Key Laboratory for Advanced Materials, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, PR China.
Key Lab of Resource Chemistry of MOE & Shanghai Key Lab of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, P R China.
Colloids Surf B Biointerfaces. 2023 Oct;230:113513. doi: 10.1016/j.colsurfb.2023.113513. Epub 2023 Aug 9.
In situ mitochondrial oxidative stress amplification is an effective strategy to improve efficacy of cancer treatment. In this work, a tumor and mitochondria dual-targeted multifunctional nanoplatform CMS@AIPH@PDA@COTPP@FA (CAPCTF) was prepared, in which a thermally decomposable radical initiator AIPH was loaded inside the mesoporores of CuMoS (CMS) nanoparticles with polydopamine (PDA) covered films that were further covalently functionalized by a mitochondria-targeted CO donor (COTPP) and a directing group of folic acid (FA). The prepared CAPCTF nanoplatform selectively accumulated in cancer cells and further targeted the mitochondrial organelle where carbon monoxide (CO) and O-independent free radicals (•OH/•R) were in situ generated upon 1064 nm laser irradiation. Furthermore, the CMS nanocarrier was capable of depleting the GSH overexpressed in the tumor microenvironment (TME), thus preventing free radical scavenging. As a result, the CAPCTF nanoplatform exhibited outstanding in vitro and in vivo antitumor efficacy under hypoxic conditions. This provides an innovative strategy that combines O-independent free radicals (•OH/•R) generation, CO delivery and GSH consumption to amplify intracellular oxidative stresses and induce mitochondrial dysfunction, thus leading to cancer cells eradication, which may have significant implications for personalized hypoxic tumor treatment.
原位线粒体氧化应激放大是提高癌症治疗效果的有效策略。在这项工作中，制备了一种肿瘤和线粒体双重靶向的多功能纳米平台 CMS@AIPH@PDA@COTPP@FA（CAPCTF），其中，热分解自由基引发剂 AIPH 装载在具有聚多巴胺（PDA）覆盖膜的 CuMoS（CMS）纳米粒子的介孔中，进一步通过线粒体靶向 CO 供体（COTPP）和叶酸（FA）的导向基团进行共价功能化。所制备的 CAPCTF 纳米平台选择性地在癌细胞中积累，并进一步靶向线粒体细胞器，在 1064nm 激光照射下原位产生一氧化碳（CO）和 O 独立自由基（•OH/•R）。此外，CMS 纳米载体能够耗竭肿瘤微环境（TME）中过度表达的 GSH，从而防止自由基清除。结果，CAPCTF 纳米平台在缺氧条件下表现出优异的体外和体内抗肿瘤疗效。这为结合 O 独立自由基（•OH/•R）生成、CO 传递和 GSH 消耗来放大细胞内氧化应激并诱导线粒体功能障碍从而导致癌细胞消除提供了一种创新策略，这可能对个性化缺氧肿瘤治疗具有重要意义。
