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Glutathione-Responsive Prodrug Nanoparticles for Effective Drug Delivery and Cancer Therapy.
ACS Nano ( IF 15.8 ) Pub Date : 2018-12-04 , DOI: 10.1021/acsnano.8b06400 Xiang Ling 1 , Jiasheng Tu 2 , Junqing Wang 1 , Aram Shajii 1 , Na Kong 1, 3, 4 , Chan Feng 1 , Ye Zhang 1 , Mikyung Yu 1 , Tian Xie 3 , Zameer Bharwani 1 , Bader M Aljaeid 5 , Bingyang Shi 1 , Wei Tao 1 , Omid C Farokhzad 1
ACS Nano ( IF 15.8 ) Pub Date : 2018-12-04 , DOI: 10.1021/acsnano.8b06400 Xiang Ling 1 , Jiasheng Tu 2 , Junqing Wang 1 , Aram Shajii 1 , Na Kong 1, 3, 4 , Chan Feng 1 , Ye Zhang 1 , Mikyung Yu 1 , Tian Xie 3 , Zameer Bharwani 1 , Bader M Aljaeid 5 , Bingyang Shi 1 , Wei Tao 1 , Omid C Farokhzad 1
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Spurred by recent progress in medicinal chemistry, numerous lead compounds have sprung up in the past few years, although the majority are hindered by hydrophobicity, which greatly challenges druggability. In an effort to assess the potential of platinum (Pt) candidates, the nanosizing approach to alter the pharmacology of hydrophobic Pt(IV) prodrugs in discovery and development settings is described. The construction of a self-assembled nanoparticle (NP) platform, composed of amphiphilic lipid-polyethylene glycol (PEG) for effective delivery of Pt(IV) prodrugs capable of resisting thiol-mediated detoxification through a glutathione (GSH)-exhausting effect, offers a promising route to synergistically improving safety and efficacy. After a systematic screening, the optimized NPs (referred to as P6 NPs) exhibited small particle size (99.3 nm), high Pt loading (11.24%), reliable dynamic stability (∼7 days), and rapid redox-triggered release (∼80% in 3 days). Subsequent experiments on cells support the emergence of P6 NPs as a highly effective means of transporting a lethal dose of cargo across cytomembranes through macropinocytosis. Upon reduction by cytoplasmic reductants, particularly GSH, P6 NPs under disintegration released sufficient active Pt(II) metabolites, which covalently bound to target DNA and induced significant apoptosis. The PEGylation endowed P6 NPs with in vivo longevity and tumor specificity, which were essential to successfully inhibiting the growth of cisplatin-sensitive and -resistant xenograft tumors, while effectively alleviating toxic side-effects associated with cisplatin. P6 NPs are, therefore, promising for overcoming the bottleneck in the development of Pt drugs for oncotherapy.
中文翻译：
谷胱甘肽反应前药纳米颗粒可有效地递送药物和治疗癌症。
在药物化学的最新进展的推动下，过去几年中涌现出许多先导化合物，尽管大多数都受到疏水性的阻碍，而疏水性极大地挑战了可药物性。为了评估铂（Pt）候选物的潜力，描述了在发现和开发环境中改变疏水性Pt（IV）前药药理学的纳米化方法。由两亲脂质-聚乙二醇（PEG）组成的自组装纳米颗粒（NP）平台的构建，可有效递送能够通过谷胱甘肽（GSH）耗尽效应抵抗硫醇介导的解毒作用的Pt（IV）前药。协同改善安全性和功效的一种有前途的途径。经过系统筛选后，优化的NP（称为P6 NP）显示出较小的粒径（99.3 nm），高Pt负载量（11.24％），可靠的动态稳定性（〜7天）和快速的氧化还原触发释放（3天〜80％）。随后的细胞实验支持P6 NPs的出现，将其作为通过巨胞饮作用跨细胞膜运输致死剂量货物的高效手段。通过胞质还原剂，特别是谷胱甘肽还原，还原后的P6 NPs释放出足够的活性Pt（II）代谢产物，它们共价结合到靶DNA并诱导明显的细胞凋亡。PEG化赋予P6 NPs以体内寿命和肿瘤特异性，这对于成功抑制顺铂敏感和耐药的异种移植肿瘤的生长至关重要，同时有效减轻了与顺铂相关的毒性副作用。因此，P6 NP是
更新日期：2018-11-28
中文翻译：
谷胱甘肽反应前药纳米颗粒可有效地递送药物和治疗癌症。
在药物化学的最新进展的推动下，过去几年中涌现出许多先导化合物，尽管大多数都受到疏水性的阻碍，而疏水性极大地挑战了可药物性。为了评估铂（Pt）候选物的潜力，描述了在发现和开发环境中改变疏水性Pt（IV）前药药理学的纳米化方法。由两亲脂质-聚乙二醇（PEG）组成的自组装纳米颗粒（NP）平台的构建，可有效递送能够通过谷胱甘肽（GSH）耗尽效应抵抗硫醇介导的解毒作用的Pt（IV）前药。协同改善安全性和功效的一种有前途的途径。经过系统筛选后，优化的NP（称为P6 NP）显示出较小的粒径（99.3 nm），高Pt负载量（11.24％），可靠的动态稳定性（〜7天）和快速的氧化还原触发释放（3天〜80％）。随后的细胞实验支持P6 NPs的出现，将其作为通过巨胞饮作用跨细胞膜运输致死剂量货物的高效手段。通过胞质还原剂，特别是谷胱甘肽还原，还原后的P6 NPs释放出足够的活性Pt（II）代谢产物，它们共价结合到靶DNA并诱导明显的细胞凋亡。PEG化赋予P6 NPs以体内寿命和肿瘤特异性，这对于成功抑制顺铂敏感和耐药的异种移植肿瘤的生长至关重要，同时有效减轻了与顺铂相关的毒性副作用。因此，P6 NP是
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