Enhancing metformin-induced tumor metabolism destruction by glucose oxidase for triple-combination therapy
Enhancing metformin-induced tumor metabolism destruction by glucose oxidase for triple-combination therapy
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DOI：
10.1016/j.jpha.2023.09.015
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发表时间：
2024-04-01
影响因子：
8.8
通讯作者：
Xu，Jianguo
中科院分区：
文献类型：
--
作者：
Fan，Rangrang;Cai，Linrui;Xu，Jianguo
尽管经过数十年的实验室和临床试验，乳腺癌仍然是女性癌症相关疾病负担的主要原因。考虑到二甲双胍（Metformin，Met）的代谢破坏作用和葡萄糖氧化酶（glucose oxidase，GOx）诱导的癌细胞饥饿效应，GOx和Met在有效递送至肿瘤部位后，可能会消耗大量的葡萄糖并在原位产生足够的过氧化氢。在此，构建了pH响应性表没食子儿茶素没食子酸酯（EGCG）缀合的低分子量壳聚糖（LC-EGCG，LE）纳米颗粒（Met-GOx/Fe@LE NPs）。铁离子（Fe 3+）与EGCG在该纳米平台中的配位可以通过芬顿反应增强化学动力学治疗的功效。Met-GOx/Fe@LE NP允许GOx保留其酶活性，同时提高其稳定性。此外，这种pH响应性纳米平台呈现可控的药物释放行为。体内生物分布研究表明，由该纳米平台递送的GOx的颅内蓄积是游离药物的3.6倍。体内抗肿瘤实验结果表明，这种代谢破坏/饥饿/化学动力学三联疗法可诱导肿瘤细胞凋亡/死亡增加，抑制其增殖。这种三联疗法有望用于有效和靶向的癌症治疗。
Despite decades of laboratory and clinical trials, breast cancer remains the main cause of cancer-related disease burden in women. Considering the metabolism destruction effect of metformin (Met) and cancer cell starvation induced by glucose oxidase (GOx), after their efficient delivery to tumor sites, GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxidein situ. Herein, a pH-responsive epigallocatechin gallate (EGCG)-conjugated low-molecular-weight chitosan (LC-EGCG, LE) nanoparticle (Met–GOx/Fe@LE NPs) was constructed. The coordination between iron ions (Fe3+) and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction. Met–GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability. Moreover, this pH-responsive nanoplatform presents controllable drug release behavior. Anin vivobiodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug. Thein vivoanticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation. This triple-combination therapy approach is promising for efficient and targeted cancer treatment.