Nanoshell-mediated photothermal therapy can enhance chemotherapy in inflammatory breast cancer cells

Abstract

Nanoshell-mediated photothermal therapy (PTT) is currently being investigated as a standalone therapy for the treatment of cancer. The cellular effects of PTT include loss of membrane integrity, so we hypothesized that nanoshell-mediated PTT could potentiate the cytotoxicity of chemotherapy by improving drug accumulation in cancer cells. In this work, we validated our hypothesis using doxorubicin as a model drug and SUM149 inflammatory breast cancer cells as a model cancer subtype. In initial studies, SUM149 cells were exposed to nano-shells and near-infrared light and then stained with ethidium homodimer-1, which is excluded from cells with an intact plasma membrane. The results confirmed that nanoshell-mediated PTT could increase membrane permeability in SUM149 cells. In complementary experiments, SUM149 cells treated with nanoshells, near-infrared light, or a combination of the two to yield low-dose PTT were exposed to fluorescent rhodamine 123. Analyzing rhodamine 123 fluorescence in cells via flow cytometry confirmed that increased membrane permeability caused by PTT could enhance drug accumulation in cells. This was validated using fluorescence microscopy to assess intracellular distribution of doxorubicin. In succeeding experiments, SUM149 cells were exposed to subtherapeutic levels of doxorubicin, low-dose PTT, or a combination of the two treatments to determine whether the additional drug uptake induced by PTT is sufficient to enhance cell death. Analysis revealed minimal loss of viability relative to controls in cells exposed to subtherapeutic levels of doxorubicin, 15% loss of viability in cells exposed to low-dose PTT, and 35% loss of viability in cells exposed to combination therapy. These data indicate that nanoshell-mediated PTT is a viable strategy to potentiate the effects of chemotherapy and warrant further investigation of this approach using other drugs and cancer subtypes.

Keywords:

• nanoshells
• photothermal therapy
• hyperthermia
• chemotherapy
• sensitization
• breast cancer

Acknowledgments

This project was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under grant number U54-GM104941. The Delaware INBRE program, with a grant from NIGMS (P20-GM103446) from the NIH, also supported this project. The authors acknowledge Deborah Powell from the Delaware Bio-Imaging Center for assistance with scanning electron microscopy.

Disclosure

BLF received support from the University of Delaware Summer Scholars program. JRM received support from the Department of Defense through a National Defense Science and Engineering Graduate Fellowship. The authors report no other conflicts of interest in this work.