Department of Biomedical Engineering, School of Medicine , Tsinghua University , Beijing 100084 , China.
Biomedical Engineering Department , Peking University , Beijing 100191 , China.
ACS Appl Mater Interfaces. 2019 Mar 13;11(10):9756-9762. doi: 10.1021/acsami.8b20956. Epub 2019 Feb 27.
Hydrogen peroxide (HO)-generating enzymes (HGEs) are potentially useful for tumor therapy, but the potential is limited by the challenge in regulating HO production. Herein, we present site-specific in situ growth of a cationic polymer poly( N, N'-dimethylamino-2-ethyl methacrylate) (PDMA) from the N-terminus of glucose oxidase (GOX) to generate a site-specific and cationic GOX-PDMA conjugate with well-retained activity and enhanced stability to regulate HO generation for cancer starvation and HO therapy. Notably, the efficiency of endocytosis of the conjugate was 4-fold higher than that of free GOX. As a result, relative to free GOX, the conjugate showed 1.5-fold increased cytotoxicity, 2-fold enhanced tumor retention, and 5-fold increased tolerability after intratumoral injection. Importantly, a single intratumoral injection of the conjugate completely abolished colon tumors without detectable side effects, whereas free GOX was ineffective and systemically toxic. This chemistry may provide a new, simple, general, and efficient solution to regulate HO production and thereby to dramatically improve the antitumor efficacy of HGEs while reducing side effects.
过氧化氢（HO）生成酶（HGEs）在肿瘤治疗中具有潜在的应用价值，但由于 HO 生成的调控具有挑战性，其应用受到限制。在此，我们提出了一种从葡萄糖氧化酶（GOX）的 N 端特异性原位生长阳离子聚合物聚（N，N'-二甲基氨基-2-乙基甲基丙烯酰胺）（PDMA）的方法，生成一种具有特异性和正电性的 GOX-PDMA 缀合物，其活性和稳定性均得到很好的保留，可用于调节 HO 的产生以实现肿瘤饥饿和 HO 治疗。值得注意的是，该缀合物的内吞效率比游离 GOX 高 4 倍。因此，与游离 GOX 相比，该缀合物的细胞毒性增加了 1.5 倍，肿瘤保留增加了 2 倍，肿瘤内注射后的耐受性增加了 5 倍。重要的是，单次肿瘤内注射该缀合物可完全消除结肠肿瘤，且无明显副作用，而游离 GOX 无效且具有全身毒性。这种化学方法可能为调控 HO 生成提供了一种新的、简单的、通用的和有效的解决方案，从而显著提高 HGEs 的抗肿瘤疗效，同时降低副作用。
