4.8 Article

Reactive oxygen species-activated self-amplifying prodrug nanoagent for tumor-specific Cu-chelate chemotherapy and cascaded photodynamic therapy

期刊

BIOMATERIALS
卷 284, 期 -, 页码 -

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2022.121513

关键词

Reactive oxygen species; Disulfiram; ROS-Responsiveness; Self-amplifying; Photodynamic therapy; Tumor-specific therapy

资金

  1. National Natural Science Foundation of China [81973256/H3008, 82173748/H3408]

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In this study, a reactive oxygen species-activatable self-amplifying prodrug nanoagent was developed for the tumor-specific dual-activation of chemotherapy and photodynamic therapy. The results showed a significant tumor-killing effect with little systemic toxicity.
Disulfiram (DSF), an effective FDA-approved anti-alcoholism drug, shows potent antitumor activity by producing Cu(DTC)(2), a chelate of its metabolite diethyldithiocarbamate (DTC) and copper. However, the rapid metabolism and unselective distribution of DSF and the insufficient endogenous copper severely restrict enough bioactive Cu (DTC)(2) generation in tumor tissues to achieve satisfactory antitumor effect. Moreover, directly Cu(DTC)(2) administration also suffers from serious systemic toxicity. Herein, a reactive oxygen species (ROS)-activatable self-amplifying prodrug nanoagent (HA-DQ@MOF) was developed for the stable co-delivery of DTC prodrug and Cu-quenched photosensitizer, aiming to achieve tumor-specific dual-activation of highly-toxic Cu(DTC)(2)-medi-ated chemotherapy and cascaded photodynamic therapy (PDT). The ROS-cleavable hyaluronic acid-conjugated DTC prodrug (HA-DQ) was decorated on Cu2+ and photosensitizer Zn-TCPP coordinated MOF (PDT-shielded state) to construct HA-DQ@MOF. HA-DQ@MOF could specifically activated in ROS-overexpressed tumor cells to rapidly release DTC, while remaining relatively stable in normal cells. The free DTC immediately grabbed Cu2+ from MOF to in situ generate highly-cytotoxic Cu(DTC)(2) chelate, accompanied by MOF dissociation to restore the PDT effect of Zn-TCPP. Importantly, ROS produced by PDT could in turn trigger more DTC release, which further promoted Zn-TCPP liberation, forming a self-amplifying prodrug/photosensitizer activation positive feedback loop. Experimental results confirmed the dual-activated and combined tumor-killing effect of Cu(DTC)(2)-medi-ated chemotherapy and Zn-TCPP-based PDT with little systemic toxicity. This work provides a dual-activated low toxic-to-toxic transformable treatment pattern for tumor-specific chemo-photodynamic therapy.

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