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.
Wei Zhang,Wenjun Zhu,Ruiyu He,Shuo Fang,Yemin Zhang,Chen Yao,Muhammad Ismail,Xinsong Li
Chlorambucil is a classic nitrogen mustard drug that has been used in the treatment of cancers. It may induce neutropenia, thrombocytopenia and other side effects because of its short lifetime and off-target effect. In this report, chlorambucil-tetrapeptide (AAAK, A 3 K) conjugate vesicles were developed to improve the stability and bioactivity of chlorambucil. First of all, chlorambucil-A 3 K conjugate was synthesized by solid phase synthesis strategy. Secondly, the chlorambucil-A 3 K conjugate was assembled and characterized by critical aggregation concentration, circular dichroism, dynamic light scattering and transmission electron microscopy. The results indicated that the chlorambucil-A 3 K conjugate can be assembled to form spherical vesicles with an average diameter of 390.5 nm, and high drug loading about 47.1% is reached. Surprisingly, the preliminary biological evaluation of the chlorambucil-A 3 K conjugate vesicles revealed the best in vitro anticancer activity against HeLa, HepG-2 and MCF-7 cell lines compared with chlorambucil and chlorambucil-A 3 K conjugate free drugs. Furthermore, conjugate vesicles showed excellent in vivo antitumoral activity. It can be partly attributed to their vesicular structure which isolates chlorambucil active moiety from aqueous solution to retard degradation before killing cancer cells. Therefore, chlorambucil-peptide (A 3 K) conjugate vesicles may be an alternative delivery system of chlorambucil.
危险品化学品经营许可证（带存储）