Enhanced Copper-Temozolomide Interactions by Protein for Chemotherapy against Glioblastoma Multiforme
Enhanced Copper-Temozolomide Interactions by Protein for Chemotherapy against Glioblastoma Multiforme
复制标题
通过蛋白质增强铜-替莫唑胺相互作用，用于针对多形性胶质母细胞瘤的化疗。
DOI：
10.1021/acsami.9b14849
复制
发表时间：
2019-11-13
影响因子：
9.5
通讯作者：
Feng, Fude
中科院分区：
文献类型：
--
作者：
Li, Xiao;Shao, Fenli;Feng, Fude
目前治疗复发性多形胶质母细胞瘤（GBM）需要高剂量替莫唑胺（TMZ），这是一种5-（3-甲基三氮-1-酰基）咪唑-4-羧酰胺（MTIC）的前药，基于TMZ在碱性ph下的自发水解。然而，如何控制MTIC的活性仍然未知，这给寻找可靠的MTIC受体带来了特别的挑战。本研究发现，在TMZ降解过程中，铜可以识别并结合MTIC，这意味着铜在提高TMZ衍生的MTIC的生物利用度方面发挥了重要作用。以载铁蛋白为模型铜结合蛋白，研究了蛋白中铜与tmz的相互作用。通过高结合效率（基于原始TMZ高达92.9%）和容量（每个蛋白高达185个MTIC片段），实现了高效的MTIC固定。该体系在碱性和酸性条件下均稳定，可被谷胱甘肽激活释放MTIC，为tmz敏感和tmz耐药GBM化疗提供DNA烷基化剂铺平了道路。这项新研究为了解特殊的GBM微环境（特异性铜积累）与TMZ治疗效果之间的潜在关系提供了新的视角。
Current treatment of recurrent glioblastoma multiforme (GBM) demands dose-intense temozolomide (TMZ), a prodrug of 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), based on the spontaneous hydrolysis of TMZ at basic pH. However, how to control the activity of MTIC remains unknown, which poses a particular challenge to search a reliable MTIC receptor. In the present work, copper is found to recognize and bind MTIC in the process of TMZ degradation, which means copper can play an important role in enhancing the bioavailability of MTIC derived from TMZ. Using apoferritin as a model copper-bound protein, copper-TMZ interaction in protein was studied. Efficient MTIC immobilization was achieved with high binding efficiency (up to 92.9% based on original TMZ) and capacity (up to 185 MTIC moieties per protein). The system was stable against both alkaline and acidic pH and could be activated by glutathione to liberate MTIC, which paves a way to deliver DNA alkylating agent for both TMZ-sensitive and TMZ-resistant GBM chemotherapy. The new study provides a new insight for understanding the potential relationship be-tween the special GBM microenvironment (specific copper accumulation) and therapeutic effect of TMZ.