title: Efficacy, long-term toxicity, and mechanistic studies of gold nanorods photothermal therapy of cancer in xenograft mice.
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/cm2) 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. Cytochromecand 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.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Moustafa R K
authors.initials: MR
authors.lastname: Ali
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Mohammad Aminur
authors.initials: MA
authors.lastname: Rahman
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Tiegang
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Peng
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Mackey
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Quest Diagnostics, Atlanta, GA 30308.
authors.forename: Hyung Ju
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Zhuo G
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Haopeng
authors.initials: H
authors.lastname: Xiao
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Ronghu
authors.initials: R
authors.lastname: Wu
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322; dmshin@emory.edu melsayed@gatech.edu.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332; dmshin@emory.edu melsayed@gatech.edu.|School of Chemistry, King Abdul Aziz University, Jeddah 23218, Kingdom of Saudi Arabia.
authors.forename: Mostafa A
authors.initials: MA
authors.lastname: El-Sayed
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D005260:Female; D006046:Gold / Q000737:chemistry / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D006979:Hyperthermia, Induced; D007834:Lasers; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D043942:Nanotubes / Q000737:chemistry*; D010789:Phototherapy; D040901:Proteomics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D006046:Gold
keywords: apoptosis; gold nanorods; long-term toxicity; plasmonic photothermal therapy; xenograft mice