CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, China.
Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China.
J Control Release. 2021 May 10;333:500-510. doi: 10.1016/j.jconrel.2021.04.007. Epub 2021 Apr 13.
Chemodynamic therapy (CDT) has been proposed to convert tumoral HO into toxic hydroxyl radicals (OH) via Fenton or Fenton-like reactions for antitumor efficacy, which is frequently limited by low HO concentrations or lack of enough metal ions inside tumor tissues. In this report, we present ferrocene-containing responsive polymersome nanoreactors via loading glucose oxidase (GOD) and hypoxia-activable prodrug tirapazamine (TPZ) in the inner aqueous cavities. After intravenous injection, the polymersome nanoreactors with the optimized nanoparticle size of ~100 nm and poly(ethylene glycol) corona facilitate tumor accumulation. The tumor acidic microenvironment can trigger the permeability of the polymersome membranes to activate the nanoreactors and release the loaded TPZ prodrugs. Tumor oxygen and glucose can enter the polymersome nanoreactors and are transformed into HO under the catalysis of GOD, which are further converted into OH via Fenton reaction under catalysis of ferrocene moieties. The oxygen consumption can aggravate tumor hypoxia to activate hypoxia-responsive TPZ prodrugs which can produce benzotriazinyl (BTZ) radicals and OH. All the produced radicals synergistically kill tumor cells via the amplified CDT and suppress the tumor growth efficiently. Thus, the ferrocene-containing responsive polymersome nanoreactors loading GOD and TPZ represent a potent nanoplatform to exert amplified CDT for improved anticancer efficacy.
化学动力学疗法 (CDT) 通过芬顿或类芬顿反应将肿瘤中的 HO 转化为有毒的羟基自由基 (OH) 以达到抗肿瘤的效果，但该方法常常受到肿瘤组织中 HO 浓度低或金属离子不足的限制。在本报告中，我们通过在内部水腔中装载葡萄糖氧化酶 (GOD) 和缺氧激活前药替拉扎明 (TPZ) ，制备了含有二茂铁的响应聚合物囊泡纳米反应器。经静脉注射后，具有优化的纳米颗粒尺寸 (~100nm) 和聚乙二醇冠的聚合物囊泡纳米反应器有助于肿瘤聚集。肿瘤酸性微环境可触发聚合物膜的通透性，以激活纳米反应器并释放负载的 TPZ 前药。肿瘤中的氧气和葡萄糖可以进入聚合物囊泡纳米反应器，在 GOD 的催化下转化为 HO，然后在二茂铁部分的催化下通过芬顿反应进一步转化为 OH。耗氧量会加剧肿瘤缺氧，从而激活缺氧反应性 TPZ 前药，产生苯并三嗪基 (BTZ) 自由基和 OH。所有产生的自由基通过放大的 CDT 协同杀死肿瘤细胞，并有效地抑制肿瘤生长。因此，负载 GOD 和 TPZ 的含二茂铁的响应聚合物囊泡纳米反应器代表了一种有效的纳米平台，可发挥放大的 CDT 作用，提高抗癌效果。
