Lenvatinib-zinc phthalocyanine conjugates as potential agents for enhancing synergistic therapy of multidrug-resistant cancer by glutathione depletion

Abstract

The therapeutic efficacy of targeted therapy is dramatically hindered by multidrug resistance (MDR) because of elevated GSH levels. Thus, depletion of intracellular GSH level is highly desirable for targeted-therapeutic agents to reverse tumor drug resistance. In this study, a photosensitive multifunctional conjugate ZnPc-C₈-Len, in which lenvatinib (a VEGFR inhibitor) is linked to a photosensitizer ZnPc through an alkyl chains, was synthesized to realize photodynamic therapy to reverse multidrug resistance and enhanced antitumor therapy. Upon the irradiation, ZnPc-C₈-Len could generate ROS to deplete intracellular GSH. The decreased GSH would enhance apoptotic cell death by Bcl-2/caspase 3 pathway and reduce expression of P-gp to reverse lenvatinib resistance. Moreover, through PEG₂₀₀₀-PLA₂₀₀₀ encapsulation, ZnPc-C₈-Len NPs displayed significantly enhanced tumor accumulation and excellent in vivo antitumor activity. And the fluorescence characteristics of ZnPc-C₈-Len could monitor the changes of nanoparticles in vivo in real time to guide when and where to conduct the subsequent therapy. As a result, conjugate ZnPc-C₈-Len had an outstanding capability to enhance synergistic therapy of multidrug-resistant cancer by glutathione depletion. And the approach reported here provide a promising strategy in development of conjugate integrated targeted therapy with photodynamic therapy to reverse targeted drug multidrug resistance and enhance synergistic therapy.

Keywords: Glutathione depletion; Multidrug resistance; Photodynamic therapy; Reactive oxygen species; Targeted therapy.