Chemodynamic therapy holds great potential for cancer treatment due to its reliable curative effects, minimal invasiveness, and few systemic side effects. However, the limited amount of intracellular H2O2 makes achieving high-performance chemodynamic therapy challenging. Herein, we report a core-shell nanoplatform with dual-responsive disassembly that self-supplies H2O2 and undergoes an autocatalytic Fenton reaction for enhanced chemodynamic therapy. The platform was designed by coating glucose oxidase-mimicking nanozyme gold nanoparticles (AuNPs) with a metal-polyphenol network (Au@MPN). Both ATP and low pH can disassemble the Au@MPN to release Fe(III), which can then be reduced into Fe(II) by the simultaneously released tannic acid (TA). In particular, the exposed AuNPs can catalyze the oxidation of intracellular glucose to produce H2O2. Subsequently, Fe(II) and the self-supplied H2O2 induce an efficient Fenton reaction for chemodynamic therapy by generating hydroxyl radicals (•OH) that are highly toxic to cancer cells. Moreover, tumor growth can be effectively suppressed after both intratumoral and intravenous Au@MPN administration. Additionally, metastatic melanoma lung tumors could be inhibited by intratracheal instillation of Au@MPN. Thus, this work not only reports a facile method to construct a chemodynamic agent with self-supplied H2O2 and high therapeutic efficiency but also provides insight into the design of nanoplatforms with enhanced efficiency for chemodynamic therapy.

BackgroundPatients with systemic internal diseases present high risks for invasive fungal infections, which results in increased morbidity and mortality. Identification of high-risk departments and susceptibility systems could help to reduce the infective rate clinically. Correct selection of sensitive anti-fungal drugs not only could improve the cure rate but also could reduce the adverse reactions and complications caused by long-term antifungal drug treatment, which can be especially important in patients with serious systemic diseases. Therefore, the distribution changes of invasive fungal strains in patients with systemic internal diseases and the choice of antifungal drugs in clinical practice should be updated.ObjectiveThis work aimed to investigate the incidence, strain distributions, and drug susceptibility of invasive fungal strains isolated from patients with systemic internal diseases.MethodsSamples were collected from 9,430 patients who were diagnosed with internal diseases in our hospital from January to December 2018. We then cultured and identified the fungal strains using API 20C AUX. We performed drug sensitivity analysis via the ATB Fungus-3 fungal susceptibility strip. Resistance was defined using the revised Clinical Laboratory Standardization Committee of United States breakpoints/epidemiological cutoff values to assign susceptibility or wild-type status to systemic antifungal agents.ResultsA total of 179 patients (49 female, 130 male) with fungal infection were included. The high-incidence departments were determined to be the respiratory department (34.64%), intensive care unit (ICU; 21.79%), and hepatology department (9.50%). The susceptible systems for infection were the respiratory tract (sputum, 68.72%, 123/179; secretion retained in the tracheal catheter, 3.35%, 6/179), urinary tract (urine, 9.50%, 17/179), and gastrointestinal tract (feces, 9.50%, 17/179). The major pathogens were Candida (90.50%), Aspergillus (8.93%), and Cryptococcus neoformans (0.56%). The infective candida subgroups were Candida albicans (70.95%), Candida krusei (6.15%), Candida glabrata (5.59%), Candida parapsilosis (3.91%), and Candida tropicalis (3.91%). The susceptibility of non-Aspergillus fungi for amphotericin B was 100.0%. The susceptibility rates of 5-fluorocytocine (5-FC) and voriconazole were 72.73 and 81.82%, respectively, for C. krusei, 98.43 and 100% for C. albicans, and 100% for both drugs for C. glabrata, C. parapsilosis, and C. tropicalis. The susceptibility rates of fluconazole and itraconazole were 0 and 54.55%, respectively, for C. krusei, 20 and 20% for C. glabrata, and 57.14 and 57.14% for C. tropicalis. The resistance rate of C. tropicalis for both fluconazole and itraconazole was 41.43%.ConclusionPatients in the respiratory department, ICU, and hepatology department presented high rates of invasive fungal infections and should include special attention during clinical treatment. The respiratory tract, urinary tract, and gastrointestinal tract were the susceptible systems. Candida, especially C. albicans, was the main pathogen. From the perspective of drug sensitivity, amphotericin B should be given priority in treating the non-Aspergillus fungi infection in patients with systemic internal diseases, while the susceptibility of invasive fungal strains to azoles was variant. These data might provide clinical evidence for the prevention and treatment of invasive fungal infection in patients with systemic internal diseases.

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The incidence of primary cutaneous melanoma continues to increase annually and is one of the most aggressive malignancies in humans and need to develop more novel non-surgical therapies. Autophagy and cathepsin B targeted therapy was reported to improve melanoma treatment. Cepharanthine (CEP), a natural alkaloid extracted from the genus Cephalophyllum has been reported to have the function of inhibiting cancers. We found that CEP inhibited human primary cutaneous melanoma cells viability and proliferation in 24 h in vitro, and topical application or intra-tumoral injection of CEP decreased the growth of cutaneous melanoma in mice within 4 weeks. CEP preparations below 50% concentration did not induce skin irritation and allergy reaction on human skin in vivo. Primary cutaneous melanoma cells incubated with CEP, the expression of cathepsin B was decreased and the LC3-I and LC3-II expression changed in a dose-dependent manner, while p53, p21Cip1p, and p16Inka gene expression was up-regulated. We demonstrated the effects of CEP as a novel tumor-regional therapy for cutaneous melanoma and provided a preliminary research basis for future clinical treatment researches and the exploration of integrated treatments with systemic therapy, radiotherapy, and surgery for human primary cutaneous melanoma.

Chemodynamic therapy holds great potential for cancer treatment due to the reliable curative effect, minimal invasiveness, and few systemic side effects. However, the limited amount of intracellular H2O2 makes it remain challenging to achieve high performance for chemodynamic therapy. Herein, we reported dual-responsive disassembly of core-shell nanoplatform with self-supplied H2O2 and autocatalytic Fenton reaction for enhanced chemodynamic therapy. The platform was designed by coating glucose oxidase mimic nanozyme gold nanoparticles (AuNPs) with metal polyphenol network (Au@MPN). Both ATP and low pH could disassemble Au@MPN to release Fe(III), which could be reduced by the simultaneously released tannic acid (TA) into Fe (II). Especially, the exposed AuNPs could catalyze the oxidation of intracellular glucose to produce H2O2. Subsequently, the Fe(II) and self-supplied H2O2 induced efficient Fenton reaction to generate highly toxic hydroxyl radical (•OH), which revealed cytotoxicity to cancer cells through chemodynamic therapy. Besides, tumor growth can be effectively suppressed by Au@MPN through both intratumoral and intravenous administration routes. Additionally, melanoma metastatic lung cancer could be inhibited by intratracheal instillation of Au@MPN. Therefore, this work not only reports a facile method to construct a chemodynamic agent with self-supplied H2O2 and high therapeutic efficiency, but also provides insight into the design of nanoplatform with enhanced efficiency for chemodynamic therapy.