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Glutathione-Scavenging Poly(disulfide amide) Nanoparticles for the Effective Delivery of Pt(IV) Prodrugs and Reversal of Cisplatin Resistance
Nano Letters ( IF 9.6 ) Pub Date : 2018-06-14 00:00:00 , DOI: 10.1021/acs.nanolett.8b01924 Xiang Ling 1 , Xing Chen 2 , Imogen A Riddell 3 , Wei Tao 1 , Junqing Wang 1 , Geoffrey Hollett 1 , Stephen J Lippard 3 , Omid C Farokhzad 1 , Jinjun Shi 1 , Jun Wu 2
Nano Letters ( IF 9.6 ) Pub Date : 2018-06-14 00:00:00 , DOI: 10.1021/acs.nanolett.8b01924 Xiang Ling 1 , Xing Chen 2 , Imogen A Riddell 3 , Wei Tao 1 , Junqing Wang 1 , Geoffrey Hollett 1 , Stephen J Lippard 3 , Omid C Farokhzad 1 , Jinjun Shi 1 , Jun Wu 2
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Despite the broad antitumor spectrum of cisplatin, its therapeutic efficacy in cancer treatment is compromised by the development of drug resistance in tumor cells and systemic side effects. A close correlation has been drawn between cisplatin resistance in tumor cells and increased levels of intracellular thiol-containing species, especially glutathione (GSH). The construction of a unique nanoparticle (NP) platform composed of poly(disulfide amide) polymers with a high disulfide density for the effective delivery of Pt(IV) prodrugs capable of reversing cisplatin resistance through the disulfide-group-based GSH-scavenging process, as described herein, is a promising route by which to overcome limitations associated with tumor resistance. Following systematic screening, the optimized NPs (referred to as CP5 NPs) showed a small particle size (76.2 nm), high loading of Pt(IV) prodrugs (15.50% Pt), a sharp response to GSH, the rapid release of platinum (Pt) ions, and notable apoptosis of cisplatin-resistant A2780cis cells. CP5 NPs also exhibited long blood circulation and high tumor accumulation after intravenous injection. Moreover, in vivo efficacy and safety results showed that CP5 NPs effectively inhibited the growth of cisplatin-resistant xenograft tumors with an inhibition rate of 83.32% while alleviating serious side effects associated with cisplatin. The GSH-scavenging nanoplatform is therefore a promising route by which to enhance the therapeutic index of Pt drugs used currently in cancer treatment.
中文翻译：
谷胱甘肽清除聚二硫酰胺纳米颗粒可有效递送 Pt(IV) 前药并逆转顺铂耐药性
尽管顺铂具有广泛的抗肿瘤谱，但其在癌症治疗中的疗效因肿瘤细胞耐药性的发展和全身副作用而受到损害。肿瘤细胞中的顺铂耐药性与细胞内含硫醇物质（尤其是谷胱甘肽 (GSH)）水平升高之间存在密切相关性。构建了由具有高二硫键密度的聚（二硫酰胺）聚合物组成的独特纳米颗粒（NP）平台，用于有效递送 Pt（IV）前药，能够通过基于二硫键的 GSH 清除过程逆转顺铂耐药性，如本文所述，这是克服与肿瘤抗性相关的限制的有前途的途径。经过系统筛选，优化后的纳米颗粒（简称 CP 5纳米颗粒）表现出粒径小（76.2 nm）、Pt(IV)前药负载量高（15.50% Pt）、对 GSH 响应灵敏、铂快速释放等特点。 (Pt) 离子，以及顺铂耐药 A2780cis 细胞的显着凋亡。 CP 5 NPs 静脉注射后还表现出较长的血液循环和较高的肿瘤积累。此外，体内疗效和安全性结果表明，CP 5 NPs能有效抑制顺铂耐药异种移植肿瘤的生长，抑制率为83.32%，同时减轻顺铂相关的严重副作用。因此，GSH 清除纳米平台是提高目前用于癌症治疗的 Pt 药物治疗指数的一条有前途的途径。
更新日期：2018-06-14
中文翻译：
谷胱甘肽清除聚二硫酰胺纳米颗粒可有效递送 Pt(IV) 前药并逆转顺铂耐药性
尽管顺铂具有广泛的抗肿瘤谱，但其在癌症治疗中的疗效因肿瘤细胞耐药性的发展和全身副作用而受到损害。肿瘤细胞中的顺铂耐药性与细胞内含硫醇物质（尤其是谷胱甘肽 (GSH)）水平升高之间存在密切相关性。构建了由具有高二硫键密度的聚（二硫酰胺）聚合物组成的独特纳米颗粒（NP）平台，用于有效递送 Pt（IV）前药，能够通过基于二硫键的 GSH 清除过程逆转顺铂耐药性，如本文所述，这是克服与肿瘤抗性相关的限制的有前途的途径。经过系统筛选，优化后的纳米颗粒（简称 CP 5纳米颗粒）表现出粒径小（76.2 nm）、Pt(IV)前药负载量高（15.50% Pt）、对 GSH 响应灵敏、铂快速释放等特点。 (Pt) 离子，以及顺铂耐药 A2780cis 细胞的显着凋亡。 CP 5 NPs 静脉注射后还表现出较长的血液循环和较高的肿瘤积累。此外，体内疗效和安全性结果表明，CP 5 NPs能有效抑制顺铂耐药异种移植肿瘤的生长，抑制率为83.32%，同时减轻顺铂相关的严重副作用。因此，GSH 清除纳米平台是提高目前用于癌症治疗的 Pt 药物治疗指数的一条有前途的途径。
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