Jung Eunkyeong, Jeong Seung Won, Lee Yeongjong, Jeon Chanhee, Shin Hyunbin, Song Nanhee, Lee Yujin, Lee Dongwon
Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Baekjedaero 567, Jeonju, Jeonbuk, 54896, Republic of Korea.
Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Baekjedaero 567, Jeonju, Jeonbuk, 54896, Republic of Korea; Department of Polymer⋅Nano Science and Technology, Jeonbuk National University, Baekjedaero 567, Jeonju, Jeonbuk, 54896, Republic of Korea.
Biomaterials. 2022 Aug;287:121681. doi: 10.1016/j.biomaterials.2022.121681. Epub 2022 Jul 18.
Stimulus-responsive self-assembling prodrug-based nanomedicine has emerged as a novel paradigm in controlled drug delivery. All-trans retinoic acid (RA), one of vitamin A metabolites, induces apoptotic cancer cell death, but its clinical applications are limited by weak anticancer efficacy. To fully maximize the therapeutic potential of RA, we exploited the unique chemistry of arylboronic acid which undergoes hydrogen peroxide (HO)-triggered degradation to release quinone methide (QM) that alkylates glutathione (GSH) to disrupt redox homeostasis and is also converted into hydroxybenzyl alcohol (HBA) to suppress the expression of vascular endothelial growth factor (VEGF). Here, we report that boronated retinoic acid prodrug (RABA) can be formulated into self-deliverable nanoassemblies which release both RA and QM in a HO-triggered self-immolative manner to exert cooperative anticancer activities. RABA nanoassemblies exert anticancer effects by inducing reactive oxygen species (ROS)-mediated apoptosis, eliciting immunogenic cell death (ICD) and suppressing angiogenic VEGF expression. The excellent anticancer efficacy of RABA nanoassemblies can be explained by benefits of self-assembling prodrug-based drug self-delivery and cooperative anticancer actions. The design strategy of RABA would provide a new insight into the rational design of self-deliverable and self-immolative boronated prodrug nanoassemblies for targeted cancer therapy.
基于刺激响应性自组装前药的纳米药物已成为可控药物递送的一种新范式。全反式维甲酸（RA）是维生素A的代谢产物之一，可诱导癌细胞凋亡死亡，但其临床应用受到抗癌疗效较弱的限制。为了充分发挥RA的治疗潜力，我们利用了芳基硼酸的独特化学性质，其在过氧化氢（HO）触发下发生降解，释放出醌甲基化物（QM），QM可使谷胱甘肽（GSH）烷基化以破坏氧化还原稳态，同时还可转化为羟基苄醇（HBA）以抑制血管内皮生长因子（VEGF）的表达。在此，我们报道硼化维甲酸前药（RABA）可被制备成自递送纳米组装体，其以HO触发的自牺牲方式释放RA和QM，从而发挥协同抗癌活性。RABA纳米组装体通过诱导活性氧（ROS）介导的凋亡、引发免疫原性细胞死亡（ICD）以及抑制血管生成性VEGF表达来发挥抗癌作用。RABA纳米组装体优异的抗癌疗效可通过基于自组装前药的药物自递送和协同抗癌作用来解释。RABA的设计策略将为用于靶向癌症治疗的自递送和自牺牲硼化前药纳米组装体合理设计提供新的见解。
