Nanoclustered Cascaded Enzymes for Targeted Tumor Starvation and Deoxygenation-Activated Chemotherapy without Systemic Toxicity
Nanoclustered Cascaded Enzymes for Targeted Tumor Starvation and Deoxygenation-Activated Chemotherapy without Systemic Toxicity
复制标题
用于靶向肿瘤饥饿和脱氧激活化疗且无全身毒性的纳米簇级联酶
DOI：
10.1021/acsnano.9b02466
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发表时间：
2019-08-01
期刊：
影响因子：
17.1
通讯作者：
Wang, Jun
中科院分区：
文献类型：
--
作者：
Ma, Yinchu;Zhao, Yangyang;Wang, Jun
肿瘤内葡萄糖消耗诱导的癌症饥饿是抗癌治疗的重要策略，但它往往受到全身毒性、非特异性和并行能量供应的适应性发展的限制。在这里，我们介绍了级联催化纳米医学的概念，通过结合靶向肿瘤饥饿和脱氧激活化疗，以降低全身毒性的有效癌症治疗。简言之，通过经由pH响应性聚合物共价交联葡萄糖氧化酶（GOx）和过氧化氢酶（CAT）来合成纳米簇级联酶。酶的释放可以首先由弱酸性肿瘤微环境触发，然后由随后产生的葡萄糖酸自我加速。一旦释放，GOx可以迅速耗尽肿瘤细胞中的葡萄糖和分子氧，而毒性副产物，即，过氧化氢（H2O2）可被过氧化氢酶（CAT）分解，用于肿瘤的定位和低毒性饥饿。此外，酶级联反应还产生了局部缺氧，氧消耗和还原酶激活的前药用于额外的化疗。目前的报告代表了一种有前途的组合方法，使用级联催化纳米医学，以达到同时选择性和效率的癌症治疗。
Intratumoral glucose depletion-induced cancer starvation represents an important strategy for anticancer therapy, but it is often limited by systemic toxicity, nonspecificity, and adaptive development of parallel energy supplies. Herein, we introduce a concept of cascaded catalytic nanomedicine by combining targeted tumor starvation and deoxygenation-activated chemotherapy for an efficient cancer treatment with reduced systemic toxicity. Briefly, nanoclustered cascaded enzymes were synthesized by covalently cross-linking glucose oxidase (GOx) and catalase (CAT) via a pH-responsive polymer. The release of the enzymes can be first triggered by the mildly acidic tumor microenvironment and then be self-accelerated by the subsequent generation of gluconic acid. Once released, GOx can rapidly deplete glucose and molecular oxygen in tumor cells while the toxic side product, i.e., H2O2, can be readily decomposed by CAT for site-specific and low-toxicity tumor starvation. Furthermore, the enzymatic cascades also created a local hypoxia with the oxygen consumption and reductase-activated prodrugs for an additional chemotherapy. The current report represents a promising combinatorial approach using cascaded catalytic nanomedicine to reach concurrent selectivity and efficiency of cancer therapeutics.