Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, P. R. China.
Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, P. R. China.
Adv Healthc Mater. 2022 Feb;11(3):e2102038. doi: 10.1002/adhm.202102038. Epub 2021 Nov 11.
Glutamine metabolism of tumor cells plays a crucial role in maintaining cell homeostasis and reducing oxidative damage. Herein, a valid strategy of inhibiting glutamine metabolism is proposed to amplify the oxidative damage of photodynamic therapy (PDT) to tumor cells. Specifically, the authors develop a drug co-delivery system (designated as CeV) based on chlorine e6 (Ce6) and V9302 via the self-assembly technology. In spite of the strong hydrophobicity of therapeutic agents, the assembled CeV holds a favorable dispersibility in water and an improved cellular uptake capability. Under light irradiation, the internalized CeV is capable of generating abundant reactive oxygen species (ROS) for PDT. More importantly, CeV can reduce the uptake of glutamine through V9302-mediated alanine-serine-cysteine transporter of type-2 (ASCT2) inhibition, leading to a reduced glutathione (GSH) production and an amplified oxidative stress. As a result, CeV has a robust PDT efficacy on tumor inhibition by the blockade of glutamine transport. Notably, CeV exhibits a superiority on tumor suppression over the single treatment as well as the combined administration of Ce6 and V9302, which indicates the advantage of CeV for synergistic treatment. It may serve as a novel nanoplatform for developing a drug co-delivery system to improve PDT efficiency by inhibiting cell metabolism.
肿瘤细胞的谷氨酰胺代谢在维持细胞内稳态和减少氧化损伤方面发挥着关键作用。在此，提出了一种有效的抑制谷氨酰胺代谢的策略，以放大光动力疗法（PDT）对肿瘤细胞的氧化损伤。具体而言，作者通过自组装技术开发了一种基于氯 e6（Ce6）和 V9302 的药物共递送系统（命名为 CeV）。尽管治疗剂具有很强的疏水性，但组装后的 CeV 在水中具有良好的分散性和提高的细胞摄取能力。在光照射下，内化的 CeV 能够产生丰富的活性氧（ROS）用于 PDT。更重要的是，CeV 可以通过 V9302 介导的 II 型天冬氨酸-丝氨酸-半胱氨酸转运体（ASCT2）抑制来减少谷氨酰胺的摄取，导致谷胱甘肽（GSH）产生减少和氧化应激放大。因此，CeV 通过阻断谷氨酰胺转运来抑制肿瘤生长，具有强大的 PDT 疗效。值得注意的是，CeV 在肿瘤抑制方面优于单一治疗以及 Ce6 和 V9302 的联合给药，这表明 CeV 在协同治疗方面具有优势。它可以作为一种新型纳米平台，通过抑制细胞代谢来开发药物共递送系统，以提高 PDT 效率。
