Reactive oxygen species-activatable self-amplifying Watson-Crick base pairing-inspired supramolecular nanoprodrug for tumor-specific therapy.
Reactive oxygen species-activatable self-amplifying Watson-Crick base pairing-inspired supramolecular nanoprodrug for tumor-specific therapy.
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DOI：
10.1016/j.biomaterials.2021.121128
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发表时间：
2021-09
期刊：
影响因子：
14
通讯作者：
Xiaoyu Xu;Zishan Zeng;Xin Ding;Ting-Tian Shan;Qiuxing Liu;Meixu Chen;Jie Chen;Meng Xia
中科院分区：
文献类型：
--
作者：
Xiaoyu Xu;Zishan Zeng;Xin Ding;Ting-Tian Shan;Qiuxing Liu;Meixu Chen;Jie Chen;Meng Xia
肿瘤内上调的活性氧（ROS）已被广泛利用作为唯一的刺激，以激活药物释放的肿瘤特异性治疗。然而，内源性ROS不足和肿瘤异质性严重限制了当前ROS响应性药物递送系统的临床转化。在此，开发了定制的ROS可激活的自放大超分子纳米前药，用于增强ROS响应性和高选择性抗肿瘤治疗。合成了一种新的ROS可切割的CA基硫缩醛接头CASOH，并将ROS产生剂肉桂醛（CA）引入其分子结构中，巧妙地实现了“ROS激活CA释放与CA诱导ROS再生”的自放大正反馈回路。用胞嘧啶类似物吉西他滨（GEM）修饰CASOH，得到ROS可激活的自我牺牲型前体药物CAG，该前体药物CAG在肿瘤细胞中可选择性激活，并通过ROS补偿实现自我增强的“滚雪球”激活，而在正常细胞中保持失活。CAG通过Watson-Crick核碱基配对（G → C）样氢键与相应的富含鸟嘌呤的阿昔洛韦修饰的透明质酸偶联物HA-ACV有效交联，自组装成pH/ROS双响应的超分子纳米前药HCAG。HCAG纳米制剂具有高稳定性、有益的肿瘤靶向能力和pH/ROS响应性，表现出显著的体内抗肿瘤功效，全身毒性最小。基于独特的肿瘤特异性自放大前药激活和沃森-克里克碱基配对启发的超分子自组装，这项研究提供了一个启发性的策略，开发新的ROS响应性纳米平台，增强响应性和特异性，为未来的临床翻译。
Intratumoral upregulated reactive oxygen species (ROS) has been extensively exploited as exclusive stimulus to activate drug release for tumor-specific therapy. However, insufficient endogenous ROS and tumor heterogeneity severely restrict clinical translation of current ROS-responsive drug delivery systems. Herein, a tailored ROS-activatable self-amplifying supramolecular nanoprodrug was developed for reinforced ROS-responsiveness and highly selective antitumor therapy. A novel ROS-cleavable CA-based thioacetal linker CASOH was synthesized with ROS generator cinnamaldehyde (CA) incorporated into its molecular structure, to skillfully realize self-amplifying positive feedback loop of “ROS-activated CA release with CA-induced ROS regeneration”. CASOH was modified with a cytosine analogue gemcitabine (GEM) to obtain ROS-activatable self-immolative prodrug CAG, which could be selectively activated in tumor cells and further achieve self-boosting “snowballing” activation via ROS compensation, while keep inactive in normal cells. Through Watson-Crick nucleobase pairing (G≡C)-like hydrogen bonds, CAG efficiently crosslinked with a matched guanine-rich acyclovir-modified hyaluronic acid conjugate HA-ACV, to self-assemble into pH/ROS dual-responsive supramolecular nanoprodrug HCAG. With high stability, beneficial tumor targeting capacity and pH/ROS-responsiveness, HCAG nanoformulation exhibited remarkable in vivo antitumor efficacy with minimal systemic toxicity. Based on unique tumor-specific self-amplifying prodrug activation and Watson-Crick base pairing-inspired supramolecular self-assembly, this study provides an inspirational strategy of exploiting novel ROS-responsive nanoplatform with reinforced responsiveness and specificity for future clinical translation.