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Author Notes:

To whom correspondence may be addressed. Email: dmshin@emory.edu or melsayed@gatech.edu

M.R.K.A. and M.A.R. contributed equally to this work.

Author contributions: M.R.K.A., M.A.R., Z.G.C., D.M.S., and M.A.E.-S. designed research; M.R.K.A., M.A.R., Y.W., X.P., and M.A.M. performed research; M.R.K.A., T.H., D.W., H.J.S., H.X., R.W., and Y.T. contributed new reagents/analytic tools; M.R.K.A., M.A.R., Y.W., T.H., Z.G.C., D.M.S., and M.A.E.-S. analyzed data; and M.R.K.A., M.A.R., Y.W., D.M.S., and M.A.E.-S. wrote the paper.

We thank Dr. Kuangcai Chen and Prof. Ning Fang (Georgia State University) for the DIC microscopic images and Dr. Anthea Hammond for her assistance in critical reading and editing of the manuscript.

The authors declare no conflict of interest.

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Research Funding:

This work was supported by National Cancer Institute Cancer Nanotechnology Platform Partner Grant U01 CA151802 to Emory University and National Science Foundation Division of Chemistry Grant 1608801 to the Georgia Institute of Technology.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • gold nanorods
  • plasmonic photothermal therapy
  • apoptosis
  • xenograft mice
  • long-term toxicity
  • HUMAN DERMAL FIBROBLASTS
  • PTEN INDUCES APOPTOSIS
  • DNA-DAMAGE
  • THERMAL THERAPY
  • CELLULAR UPTAKE
  • DRUG-DELIVERY
  • IN-VITRO
  • NANOPARTICLES
  • PROTEIN
  • CELLS

Efficacy, long-term toxicity, and mechanistic studies of gold nanorods photothermal therapy of cancer in xenograft mice

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 114, Number 15

Publisher:

, Pages E3110-E3118

Type of Work:

Article | Final Publisher PDF

Abstract:

Gold nanorods (AuNRs)-assisted plasmonic photothermal therapy (AuNRs-PPTT) is a promising strategy for combating cancer in which AuNRs absorb near-infrared light and convert it into heat, causing cell death mainly by apoptosis and/or necrosis. Developing a valid PPTT that induces cancer cell apoptosis and avoids necrosis in vivo and exploring its molecular mechanism of action is of great importance. Furthermore, assessment of the long-term fate of the AuNRs after treatment is critical for clinical use. We first optimized the size, surface modification [rifampicin (RF) conjugation], and concentration (2.5 nM) of AuNRs and the PPTT laser power (2 W/cm(2)) to achieve maximal induction of apoptosis. Second, we studied the potential mechanism of action of AuNRs-PPTT using quantitative proteomic analysis in mouse tumor tissues. Several death pathways were identified, mainly involving apoptosis and cell death by releasing neutrophil extracellular traps (NETs) (NETosis), which were more obvious upon PPTT using RF-conjugated AuNRs (AuNRs@RF) than with polyethylene glycol thiol-conjugated AuNRs. Cytochrome c and p53-related apoptosis mechanisms were identified as contributing to the enhanced effect of PPTT with AuNRs@RF. Furthermore, Pin1 and IL18-related signaling contributed to the observed perturbation of the NETosis pathway by PPTT with AuNRs@RF. Third, we report a 15-month toxicity study that showed no long-term toxicity of AuNRs in vivo. Together, these data demonstrate that our AuNRs-PPTT platform is effective and safe for cancer therapy in mouse models. These findings provide a strong framework for the translation of PPTT to the clinic.

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© Ali et al.

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