Qi Hongzhao, Wang Yin, Yuan Xubo, Li Peifeng, Yang Lijun
Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
Nanoscale. 2020 Dec 21;12(47):24030-24043. doi: 10.1039/d0nr06823c. Epub 2020 Dec 8.
The metabolic enzyme-based arginine deprivation represents a tremendous opportunity to treat argininosuccinate synthetase (ASS1)-deficient tumors. Arginine deiminase (ADI), a typical representative, has aroused great interest. To date, the functional modification of ADI, such as PEGylation, has been applied to improve its weakness significantly, reducing its immunogenicity and extending its blood circulation time. However, the advantages of ADI, such as the cellular non-uptake property, are often deprived by current modification methods. The cellular non-uptake property of ADI only renders extracellular arginine degradation that negligibly influences normal cells. However, current-functionalized ADIs can be readily phagocytized by cells, causing the imbalance of intracellular amino acids and the consequent damage to normal cells. Therefore, it is necessary to exploit a new method that can simultaneously improve the weakness of ADI and maintain its advantage of cellular non-uptake. Here, we utilized a kind of phosphorylcholine (PC)-rich nanocapsule to load ADI. These nanocapsules possessed extremely weak cellular interaction and could avoid uptake by endothelial cells (HUVEC), immune cells (RAW 264.7), and tumor cells (H22), selectively depriving extracellular arginine. Besides, these nanocapsules increased the blood half-life time of ADI from the initial 2 h to 90 h and efficiently avoided its immune or inflammatory responses. After a single injection of ADI nanocapsules into H22 tumor-bearing mice, tumors were stably suppressed for 25 d without any detectable side effects. This new strategy first realizes the selective extracellular arginine deprivation for the treatment of ASS1-deficient tumors, potentially promoting the clinical translation of metabolic enzyme-based amino acid deprivation therapy. Furthermore, the research reminds us that the functionalization of drugs can not only improve its weakness but also maintain its advantages.
基于代谢酶的精氨酸剥夺为治疗精氨酸琥珀酸合成酶（ASS1）缺陷型肿瘤提供了巨大机遇。典型代表精氨酸脱亚氨酶（ADI）已引起极大关注。迄今为止，ADI的功能修饰，如聚乙二醇化，已被应用以显著改善其弱点，降低其免疫原性并延长其血液循环时间。然而，ADI的优势，如细胞非摄取特性，常常被当前的修饰方法所剥夺。ADI的细胞非摄取特性仅导致细胞外精氨酸降解，对正常细胞的影响可忽略不计。然而，当前功能化的ADI可被细胞轻易吞噬，导致细胞内氨基酸失衡，进而对正常细胞造成损害。因此，有必要开发一种新方法，既能同时改善ADI的弱点，又能保持其细胞非摄取优势。在此，我们利用一种富含磷酸胆碱（PC）的纳米胶囊来负载ADI。这些纳米胶囊具有极其微弱的细胞相互作用，可避免被内皮细胞（HUVEC）、免疫细胞（RAW 264.7）和肿瘤细胞（H22）摄取，选择性地剥夺细胞外精氨酸。此外，这些纳米胶囊将ADI的血液半衰期从最初的2小时延长至90小时，并有效避免了其免疫或炎症反应。将ADI纳米胶囊单次注射到荷H22肿瘤小鼠体内后，肿瘤被稳定抑制25天，且无任何可检测到的副作用。这种新策略首次实现了选择性细胞外精氨酸剥夺以治疗ASS1缺陷型肿瘤，有望推动基于代谢酶的氨基酸剥夺疗法的临床转化。此外，该研究提醒我们，药物功能化不仅可以改善其弱点，还能保持其优势。
