Xiao Wenjing, Yang Xiao, Wang Mengzhen, Jiang Zeyu, Zhang Heyi, Gong Mengqing, Zhao Lin, Song Jibin, Fu Qinrui
Department of Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266021, China.
Institute of Chronic Disease, College of Medicine, Qingdao University, Qingdao, 266071, China.
J Nanobiotechnology. 2025 Jun 13;23(1):440. doi: 10.1186/s12951-025-03531-7.
The standard treatment for various types of cancers typically involves the combination of concurrent localized radiotherapy and systemic chemotherapy. However, no treatment options have been reported that utilize chemotherapy cascade-enhanced radiotherapy. In this study, we report a core-satellite nanomedicine designed to enhance radiotherapeutic effects through a cascade mechanism by triggering the release of a potent chemotherapeutic agent in response to trypsin. We synthesized a functional enzyme-sequential responsive nanomedicine, DOX@Gel-DEVD-AuNR, which consists of gelatin nanoparticles loaded with the chemotherapeutic drug doxorubicin (DOX). These nanoparticles are covalently linked to gold nanorods (AuNR) via a caspase-3 specific DEVD peptide substrate. Upon trypsin activation, the DOX@Gel-DEVD-AuNR formulation releases DOX, thereby enhancing chemotherapy efficacy against tumors. Simultaneously, it activates caspase-3, inducing the aggregation of AuNRs, which in turn activates a near-infrared-II photoacoustic signal. This signal is crucial for determining the optimal timing for X-ray irradiation. The resulting large-size AuNRs aggregates promote their accumulation within tumors by preventing the migration and backflow of AuNRs, thereby improving radiotherapeutic effects. Consequently, when combined with image-guided X-ray irradiation, DOX@Gel-DEVD-AuNR induces significant cytotoxicity in cancer cells and effectively inhibits tumor growth. Our study underscores the potential application of enzyme catalysis-mediated chemistry in activating nanomedicine for activatable image-guided chemotherapy cascade-enhanced radiotherapy.
各种类型癌症的标准治疗通常包括同步局部放疗和全身化疗。然而，尚未有利用化疗级联增强放疗的治疗方案的报道。在本研究中，我们报告了一种核-卫星纳米药物，其设计通过级联机制增强放射治疗效果，即响应胰蛋白酶触发强效化疗药物的释放。我们合成了一种功能性酶顺序响应纳米药物DOX@Gel-DEVD-AuNR，它由负载化疗药物阿霉素（DOX）的明胶纳米颗粒组成。这些纳米颗粒通过半胱天冬酶-3特异性DEVD肽底物与金纳米棒（AuNR）共价连接。在胰蛋白酶激活后，DOX@Gel-DEVD-AuNR制剂释放DOX，从而增强对肿瘤的化疗效果。同时，它激活半胱天冬酶-3，诱导AuNRs聚集，进而激活近红外-II光声信号。该信号对于确定X射线照射的最佳时机至关重要。由此产生的大尺寸AuNRs聚集体通过阻止AuNRs的迁移和回流促进其在肿瘤内的积累，从而提高放射治疗效果。因此，当与图像引导的X射线照射相结合时，DOX@Gel-DEVD-AuNR在癌细胞中诱导显著的细胞毒性并有效抑制肿瘤生长。我们的研究强调了酶催化介导的化学在激活纳米药物用于可激活图像引导化疗级联增强放疗方面的潜在应用。
