Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 169, Issue -, Pages 53-64Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.02.065
Keywords
Photodynamic therapy; Targeted therapy; Multidrug resistance; Glutathione depletion; Reactive oxygen species
Categories
Funding
- National Natural Science Foundation of China [81673369, 81703335]
- Natural Science Foundation of Guangdong [2017A030313069]
- Guangdong Medical Research Foundation [A2017114]
- Fundamental Research Funds for the Central Universities [18ykpy25]
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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-C-8-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-C-8-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 PEG(2000)-PLA(2000) encapsulation, ZnPc-C-8-Len NPs displayed significantly enhanced tumor accumulation and excellent in vivo antitumor activity. And the fluorescence characteristics of ZnPc-C-8-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-C-8-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. (C) 2019 Elsevier Masson SAS. All rights reserved.
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