Guangdong Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
The First Clinical Medical School, Southern Medical University, Guangzhou 510515, China.
J Control Release. 2022 Jul;347:389-399. doi: 10.1016/j.jconrel.2022.05.022. Epub 2022 May 18.
Nonspecific biodistribution and poor permeability of conventional therapeutic agents in solid tumors severely compromised the antitumor efficacy. Herein, we report a cascade tumor therapeutic nanoplatform consisting of docosahexaenoic acid (DHA) and nicorandil (NI), namely DNP, to specifically produce cytotoxic agents in tumor cells as well as dilating blood vessels to increase the intratumoral oxidative stress levels. The DHA embedded in the membrane could generate reactive oxygen species (ROS) meanwhile NI produced nitric oxide (NO) in response to intracellular glutathione (GSH) in tumors. Notably, the two functional species could further react in situ to form a more tumoricidal reactive nitrogen species (RNS), causing selectively cascade amplification of antitumor performance. In addition, NO-induced vasodilation could consequently result in a series of functions, including hypoxia relief and deep tumor transportation. In general, we anticipate that the DNP could show great potential for tumor-specific treatment by selectively producing RNS precursors in response to the interior environment of tumor cells for hypoxia normalization and tumor inhibition.
传统治疗药物在实体瘤中的非特异性分布和较差的通透性严重限制了其抗肿瘤疗效。在此，我们报告了一种级联肿瘤治疗纳米平台，由二十二碳六烯酸（DHA）和尼克地尔（NI）组成，即 DNP，以特异性地在肿瘤细胞中产生细胞毒性剂，并扩张血管以增加肿瘤内的氧化应激水平。嵌入在膜中的 DHA 可以产生活性氧（ROS），同时 NI 在肿瘤细胞内的谷胱甘肽（GSH）的作用下产生一氧化氮（NO）。值得注意的是，这两种功能物质可以进一步在原位反应，形成更具杀瘤活性的活性氮物质（RNS），从而导致抗肿瘤性能的选择性级联放大。此外，NO 诱导的血管扩张可导致一系列功能，包括缓解缺氧和肿瘤深部输送。总的来说，我们预计 DNP 通过响应肿瘤细胞内部环境选择性地产生 RNS 前体，用于缺氧正常化和肿瘤抑制，将具有很大的肿瘤特异性治疗潜力。
