Tumor microenvironment-responsive artesunate loaded Z-scheme heterostructures for synergistic photo-chemodynamic therapy of hypoxic tumor.

Tumor microenvironment (TME) with the particular features of severe hypoxia, insufficient endogenous H2O2, and overexpression of glutathione (GSH) markedly reduced the antitumor efficacy of monotherapy. Herein, a TME-responsive multifunctional nanoplatform (Bi2S3@Bi@PDA-HA/Art NRs) was presented for synergistic photothermal therapy (PTT), chemodynamic therapy (CDT), and photodynamic therapy (PDT) to achieve better therapeutic outcomes. The Z-scheme heterostructured bismuth sulfide@bismuth nanorods (Bi2S3@Bi NRs) guaranteed excellent photothermal performance of the nanoplatform. Moreover, its ability to produce O2 and reactive oxygen species (ROS) synchronously could relieve tumor hypoxia and improve PDT outcomes. The densely coated polydopamine/ammonium bicarbonate (PDA/ABC) and hyaluronic acid (HA) layers on the surface of the nanoplatform enhanced the cancer-targeting capacity and induced the acidic TME-triggered in situ "bomb-like" release of Art. The CDT treatment was achieved by activating the released Art through intracellular Fe2+ ions in an H2O2-independent manner. Furthermore, decreasing the glutathione peroxidase 4 (GPX4) levels by Art could also increase the PDT efficiency of Bi2S3@Bi NRs. Owing to the synergistic effect, this nanoplatform displayed improved antitumor efficacy with minimal toxicity both in vitro and in vivo. Our design sheds light on the application of phototherapy combined with the traditional Chinese medicine monomer-artesunate in treating the hypoxic tumor.

Mitochondria-targeting multifunctional nanoplatform for cascade phototherapy and hypoxia-activated chemotherapy.

Despite considerable progress has been achieved in hypoxia-associated anti-tumor therapy, the efficacy of utilizing hypoxia-activated prodrugs alone is not satisfied owing to the inadequate hypoxia within the tumor regions. In this work, a mitochondrial targeted nanoplatform integrating photodynamic therapy, photothermal therapy and hypoxia-activated chemotherapy has been developed to synergistically treat cancer and maximize the therapeutic window. Polydopamine coated hollow copper sulfide nanoparticles were used as the photothermal nanoagents and thermosensitive drug carriers for loading the hypoxia-activated prodrug, TH302, in our study. Chlorin e6 (Ce6) and triphenyl phosphonium (TPP) were conjugated onto the surface of the nanoplatform. Under the action of TPP, the obtained nanoplatform preferentially accumulated in mitochondria to restore the drug activity and avoid drug resistance. Using 660 nm laser to excite Ce6 can generate ROS and simultaneously exacerbate the cellular hypoxia. While under the irradiation of 808 nm laser, the nanoplatform produced local heat which can increase the release of TH302 in tumor cells, ablate cancer cells as well as intensify the tumor hypoxia levels. The aggravated tumor hypoxia then significantly boosted the anti-tumor efficiency of TH302. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional hypoxia-associated chemotherapy. This work highlights the potential of using a combination of hypoxia-activated prodrugs plus phototherapy for synergistic cancer treatment.

Ion channel-targeting near-infrared photothermal switch with synergistic effect for specific cancer therapy.

Despite significant achievement in chemotherapy, the off-target actions and low pharmaceutical selectivity of the therapeutic agents still limit their clinical efficacy. Herein, a multifunctional nanoplatform which integrates chemotherapy, chemodynamic therapy (CDT) and photoactivation of TRPV1 channels has been successfully established for specific cancer therapy. Polydopamine (PDA) coated hollow prussian blue nanocages (hPBNCs) are used as the photothermal switches and drug carriers for loading chemotherapeutic drug, doxorubicin (Dox). Conjugating with the TRPV1 antibodies enables the nanoplatform to bind specifically to TRPV1 channels on the plasma membrane of the TRPV1-positive cancer cells and then activate them by local heating upon NIR irradiation, leading to the over-influx of Ca2+. Critically, the laser irradiation can be carefully controlled to not only open the TRPV1 channels but also avoid burning of tumors by hyperthermia. Moreover, the exposed hPBNCs in the acidic tumor cells can decompose endogenous H2O2 into ˙OH by Fenton reaction to realize CDT, which further aggravates cancer cell apoptosis. Together with the chemotherapy caused by Dox, our nanoplatform displays an enhanced anticancer effect both in vitro and in vivo. Our work provides a powerful means for site-specific cancer synergetic therapy with high spatial and temporal resolution.