Intelligent Nanomedicine Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine , University of Science and Technology of China , Hefei , Anhui 230001 , China.
Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences , University of Science and Technology of China , Hefei 230027 , China.
ACS Nano. 2019 Aug 27;13(8):8890-8902. doi: 10.1021/acsnano.9b02466. Epub 2019 Jul 15.
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) 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, , HO, 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.
肿瘤内葡萄糖耗竭诱导的肿瘤饥饿是一种重要的抗癌治疗策略，但它常常受到全身毒性、非特异性和并行能量供应的适应性发展的限制。在这里，我们通过结合靶向肿瘤饥饿和乏氧激活化疗，引入级联催化纳米医学的概念，以实现降低全身毒性的高效癌症治疗。简而言之，通过共价交联葡萄糖氧化酶 (GOx) 和过氧化氢酶 (CAT) 到 pH 响应性聚合物上来合成纳米簇级联酶。在随后产生的葡萄糖酸的作用下，酶的释放可以首先被轻度酸性的肿瘤微环境触发，然后被自我加速。一旦释放，GOx 可以迅速耗尽肿瘤细胞中的葡萄糖和分子氧，而有毒的副产物 ，HO ，可以很容易地被 CAT 分解，用于肿瘤特异性和低毒性的肿瘤饥饿。此外，酶级联反应还产生了局部缺氧，消耗氧气并激活还原酶激活的前药，以进行额外的化疗。本报告代表了一种使用级联催化纳米医学的有前途的联合方法，以达到癌症治疗的同步选择性和效率。
