RESUMEN
The traditional nanocarriers are typically constructed to deliver anticancer agents for improving drug bioavailability and enhancing chemotherapeutic efficacy, but this strategy suffers from the critical issue of nanocarrier biosafety that hinders further clinical translation. In this work, a unique nanomedicine (PTX@ICG) has been rationally constructed by combining two clinically approved agents, i.e., paclitaxel (PTX) and indocyanine green (ICG), by a facile ultrasound-assisted self-assembly methodology. The formation of the nanostructure can effectively increase the enrichment of PTX and ICG molecules in the tumor site, and improve the utilization factor of hydrophobic PTX. Moreover, since the molecule interaction in PTX@ICG is mainly Van der Waals forces, the self-assembled structure can be spontaneously dissociated under laser irradiation and release PTX in situ to achieve safe tumor-targeted chemotherapy. Simultaneously, the released ICG can act as photothermic agents for photothermal therapy (PTT), thus combining chemotherapy and PTT to obtain an enhanced tumor nanotherapy via facile self-assembly. The synergistic chemo/photothermal tumor nanotherapy achieved the efficient tumor cell-killing effect and tumor-ablation ability, as systematically demonstrated both in vitro and in vivo. This work provides a distinct paradigm of the self-assembled nanomedicine design for effectively improving the drug bioavailability to achieve high antitumor efficacy.
RESUMEN
Ferroptosis and autophagy, playing significant roles in tumor treatment, are two typical forms of the programmed cell death. However, the rational combination of ferroptosis and autophagy for synergistic tumor therapy is still highly challenging. Herein, we report on an intriguing nanomedicine strategy for achieving autophagy-enhanced ferroptosis on efficiently combating cancer, which was based on the construction of trehalose-loaded mSiO2@MnOx-mPEG (TreMMM) nanoparticles with satisfactory biocompatibility. The nanoparticles are endowed with high glutathione (GSH) consumption efficiency, thereby inducing cancer-cell ferroptosis via inactivating glutathione peroxidases 4 (GPX4). Subsequently, the TreMMM degradation due to the GSH depletion and pH sensitivity contributed to the trehalose release for inducing autophagy, promoting/enhancing ferroptosis by NCOA4-mediated degradation of ferritin. A substantial in vitro and in vivo antitumor effect was achieved by such an intriguing autophagy-enhanced ferroptosis. Therefore, the rational combination of GSH-consumption-induced ferroptosis and trehalose-induced autophagy by nanomedicine design provides an alternative but effective strategy for tumor treatment.
RESUMEN
The antitumor activity of disulfiram (DSF), a traditional US Food and Drug Administration-approved drug for the treatment of "alcohol-dependence", is Cu2+-dependent, but the intrinsic anfractuous biodistribution of copper in the human body and copper toxicity induced by exogenous copper supply have severely hindered its in vivo application. Herein, we report an in situ Cu2+ chelation-enhanced DSF-based cancer chemotherapy technique, using a tumor-specific "nontoxicity-to-toxicity" transition strategy based on hollow mesoporous silica nanoparticles as the functional carrier. Cu2+-doped, DSF-loaded hollow mesoporous silica nanoparticles were constructed for the rapid release of Cu2+ ions induced by the mild acidic conditions of the tumor microenvironment. This resulted in the rapid biodegradation of the nanoparticles and accelerated DSF release once the particles were endocytosed into tumor cells. The resulting in situ chelation reaction between the coreleased Cu2+ ions and DSF generated toxic CuET products and concurrently, Fenton-like reactions between the generated Cu+ ions and the high levels of H2O2 resulted in the production of reactive oxygen species (ROS) in the acidic tumor microenvironment. Both in vitro cellular assays and in vivo tumor-xenograft experiments demonstrated the efficient Cu-enhanced and tumor-specific chemotherapeutic efficacy of DSF, with cocontributions from highly toxic CuET complexes and ROS generated within tumors. This work provides a conceptual advancement of nanoparticle-enabled "nontoxicity-to-toxicity" transformation in tumors, to achieving high chemotherapeutic efficacy and biosafety.
