School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China.
Biomater Adv. 2022 Jul;138:212957. doi: 10.1016/j.bioadv.2022.212957. Epub 2022 May 27.
The particularity of the tumor microenvironment (TME) significantly limits the efficiency of chemodynamic therapy (CDT). Although various measures have been taken to improve the efficiency of CDT, how to organically integrate them into one nanosystem to achieve efficient synergy for CDT according to predetermined procedures is still an urgent problem to be solved. This work reported a multifunctional nanosystem, TP@PP, which comprised the inner triphenylphosphine modified D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS-PPh) micelles loading iron-oxide nanoparticles (IONs), and the outer poly (dopamine-co-protocatechuic acid) (PDA-PA, PP) coating modified with carbonic anhydrase IX inhibitor (CAI). TP@PP remodeled TME by sequential function adjustment to make it suitable for the efficient Fenton reactions: CAI first inhibited the overexpressed CA IX to result in intracellular acidification, which combined with near-infrared light (NIR) irradiation to accelerate the PP coating degradation, thereby promoting the exposure and disintegration of the inner micellar structure to release TPGS-PPh and IONs. The TPGS-PPh further elevated the intracellular ROS basal level by targeting and interfering with the mitochondrial function. Therefore, the TME was transformed into an acidic microenvironment with high ROS levels, which vigorously promoted the Fenton reaction mediated by IONs with the aid of photothermal effect induced by PP coating via NIR irradiation, ultimately earning high-efficiency CDT on xenograft MDA-MB-231 tumor-bearing mice. This study improved the efficiency of Fenton reaction in biological systems through the practical design of nanostructures and provided a novel thought for ROS-mediated therapy.
肿瘤微环境（TME）的特殊性极大地限制了化学动力学治疗（CDT）的效率。尽管已经采取了各种措施来提高 CDT 的效率，但如何根据预定程序将它们有机地整合到一个纳米系统中，以实现 CDT 的高效协同作用，仍然是一个亟待解决的问题。本工作报道了一种多功能纳米系统，TP@PP，它由内部分别载有氧化铁纳米粒子（IONs）的三苯基膦修饰的 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS-PPh）胶束和外部分别修饰碳酸酐酶 IX 抑制剂（CAI）的聚多巴胺-原儿茶酸（PDA-PA，PP）涂层组成。TP@PP 通过顺序功能调整重塑 TME，使其适合高效的 Fenton 反应：CAI 首先抑制过表达的 CAIX 导致细胞内酸化，与近红外光（NIR）照射相结合，加速 PP 涂层降解，从而促进内部胶束结构的暴露和崩解，释放 TPGS-PPh 和 IONs。TPGS-PPh 通过靶向和干扰线粒体功能进一步提高细胞内 ROS 基础水平。因此，TME 转化为具有高 ROS 水平的酸性微环境，在 PP 涂层通过 NIR 照射诱导的光热效应的辅助下，大力促进由 IONs 介导的 Fenton 反应，最终在异种 MDA-MB-231 肿瘤荷瘤小鼠上实现高效 CDT。本研究通过实际设计纳米结构提高了生物系统中 Fenton 反应的效率，为 ROS 介导的治疗提供了新的思路。
