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

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

Eur J Med Chem. 2019 Mar 04;169:53-64

Authors: Wei G, Huang L, Jiang Y, Shen Y, Huang Z, Huang Y, Sun X, Zhao C

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.

PMID: 30856406 [PubMed - as supplied by publisher]