Rational Design of an Amphiphilic Chlorambucil Prodrug Realizing Self-Assembled Micelles for Efficient Anticancer Therapy

Abstract

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.

Supramolecular Hydrogel Based on Chlorambucil and Peptide Drug for Cancer Combination Therapy

“…Chlorambucil (CRB) is a Food Drug and Administration-approved DNA-alkylating anticancer agent that has been widely used for treating various cancers. − However, the clinical development of CRB is severely impeded because of its low aqueous solubility, short degradation half-life in plasma, and serious toxicity to normal tissues . The bioactive tyroservatide (YSV) tripeptide composed of l -tyrosine, l -serine, and l -valine has been proved to exhibit antitumor effects against liver carcinoma and lung carcinoma. − Nevertheless, YSV is easily degraded by digestion enzymes in vivo, which greatly restricts its clinical application. , Fortunately, self-assembling peptide-based supramolecular hydrogels could act as a suitable nanocarrier to improve the biostability and bioavailability of CRB and YSV, achieving enhanced anticancer activity with reduced drug side effects.…”

In situ misemgel as a multifunctional dual-absorption platform for nasal delivery of raloxifene hydrochloride: formulation, characterization, and in vivo performance

“…14,15 In addition, micelles have shown great potential as carriers of anticancer therapeutics. [15][16][17] Recently, an aqueous-soluble form of natural vitamin E, known as d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), has gained attention as a promising pharmaceutical excipient for developing amphiphilic micelles (alone or mixed with other biomaterials) and are capable of encapsulating hydrophobic drugs. 18,19 Nasal drug administration has attracted considerable attention in the field of drug delivery due to the distinct advantages that it can offer.…”

Redox-Responsive Heparin–Chlorambucil Conjugate Polymeric Prodrug for Improved Anti-Tumor Activity

“…However, the cumulative release of Chl in the redox stimuli in PBS containing 6 mM GSH and 0.1% H 2 O 2 was found to be faster, and 75% and 85% of Chl was released, respectively, within 72 h. Both bioactive drugs, Hep and Chl, were covalently linked to each other by disulfide bonds, which could be cleaved to activate Hep and Chl through a reducing agent GSH and an oxidizing agent H 2 O 2 [36][37][38]. Overall, this stimuli-responsive prodrug-based delivery system could facilitate the accumulation of drugs in tumor tissues and improve cancer therapeutic efficacy [14]. serum albumin (HSA) was examined.…”

“…Chlorambucil (Chl) is an aryl nitrogen mustard-based DNA-alkylating anti-cancer drug that has been widely applied for different types of cancer diseases. Chlorambucil's mechanism of action in cancer cells is binding its two reactive chloroethyl side chains with the nucleobases adenine and guanine at N3 and N7 that halt DNA replication and DNA damage through DNA strand linking [13][14][15]. Chlorambucil has a low water solubility, short half-life due to rapid degradation in the plasma, and serious toxicity to normal tissues, which are potential limitations in its clinical applications [16,17].…”