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/cm) 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 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.

Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins

“…Discussion Current advances of nanoscience and nanomedicine enable us to fabricate "intelligent" nanomaterials that can specifically target cellular and subcellular locations in living animals for treating diseases (84,85). Although larger nanoparticles (>18 nm in diameter) can accumulate in organs such as the liver and spleen and be eliminated slowly (86), the long-term effect of AuNRs in mice shows no toxic effect after 15 mo (87). The biocompatibility and special physicochemical properties of AuNRs provide us an effective and safe potential treatment of cancer.…”

“…Our previous study has shown success in treating xenograft mice and natural mammary gland tumors in dogs and cats using AuNRassisted PPTT, where no cancer relapse or metastasis occurred in any of the test subjects (87,88), implying the potential effect of AuNRs in inhibiting cancer metastasis. We also designed nuclear membrane-targeted AuNPs for inhibiting cancer cell migration and invasion, by mechanically increasing their nuclear stiffness, with greatly reduced AuNP dosage (26).…”

A new cancer immunotherapy via simultaneous DC‐mobilization and DC‐targeted IDO gene silencing using an immune‐stimulatory nanosystem

“…Although, our man‐GNR‐siRNA is highly effective for DC‐targeted delivery of siRNA and GNR has been demonstrated to be safe in the long term in vivo , there are many aspects that deserve more in‐depth study before the wide clinical applications of nanomaterials. For example, the metabolism and distribution of nanomaterials in the body, dosages for administration and so on, especially in the context of biocompatibility, need more in‐depth investigations, including for the first‐in‐class man‐GNR‐siIDO reagent described in our study …”

Gold Nanorod Photothermal Therapy Alters Cell Junctions and Actin Network in Inhibiting Cancer Cell Collective Migration

“…In PPTT, AuNRs that absorb the incident near infra-red (NIR) light to induce heat, and thereby could trigger tumor apoptosis. 14,15 AuNRs-PPTT has been applied successfully on treating tumor bearing mice, cats and dogs. In these studies, we observed that animals with induced or spontaneous tumors were effectively cured with no tumor reoccurrence or metastasis.…”