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Nanoscale Copper(II)-Diethyldithiocarbamate Coordination Polymer as a Drug Self-Delivery System for Highly Robust and Specific Cancer Therapy.
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2020-06-18 , DOI: 10.1021/acs.molpharmaceut.0c00284 Ying Peng 1 , Peng Liu 1 , Yingcai Meng 1 , Shuo Hu 2, 3 , Jinsong Ding 1 , Wenhu Zhou 1, 2, 3
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2020-06-18 , DOI: 10.1021/acs.molpharmaceut.0c00284 Ying Peng 1 , Peng Liu 1 , Yingcai Meng 1 , Shuo Hu 2, 3 , Jinsong Ding 1 , Wenhu Zhou 1, 2, 3
Affiliation
Disulfiram (DSF), an old alcohol-aversion drug, has been repurposed for cancer therapy, and mechanistic studies reveal that it needs to be metabolized to diethyldithiocarbamate (DTC) and subsequently coordinates with copper(II) to form the DTC–copper complex (CuET) for anticancer activation. Here, we utilized this mechanism to construct a CuET self-delivery nanosystem based on the metal coordination polymer for highly robust and selective cancer therapy. In our design, the nanoparticles were facilely prepared under mild conditions by virtue of the strong coordination between Cu2+ and DTC, yielding 100% CuET loading capacity and allowing for further hyaluronic acid (HA) modification (CuET@HA NPs). The CuET@HA NPs could selectively deliver into cancer cells and release the active component of CuET in response to both endo/lysosome acidic pH and intracellular abundant GSH, which induces strong cytotoxicity toward cancer cells over normal cells taking advantage of the p97 pathway interference mechanism. Upon intravenous injection, the self-assembled system could passively accumulate into a tumor and elicit potent tumor growth inhibition at a dose of 1 mg/kg without any noticeable side effects. Given the cost-effective and easily scaled-up preparation, our designed nanosystem provides a promising strategy to pave the way for clinical translation of DSF-based cancer chemotherapy.
中文翻译:
纳米级铜(II)-二乙基二硫代氨基甲酸酯配合物聚合物,用于高度健壮和特异的癌症治疗,是一种药物自我传递系统。
双硫仑(DSF)是一种避免酒精的老药,已被重新用于癌症治疗,机理研究表明,它需要先代谢为二乙基二硫代氨基甲酸酯(DTC),然后与铜(II)配合形成DTC-铜络合物( CuET)用于抗癌激活。在这里,我们利用这种机制构建了基于金属配位聚合物的CuET自递送纳米系统,用于高度健壮和选择性的癌症治疗。在我们的设计中,由于Cu 2+之间的强配位,可以在温和条件下轻松制备纳米颗粒和DTC,可产生100%的CuET负载量,并允许进一步修饰透明质酸(HA)(CuET @ HA NP)。CuET @ HA NPs可以选择性地传递到癌细胞中并释放CuET的活性成分,以响应内/溶酶体酸性pH和细胞内丰富的GSH,从而利用p97途径干扰机制对癌细胞产生比普通细胞更强的细胞毒性。静脉注射后,自组装系统可以被动积累到肿瘤中,并以1 mg / kg的剂量引起有效的肿瘤生长抑制作用,而没有任何明显的副作用。考虑到具有成本效益且易于扩展的制备方法,我们设计的纳米系统提供了一种有前途的策略,为基于DSF的癌症化学疗法的临床翻译铺平了道路。
更新日期:2020-06-18
中文翻译:
纳米级铜(II)-二乙基二硫代氨基甲酸酯配合物聚合物,用于高度健壮和特异的癌症治疗,是一种药物自我传递系统。
双硫仑(DSF)是一种避免酒精的老药,已被重新用于癌症治疗,机理研究表明,它需要先代谢为二乙基二硫代氨基甲酸酯(DTC),然后与铜(II)配合形成DTC-铜络合物( CuET)用于抗癌激活。在这里,我们利用这种机制构建了基于金属配位聚合物的CuET自递送纳米系统,用于高度健壮和选择性的癌症治疗。在我们的设计中,由于Cu 2+之间的强配位,可以在温和条件下轻松制备纳米颗粒和DTC,可产生100%的CuET负载量,并允许进一步修饰透明质酸(HA)(CuET @ HA NP)。CuET @ HA NPs可以选择性地传递到癌细胞中并释放CuET的活性成分,以响应内/溶酶体酸性pH和细胞内丰富的GSH,从而利用p97途径干扰机制对癌细胞产生比普通细胞更强的细胞毒性。静脉注射后,自组装系统可以被动积累到肿瘤中,并以1 mg / kg的剂量引起有效的肿瘤生长抑制作用,而没有任何明显的副作用。考虑到具有成本效益且易于扩展的制备方法,我们设计的纳米系统提供了一种有前途的策略,为基于DSF的癌症化学疗法的临床翻译铺平了道路。