A biomimetic nanodrug for enhanced chemotherapy of pancreatic tumors.
A biomimetic nanodrug for enhanced chemotherapy of pancreatic tumors.
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DOI：
10.1016/j.jconrel.2023.01.007
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发表时间：
2023-01
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影响因子：
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通讯作者：
Fu-You Zhang;Qi-da Hu;Bowen Li;Yong Huang;Meng Wang;S. Shao;Honglin Tang;Zhu Yao;Y. Ping;T. Liang
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文献类型：
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作者：
Fu-You Zhang;Qi-da Hu;Bowen Li;Yong Huang;Meng Wang;S. Shao;Honglin Tang;Zhu Yao;Y. Ping;T. Liang
胰腺导管腺癌（Pancreatic ductal adenocarcinoma，PDAC）由于其化疗效果差和多药耐药，一直是恶性肿瘤中最高的一种。化疗失败的一个主要原因是由于过表达的细胞外基质（ECM）基质导致药物在PDAC肿瘤组织中的不良积累，这形成了限制化疗剂深入组织渗透的主要障碍。在本文中，我们报告了一种基于PDAC细胞膜包被的金纳米笼（AuNCs）的肿瘤微环境（TME）响应性纳米药物，以共同递送化疗药物（GEM）和一氧化氮（NO）供体（L-Arg），以增强药物积累并降低耐药性。高谷胱甘肽（GSH）水平可触发纳米药物上二硫键的裂解以释放GEM。此外，升高的ROS水平可激活L-Arg产生NO，其协同促进GEM通过扩张PDAC肿瘤组织中的血管和使血管正常化而渗透到深层组织中。此外，AuNCs不仅可以作为化疗的光热剂，还可以产生光声信号来监测药物的积累和分布。正如预期的那样，该策略在治疗不同的异种移植小鼠模型，特别是原位和患者来源的异种移植（PDX）模型中表现出显著的效果。目前的研究定义了一个有用的治疗工具，用于治疗PDAC肿瘤。
Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the highest malignant tumors due to its poor chemotherapeutic efficacy and multidrug resistance. A major reason for the failure in chemotherapy is poor drug accumulation into PDAC tumor tissues due to the overexpressed extracellular matrix (ECM) stroma, which forms a major obstacle limiting the deep tissue penetration of chemotherapeutics. Herein, we report a tumor microenvironment (TME)-responsive nanodrug, based on PDAC cell membrane-coated gold nanocages (AuNCs), to co-deliver the chemotherapeutics (GEM) and nitrogen oxide (NO) donor (L-Arg) to enhance drug accumulation and reduce chemoresistance. The high glutathione (GSH) level can trigger the cleavage of the disulfide bond on nanodrug to release GEM. Moreover, the elevated ROS level could activate L-Arg to generate NO, which synergistically facilitate GEM to penetrate into deep tissues by means of vasodilation and normalization of blood vessels in the PDAC tumor tissue. In addition, AuNCs not only serve as a photothermal agent for chemotherapy, but also generate photoacoustic signals to monitor drug accumulation and distribution. As expected, the strategy demonstrates to be remarkable in treating different xenograft mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The current study defines a useful therapeutic tool for treating PDAC tumors.