Acid-Responsive Aggregated Gold Nanoparticles for Radiosensitization and Synergistic Chemoradiotherapy in the Treatment of Esophageal Cancer
Acid-Responsive Aggregated Gold Nanoparticles for Radiosensitization and Synergistic Chemoradiotherapy in the Treatment of Esophageal Cancer
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DOI：
10.1002/smll.202200115
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发表时间：
2022-03-09
期刊：
影响因子：
13.3
通讯作者：
Yuan，Yong
中科院分区：
文献类型：
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作者：
Luan，Siyuan;Xie，Rou;Yuan，Yong
低剂量放射治疗效果不足和药物生物分布的非特异性限制了放化疗的发展。为此，设计了一种载阿霉素(DOX)的酸响应型聚集纳米系统(AuNPs-D-P-DA)，用于放射增敏和协同放化疗。针对食道癌(EC)的酸性微环境，小尺寸AuNPs-D-P-DA在肿瘤组织中形成大尺寸的金纳米颗粒(AuNPs)聚集体，阻碍AuNPs的回流到循环中，从而增强肿瘤的聚集和滞留。同时，由于AuNPs在肿瘤内的浓度高、尺寸大，因此基于AuNPs的放射增敏作用显著提高，而DOX在酸性微环境触发下被特异性地输送和释放到肿瘤细胞中进行放化疗协同治疗。与无反应对照相比，酸响应性AuNPs在体外加重了辐射诱导的DNA损伤、细胞凋亡、细胞周期停滞和低克隆形成能力，并增强了体内抗肿瘤效果。当与酸响应型DOX联合使用时，通过它们的协同作用，该制剂的治疗效果进一步提高。在异种移植模型中，酸响应性AuNPs加放射治疗后，脂肪酸代谢被重新编程，这为进一步提高放射增敏提供了潜在的靶点。综上所述，酸响应型AuNPs-D-P-DA纳米系统利用了AuNPs敏化X射线照射和酸响应型DOX在治疗EC中的放射和化疗协同效应。
Radiotherapy and chemotherapy are limited by insufficient therapeutic efficacy of low‐dose radiation and nonspecific drug biodistribution. Herein, an acid‐responsive aggregated nanosystem (AuNPs‐D‐P‐DA) loaded with doxorubicin (DOX) is designed for radiosensitization and synergistic chemoradiotherapy. In response to the acid microenvironment of esophageal cancer (EC), small‐sized AuNPs‐D‐P‐DA forms large‐sized gold nanoparticle (AuNPs) aggregates in tumor tissues to hinder the backflow of AuNPs to the circulation, resulting in enhanced tumor accumulation and retention. Simultaneously, the AuNPs‐based radiosensitization is significantly improved because of the high concentration and large size of intratumoral AuNPs, while DOX are delivered and released specifically into tumor cells triggered by the acid microenvironment for chemo‐radio synergistic therapy. Acid‐responsive AuNPs exacerbate radiation‐induced DNA damage, cell apoptosis, cell cycle arrest, and low colony formation ability in vitro and enhance anti‐tumor efficacy in vivo compared to un‐responsive control. When combined with acid‐responsive DOX, the therapeutic efficacy of the formulation is further improved by their synergistic effect. After the treatment of acid‐responsive AuNPs plus radiotherapy, fatty acid metabolism is reprogrammed in xenograft models, which provides potential targets for further improvement of radiosensitization. In summary, the acid‐responsive AuNPs‐D‐P‐DA nanosystem leverages the radio‐ and chemotherapeutic synergies of AuNPs‐sensitized X‐ray irradiation and acid‐responsive DOX in the treatment of EC.