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

• Type of Material: Article
• Authors: Moustafa R. K. Ali, Georgia Institute of Technology; Mohammad Rahman, Emory University; Yue Wu, Georgia Institute of Technology; Tiegang Han, Georgia Institute of Technology; XiangHong Peng, Emory University; Megan A. Mackey, Georgia Institute of Technology; Dongsheng Wang, Emory University; Hyung Ju Shin, Quest Diagnostics; Georgia Chen, Emory University; Haopeng Xiao, Georgia Institute of Technology; Ronghu Wu, Georgia Institute of Technology; Yan Tang, Georgia Institute of Technology; Dong Shin, Emory University; Mostafa A. El-Sayed, Georgia Institute of Technology
• Language: English
• Date: 2017-04-11
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © Ali et al.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1619302114
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 114
• Issue: 15
• Start Page: E3110
• End Page: E3118
• Grant/Funding Information: 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: CELLS; HUMAN DERMAL FIBROBLASTS; PROTEIN; plasmonic photothermal therapy; CELLULAR UPTAKE; NANOPARTICLES; apoptosis; IN-VITRO; PTEN INDUCES APOPTOSIS; DRUG-DELIVERY; Science & Technology - Other Topics; Science & Technology; gold nanorods; xenograft mice; THERMAL THERAPY; long-term toxicity; DNA-DAMAGE; Multidisciplinary Sciences
• Research Categories: Health Sciences, Oncology; Chemistry, Biochemistry

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.