/s10549-015-3618-6

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  • DOI: https://doi.org/10.1007/s10549-015-3618-6

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