Optimizing Multistep Delivery of PEGylated Tumor-Necrosis-Factor-Related Apoptosis-Inducing Ligand–Toxin Conjugates for Improved Antitumor Activities,Bioconjugate Chemistry

当前位置： X-MOL 学术 › Bioconjugate Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Optimizing Multistep Delivery of PEGylated Tumor-Necrosis-Factor-Related Apoptosis-Inducing Ligand–Toxin Conjugates for Improved Antitumor Activities
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-08-01 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00327
Xiaoyue Wei ₁ , Xiaoyue Yang ₁ , Wenbin Zhao ₁ , Yingchun Xu ₁ , Liqiang Pan ₁ , Shuqing Chen ₁

Affiliation

Although TRAIL (tumor-necrosis-factor (TNF)-related apoptosis-inducing ligand) has been considered a promising broad-spectrum antitumor agent, its further application was limited by poor drug delivery and TRAIL-resistant tumors. A three-step drug delivery strategy was applied to TRAIL for solving these two obstacles in the form of PEG-TRAIL-MMAE (Monomethyl Auristatin E). PEGylation of TRAIL in the first step was carried out to improve its in vivo pharmacokinetics, while the interaction between TRAIL conjugates with death receptors in the second step was designed to activate the TRAIL extrinsic apoptosis pathway, and the further release of MMAE from the lysosome was the third step for introducing another apoptosis pathway to overcome TRAIL resistance in some tumors. Herein, in order to reach a balance among the three steps, the PEG/MMAE ratio was optimized for PEG-TRAIL-MMAE conjugates. PEG-TRAIL-MMAE conjugates with various PEG/MMAE ratios were prepared and compared with each other regarding their pharmacokinetics (PK) and pharmacodynamics (PD). As a result, PEG-TRAIL-MMAE conjugates with a PEG/MMAE ratio of 1:2 showed prolonged half-life in rats (6.8 h), and the best antitumor activity in vitro (IC₅₀ 0.31 nM) and in vivo while no sign of toxicity in xenograft models, suggesting it as a promising multistep drug delivery and antitumor strategy after optimization.

中文翻译：

优化聚乙二醇化肿瘤坏死因子相关凋亡诱导配体-毒素结合的多步递送，以改善抗肿瘤活性

尽管TRAIL（与肿瘤坏死因子（TNF）相关的凋亡诱导配体）被认为是一种有前途的广谱抗肿瘤药，但其进一步的应用受到不良药物输送和TRAIL耐药性肿瘤的限制。TRAIL采用了三步给药策略，以解决PEG-TRAIL-MMAE（Monomethyl Auristatin E）形式的这两个障碍。第一步进行TRAIL的聚乙二醇化以改善其体内药代动力学，而第二步设计TRAIL缀合物与死亡受体之间的相互作用以激活TRAIL外源性细胞凋亡途径，并进一步从溶酶体中释放MMAE。第三步是引入另一种凋亡途径来克服某些肿瘤对TRAIL的抗性。在此，为了在三个步骤之间取得平衡，PEG / MMAE比例针对PEG-TRAIL-MMAE共轭物进行了优化。制备了具有各种PEG / MMAE比的PEG-TRAIL-MMAE共轭物，并就其药代动力学（PK）和药效学（PD）进行了比较。结果，PEG / MMAE比为1：2的PEG-TRAIL-MMAE缀合物在大鼠（6.8 h）中显示出延长的半衰期，并且在体外具有最佳的抗肿瘤活性（IC₅₀ 0.31 nM）和体内，而在异种移植模型中无毒性迹象，表明它是经过优化的有希望的多步药物递送和抗肿瘤策略。

更新日期：2017-08-02

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11