Although chlorambucil (CHL) is a long-established anticancer drug, the drug failure of CHL, mediated by the intracellular defense system consisting of glutathione (GSH) and glutathione S-transferase pi (GST-pi), has significantly limited the application of CHL. To overcome this issue, we first designed a GSH-responsive small-molecule prodrug (EA-SS-CHL) by combining CHL and ethacrynic acid (EA). Subsequently, drug-loaded nanoparticles (ECPP) were formed by the self-assembly between EA-SS-CHL and amphiphilic PEG-PDLLA to improve the water solubility of the prodrug and its ability to target tumor sites. Upon exposure to high intracellular GSH concentration, EA-SS-CHL gradually degrades, leading to the release of EA and CHL. The presence of EA facilitates the depletion of GSH and inhibition of GST-pi, ultimately attenuating the detoxification of the intracellular defense system to CHL. Cytotoxicity studies and apoptosis assays demonstrate that ECPP exhibits higher therapeutic efficiency than CHL. Additionally, in vivo tumor suppression effects and biocompatibility provide further evidence for the superiority of ECPP. This work presents a promising strategy to enhance the efficacy of CHL in cancer therapy.
Imperatorin (IMP) has demonstrated potential in reversing drug resistance in various tumor cells; however, its limited clinical application and development are attributed to its poor water solubility and low bioavailability. The current work is intended to enhance the oral bioavailability of IMP and its efficacy in overcoming tamoxifen (TAM) resistance in breast cancer cells. We employed mPEG–PLLA and Cremophor RH60 (RH60) to prepare imperatorin nanomicelles (IMP-RH60/mPEG–PLLA). The freeze-dried powder of IMP-RH60/mPEG–PLLA demonstrated a porous structure, and upon reconstitution, the resulting solution exhibited clarity and transparency. The particle size was measured to be 25.48 ± 0.92 nm, with a zeta potential of −5.50 ± 1.06 mV. The encapsulation efficiency was determined to be 85.78 ± 0.84%, while the drug loading was found to be 2.66 ± 0.03%. In comparison to the active pharmaceutical ingredients (APIs) of IMP, IMP-RH60/mPEG–PLLA exhibited a significant increase in in vitro release, improved bioavailability in rats, and enhanced uptake by MCF-7/TAM cells. The coadministration of IMP-RH60/mPEG–PLLA and TAM effectively inhibited the proliferation, colony formation, migration, and invasion of MCF-7/TAM cells. This outcome could potentially be attributed to the downregulation of GST-π and MDR1 drug resistance genes, consequently augmenting the susceptibility of MCF-7/TAM cells to TAM. An experimental model of BALB/c nude xenograft, consisting of human breast cancer cells resistant to tamoxifen (TAM), was established in order to assess the potential in vivo reversal of TAM resistance through the use of IMP-RH60/mPEG–PLLA. The growth of xenografts was inhibited by IMP-RH60/mPEG–PLLA, and it induced apoptosis in tumor tissues through the downregulation of Ki-67, GST-π, and MDR1 gene expression. The findings indicated that the utilization of IMP-RH60/mPEG–PLLA micelles resulted in an enhancement of IMP’s bioavailability and its efficacy in overcoming TAM resistance.
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