pH-responsive ZIF-8 nanoplatform co-loaded with DSF and ICG for multiple synergistic antitumor therapy

Disulfiram (Allensworth et al.), an "old drug" for the treatment of chronic alcohol dependence, has received extensive attention due to its potential antitumor activity for new medical applications. However, the application of DSF in cancer therapy was limited by its extremely terrible solubility in water. Meanwhile, Cu²⁺ was used to enhance the antitumor activity of DSF in most of the current studies, while few studies related to the combination of Zn²⁺ and DSF. Herein, we developed a pH-responsive hyaluronic acid/polyethylene glycol-graft-polyglutamic acid (HPG) modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticle system (ID@ZIF-8@HPG) to achieve the co-delivery of Zn²⁺/indocyanine green (ICG)/DSF and the improvement of the solubility of DSF, which conducted an efficient anticancer effectiveness through its chemotherapy/photothermal/photodynamic multiple synergistic antitumor effects. The obtained ID@ZIF-8@HPG demonstrated acid-sensitive and photothermal-sensitive release behavior, which contributed to the release of DSF from nanoparticles within tumor cells upon laser irradiation of the tumor site and was beneficial to reduce the toxicity produced by chemotherapy. In vitro experiments demonstrated that ID@ZIF-8@HPG could be better taken up by tumor cells, resulting in excellent photothermal and photodynamic properties. In addition, ID@ZIF-8@HPG exhibited outstanding intratumor retention capacity and powerful tumor cell-killing ability while maintaining favorable biocompatibility. In summary, this study presents a promising nanoparticle delivery platform for cancer treatment, broadening the application of ZIF-8 in the field of tumor combination therapy.