Ultrasmall iron-doped zinc oxide nanoparticles for ferroptosis assisted sono-chemodynamic cancer therapy.

The efficacy and biosafety of sonodynamic therapy (SDT) are closely related to the properties of sonosensitizers. Inorganic sonosensitizers with high chemical stability and low dark toxicity are generally limited by slow metabolism and accumulation in vivo. Combined treatment strategies by inducing more redox imbalance are expected to improve the efficacy of sonodynamic antitumor therapy. Herein, we report the development of ultra-small iron-doped zinc oxide nanoparticles (FZO NPs) to achieve synergistic sono-chemodynamic therapy and low accumulation in vivo. The surface of FZO NPs with diameter of 5 nm was modified with 3-aminopropyltriethoxysilane and polyethylene glycol 600 to obtain FZO-ASP with good aqueous stability. FZO-ASP with iron doping could trigger Fenton reaction and induce ferroptosis in cancer cells. With the assistance of ultrasonic energy, FZO-ASP demonstrated enhanced inhibitory effects on proliferation of various cancer cells and murine breast tumor growth than undoped counterpart. In addition, FZO-ASP injected intravenously could be effectively excreted in vivo and showed no obvious cumulative toxicity to the treated mice. Hence, this type of ultra-small iron-doped zinc oxide nanoparticles could serve as a safe and efficient sonosensitizer agent for synergistic sono-chemodynamic cancer therapy.

Study of the mechanism of ultrasound-induced enhanced therapeutic effects of a chitosan-based nanoplatform.

Ultrasound (US) has been used in drug delivery systems for controlling drug release and activation of US-sensitive drugs for sonodynamic therapy of cancer. In our previous work, we found that erlotinib-grafted chitosan nanocomplexes loading perfluorooctyl bromide and hematoporphyrin under US irradiation showed satisfactory therapeutic effects for non-small cell lung cancer treatment. However, the underlying mechanism of US-mediated delivery and therapy has not been fully explored. In this work, the underlying mechanisms of the US-induced effects of the nanocomplexes were evaluated at the physical and biological levels after the chitosan-based nanocomplexes were characterized. The results showed that US could activate the cavitation effects and promote nanocomplexes penetrating into the depth of three-dimensional multicellular tumor spheroids (3D MCTSs) when nanocomplexes were selectively uptaken by targeted cancer cells, but push the extracellular nanocomplexes out of the 3D MCTSs. US demonstrated strong tissue penetration ability to effectively induce obvious reactive oxygen species production deep inside the 3D MCTSs. Under the US condition of 0.1 W cm-2for 1 min, US caused little mechanical damage and weak thermal effect to avoid severe cell necrosis, whereas cell apoptosis could be induced by collapse of mitochondrial membrane potential and the nucleus damage. The present study indicates that US can potentially be used jointly with nanomedicine to improve targeted drug delivery and combination therapy of deep-seated tumors.

An intelligent hypoxia-relieving chitosan-based nanoplatform for enhanced targeted chemo-sonodynamic combination therapy on lung cancer.

The clinical efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs)-based targeted molecular therapies (TMT) is inevitably hampered by the development of acquired drug resistance in non-small cell lung cancer (NSCLC) treatment. Sonodymanic therapy (SDT) is a promising new cancer treatment approach, but its effects are restricted by tumor hypoxia. Herein, a nanoplatform fabricated by erlotinib-modified chitosan loading sonosensitizer hematoporphyrin (HP) and oxygen-storing agent perfluorooctyl bromide (PFOB), namely CEPH, was developed to deliver HP to erlotinib-sensitive cells. CEPH with ultrasound could alleviate hypoxia inside the three-dimensional multicellular tumor spheroids, suppress NSCLC cell growth under normoxic or hypoxic condition, and enhance TMT/SDT synergistic effects through elevated production of reactive oxygen species, decrease of mitochondrial membrane potential, and down-regulation of the expression of the proteins EGFR, p-EGFR, and HIF-1α. Hence, CEPH could be a potential nanoplatform to improve the efficacy of oxygen-dependent SDT and overcome hypoxia-induced TMT resistance for enhanced synergistic TMT/SDT.

Isochromanoindolenines suppress triple-negative breast cancer cell proliferation partially via inhibiting Akt activation.

As the most malignant subtype of breast cancers, triple-negative breast cancer (TNBC) lacks effective targeted therapeutics clinically to date. In this study, one lead compound FZU-0025-065 with isochromanoindolenine scaffold was identified by a cell-based screening. Among nine breast cancer cell lines tested, TNBC are the most sensitive cell lines to FZU-0025-065. FZU-0025-065 inhibits TNBC cell growth in a time- and dosage-dependent manner. FZU-0025-065 suppresses the expression of cell cycle dependent kinase 4 (CDK4), Cyclin D1 and Cyclin B1; meanwhile, elevates the expression of cell cycle dependent kinase inhibitor p21 and p27. Importantly, we found that FZU-0025-065 suppresses AKT activation in a time- and dosage-dependent manner. Over-expression of constitutive active AKT partially rescues FZU-0025-065 induced cell growth inhibition in MDA-MB-468 cells, indicating FZU-0025-065 suppresses TNBC cell growth partially via inhibiting AKT activation. Finally, FZU-0025-065 suppresses TNBC cell growth in a xenograft mouse model. Taken together, our findings suggested that isochromanoindolenine derivative FZU-0025-065 inhibits TNBC via suppressing the AKT signaling and that FZU-0025-065 may be useful for TNBC treatment.

Interspecific differences in growth response and tolerance to the antibiotic sulfadiazine in ten clonal wetland plants in South China.

Pollution caused by residual antibiotics is a worldwide environmental issue. Antibiotic residues often occur in aquatic ecosystems, posing threats to the health of aquatic organisms. The effects of antibiotic residues on the growth of crop plants and on human health are reasonably well known. However, less is known about antibiotic effects on wetland plants. Therefore, we studied the response and tolerance of ten clonal wetland plants grown in soil spiked with sulfadiazine at 10 mg kg(-1) (an environmentally relevant concentration) and 100 mg kg(-1). At 10 mg kg(-1), ramet number was the least affected trait, while root number was the most affected among plant species. Plant shoot and total biomass were reduced in all species except in Cyperus malaccensis var. brevifolius and Panicum repens. Chlorophyll content was reduced in Alocasia macrorrhiza, Saururus chinensis, and Commelina diffusa. In general, Panicum paludosum and C. malaccensis var. brevifolius showed the least reduction of growth parameters, whereas growth of both A. macrorrhiza and S. chinensis was severely reduced. At 100 mg kg(-1), negative responses occurred in all species. Comprehensive tolerance analysis revealed that P. paludosum and C. malaccensis var. brevifolius were the species most resistant to sulfadiazine. These species are potential candidates for sulfadiazine polluted wetland restoration. A. macrorrhiza and S. chinensis were the most susceptible species and they should be protected from sulfadiazine pollution. Relative plant shoot biomass and height were the most useful indicators for evaluating plant tolerance to sulfadiazine. Plant tolerance to sulfadiazine was associated with the differences of plants in height and shoot biomass.