Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China.
Biomater Sci. 2018 Nov 1;6(11):2965-2975. doi: 10.1039/c8bm00899j. Epub 2018 Sep 26.
In the context of prodrug nanomedicines for cancer therapy, one of the great challenges is the slow and variable release of the parent drug in tumors. Recently, many smart redox-sensitive nanocarriers have been developed to address this problem. However, due to significant tumor heterogeneity, some redox-sensitive nanomedicines still show poor selectivity in drug release. Herein, we report the design and synthesis of a ROS-triggered prodrug nanoplatform fabricated with oxidation-responsive cabazitaxel (CTX) prodrugs for synergistic chemo-photodynamic therapy, thioether-/selenoether-linked conjugates of CTX and oleic acid (OA). These prodrugs can be readily self-assembled into nanoparticles, with pyropheophorbide a (PPa) co-encapsulated into the prodrug-nanosystem for combination therapy. The dual-source ROS-responsive prodrug nanosystems selectively and rapidly release CTX not only in response to endogenous ROS overproduced in tumor cells, but also to exogenous PPa-generated ROS under laser irradiation. Moreover, the selenium-containing linkage demonstrates significant advantages over a sulfur-containing linkage in terms of ROS-triggered drug release and cytotoxicity. The prepared prodrug-nanosystems significantly prolong the systemic circulation and tumor distribution of both CTX and PPa, thereby demonstrating synergistic chemo-photodynamic therapy in vivo. All these drug delivery advantages render the nanosystem extremely promising for cancer treatment.
在癌症治疗的前药纳米医学中，一个巨大的挑战是在肿瘤中母体药物的缓慢和可变释放。最近，已经开发出许多智能氧化还原敏感的纳米载体来解决这个问题。然而，由于肿瘤异质性显著，一些氧化还原敏感的纳米药物在药物释放方面仍然表现出较差的选择性。在这里，我们报告了一种 ROS 触发的前药纳米平台的设计和合成，该平台由氧化响应的卡巴他赛（CTX）前药制备，用于协同化学-光动力治疗，CTX 和油酸（OA）的硫醚/硒醚连接物。这些前药可以很容易地自组装成纳米颗粒，同时将原卟啉 a（PPa）共包封到前药纳米系统中用于联合治疗。双源 ROS 响应性前药纳米系统不仅可以响应肿瘤细胞中过度产生的内源性 ROS，还可以在外源 PPa 产生的 ROS 存在下进行激光照射时选择性和快速地释放 CTX。此外，与含硫键相比，含硒键在 ROS 触发的药物释放和细胞毒性方面具有显著优势。所制备的前药纳米系统显著延长了 CTX 和 PPa 的系统循环和肿瘤分布，从而在体内表现出协同的化学-光动力治疗。所有这些药物输送优势使纳米系统在癌症治疗方面极具前景。
