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Rational Design of an Amphiphilic Chlorambucil Prodrug Realizing Self-Assembled Micelles for Efficient Anticancer Therapy
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2018-02-07 00:00:00 , DOI: 10.1021/acsbiomaterials.7b00892 Xu Hu 1 , Ruiling Liu 1 , Di Zhang 1 , Jing Zhang 1 , Zhonghao Li 2 , Yuxia Luan 1
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2018-02-07 00:00:00 , DOI: 10.1021/acsbiomaterials.7b00892 Xu Hu 1 , Ruiling Liu 1 , Di Zhang 1 , Jing Zhang 1 , Zhonghao Li 2 , Yuxia Luan 1
Affiliation
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The application of anticancer drug chlorambucil (CLB) in chemotherapy is severely restricted by its insolubility, lability, and toxic side effects; therefore, it is challenging to realize a highly efficient anticancer therapy of chlorambucil. To solve the above drawbacks encountered by chlorambucil, herein we proposed an amphiphilic chlorambucil prodrug-based self-assembled micelle strategy to realize the highly efficient anticancer therapy of chlorambucil. 1,6-Hexanediamine hydrochloride (HDH) serving as the hydrophilic segment was covalently bound to hydrophobic CLB to prepare an amphiphilic prodrug CLB-HDH which could self-assemble into micelles in aqueous solution. These micelles can passively target tumor tissues via the enhanced permeability and retention (EPR) effect, leading to enhanced cellular internalization. Both the cytotoxicity assay in vitro and anticancer study in vivo confirmed the excellent therapeutic activity of CLB-HDH micelles in comparison with free chlorambucil. Moreover, the hemolysis examination and histological analysis demonstrated the designed CLB-HDH micelles are safe in drug delivery. Therefore, our designed amphiphilic prodrug CLB-HDH micelles bring new opportunity for chlorambucil clinical application to combat cancers.
中文翻译：
实现高效自体胶束的两亲氯丁酸前药的合理设计
抗癌药苯丁酸氮芥（CLB）在化学疗法中的应用受到其不溶性，不稳定性和毒性副作用的严重限制。因此，实现苯丁酸氮芥的高效抗癌治疗具有挑战性。为了解决苯丁酸氮芥遇到的上述缺点，在此我们提出了一种基于两亲性苯丁酸氮芥前药的自组装胶束策略，以实现苯丁酸氮芥的高效抗癌治疗。将作为亲水链段的1,6-己二胺盐酸盐（HDH）与疏水性CLB共价键合，制得可在水溶液中自组装成胶束的两亲性前药CLB-HDH。这些胶束可以通过增强的渗透性和保留（EPR）效果被动地靶向肿瘤组织，从而导致增强的细胞内在化。与游离苯丁酸氮芥相比，CLB-HDH胶束的体外细胞毒性测定和体内抗癌研究均证实其优异的治疗活性。此外，溶血检查和组织学分析表明，所设计的CLB-HDH胶束在药物输送中是安全的。因此，我们设计的两亲性前药CLB-HDH胶束为苯丁酸氮芥临床应用提供了新的机会来对抗癌症。
更新日期：2018-02-07
中文翻译：
实现高效自体胶束的两亲氯丁酸前药的合理设计
抗癌药苯丁酸氮芥（CLB）在化学疗法中的应用受到其不溶性，不稳定性和毒性副作用的严重限制。因此，实现苯丁酸氮芥的高效抗癌治疗具有挑战性。为了解决苯丁酸氮芥遇到的上述缺点，在此我们提出了一种基于两亲性苯丁酸氮芥前药的自组装胶束策略，以实现苯丁酸氮芥的高效抗癌治疗。将作为亲水链段的1,6-己二胺盐酸盐（HDH）与疏水性CLB共价键合，制得可在水溶液中自组装成胶束的两亲性前药CLB-HDH。这些胶束可以通过增强的渗透性和保留（EPR）效果被动地靶向肿瘤组织，从而导致增强的细胞内在化。与游离苯丁酸氮芥相比，CLB-HDH胶束的体外细胞毒性测定和体内抗癌研究均证实其优异的治疗活性。此外，溶血检查和组织学分析表明，所设计的CLB-HDH胶束在药物输送中是安全的。因此，我们设计的两亲性前药CLB-HDH胶束为苯丁酸氮芥临床应用提供了新的机会来对抗癌症。
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