Efficacy, long-term toxicity, and mechanistic studies of gold nanorods photothermal therapy of cancer in xenograft mice
Efficacy, long-term toxicity, and mechanistic studies of gold nanorods photothermal therapy of cancer in xenograft mice
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DOI：
10.1073/pnas.1619302114
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发表时间：
2017-04-11
影响因子：
11.1
通讯作者：
El-Sayed, Mostafa A.
中科院分区：
文献类型：
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作者：
Ali, Moustafa R. K.;Rahman, Mohammad Aminur;El-Sayed, Mostafa A.
金纳米棒（AuNRs）辅助等离子体光热疗法（AuNRs-PPTT）是一种很有前途的抗癌策略，其中AuNRs吸收近红外光并将其转化为热量，主要通过凋亡和/或坏死引起细胞死亡。开发一种能在体内诱导肿瘤细胞凋亡、避免肿瘤细胞坏死的PPTT，并探讨其作用的分子机制具有重要意义。此外，评估治疗后AuNR的长期命运对于临床使用至关重要。我们首先优化了AuNR的大小、表面修饰[利福平（RF）缀合]和浓度（2.5 nM）以及PPTT激光功率（2 W/cm（2）），以实现最大的细胞凋亡诱导。其次，我们研究了潜在的作用机制AuNRs-PPTT在小鼠肿瘤组织中使用定量蛋白质组学分析。鉴定了几种死亡途径，主要涉及通过释放中性粒细胞胞外陷阱（NET）（NETosis）的细胞凋亡和细胞死亡，这在使用RF缀合的AuNR（AuNRs@RF）的PPTT时比使用聚乙二醇硫醇缀合的AuNRs更明显。细胞色素c和p53相关的凋亡机制被鉴定为有助于PPTT与AuNRs@RF的增强效应。此外，Pin 1和IL 18相关的信号传导有助于通过PPTT与AuNRs@RF观察到的NETosis途径的扰动。第三，我们报告了一项为期15个月的毒性研究，表明AuNR在体内没有长期毒性。总之，这些数据表明我们的AuNRs-PPTT平台对于小鼠模型中的癌症治疗是有效和安全的。这些发现为PPTT向临床的转化提供了一个强有力的框架。
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.