A tailored series of engineered yeasts for the cell-dependent treatment of inflammatory bowel disease by rational butyrate supplementation.

Intestinal microbiota dysbiosis and metabolic disruption are considered essential characteristics in inflammatory bowel disorders (IBD). Reasonable butyrate supplementation can help patients regulate intestinal flora structure and promote mucosal repair. Here, to restore microbiota homeostasis and butyrate levels in the patient's intestines, we modified the genome of Saccharomyces cerevisiae to produce butyrate. We precisely regulated the relevant metabolic pathways to enable the yeast to produce sufficient butyrate in the intestine with uneven oxygen distribution. A series of engineered strains with different butyrate synthesis abilities was constructed to meet the needs of different patients, and the strongest can reach 1.8 g/L title of butyrate. Next, this series of strains was used to co-cultivate with gut microbiota collected from patients with mild-to-moderate ulcerative colitis. After receiving treatment with engineered strains, the gut microbiota and the butyrate content have been regulated to varying degrees depending on the synthetic ability of the strain. The abundance of probiotics such as Bifidobacterium and Lactobacillus increased, while the abundance of harmful bacteria like Candidatus Bacilloplasma decreased. Meanwhile, the series of butyrate-producing yeast significantly improved trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice by restoring butyrate content. Among the series of engineered yeasts, the strain with the second-highest butyrate synthesis ability showed the most significant regulatory and the best therapeutic effect on the gut microbiota from IBD patients and the colitis mouse model. This study confirmed the existence of a therapeutic window for IBD treatment by supplementing butyrate, and it is necessary to restore butyrate levels according to the actual situation of patients to restore intestinal flora.

Novel nanoparticles prepared from isothiocyanate derivatives for phototherapy of tumor.

Phototherapy is a new method to treat tumor, including photodynamic therapy (PDT) and photothermal therapy (PTT). However, the GSH in tumor cells could deplete ROS produced by photosensitizers, resulting in inadequate PDT. Isothiocyanate not only is a new type of anti-tumor drug, but also may combine with GSH, increasing the content of intracellular ROS and improving PDT effect. Here we synthesized a kind of water-soluble nanoparticles (BN NPs) parceling BODIPY-I-35 up with mPEG-ITC and lecithin. mPEG-ITC can react with GSH in tumor cells to reduce the consumption of ROS. BN NPs can be used as vectors to deliver drugs to tumor sites. Under 808 nm laser irradiation, BN NPs solution increased 13 °C within 10 min, indicating that BN NPs had superb photothermal performance. In vitro experiments, low dose BN NPs showed satisfactory PDT and PTT effects, and the cell viability of MCF-7 cell was only 13%. In vivo, BN NPs with excellent biocompatibility showed favorable phototherapy effect and tumor was effectively inhibited. Fluorescence imaging could present the long retention effect of BN NPs in tumor locations. In conclusion, the BN NPs showed the effect of enhancing phototherapy and provided a remarkable application prospect in the phototherapy of tumor cells.

The photodynamic/photothermal synergistic therapeutic effect of BODIPY-I-35 liposomes with urea.

Photodynamic therapy (PDT) has a successful track record in cancer. . Urea is a naturally occurring metabolite in the human body. Some studies have shown that it can inhibit the proliferation of tumor cells and cause oxidative stress. In order to explore the application of urea in enhancing the PDT effect, we synthesized a new photosensitizer (BODIPY-I-35) with good phototherapeutic effect and encapsulated it in liposomes. Compared with free BODIPY-I-35, water-soluble nanoliposomes (LipoBOD) produced a huge redshift (> 122 nm) of fluorescence emission in solution. When LipoBOD was irradiated with 808 nm laser (1 W/cm2) for 10 min, the temperature contrast increased by 20 °C, which was 4 times higher than free BODIPY-I-35. Confocal microscopy showed appreciable accumulation of LipoBOD in HeLa cells. In addition, when LipoBOD was incubated with urea in HeLa cells, we found that urea not only obviously enhanced the production of ROS, but also increased the apoptosis of HeLa cells. The synergistic effect of LipoBOD (20 µg/mL, at BODIPY-I-35-eq) with urea (250 mM) showed significantly higher phototoxicity than LipoBOD alone. Low dose can reduce the cell viability to 10%. Therefore, we have obtained an effective method of using urea to enhance the PDT effect.

Multi-functional Nanodrug Based on a Three-dimensional Framework for Targeted Photo-chemo Synergetic Cancer Therapy.

Targeted synergistic therapy has broad prospects in tumor treatments. Here, a multi-functional nanodrug GDYO-CDDP/DOX@DSPE-PEG-MTX (GCDM) based on three traditional anticancer drugs (doxorubicin (DOX), cisplatin (CDDP) and methotrexate (MTX)) modified graphdiyne oxide (GDYO) is described, for diagnosis and targeted cancer photo-chemo synergetic therapy. In this system, for the first time, these three traditional anti-cancer drugs have played new roles and can reduce multidrug resistance through synergistic anti-tumor effects. Cisplatin can be hybridized with GDYO to form a multifunctional and well-dispersed three-dimensional framework, which can not only be used as nano-drug carriers to achieve high drug loading rates (40.3%), but also exhibit excellent photothermal conversion efficiency (47%) and good photodynamic effects under NIR irradiation. Doxorubicin (DOX) is loaded onto GDYO-CDDP through π-π stacking, which is used as an anticancer drug and as a fluorescent probe for nanodrug detection. Methotrexate (MTX) can be applied in tumor targeting and play a role in synergistic chemotherapy with DOX and CDDP. The synthesized multi-functional nanodrug GCDM has good biocompatibility, active targeting, long-term retention, sustained drug release, excellent fluorescence imaging capabilities, and remarkable photo-chemo synergistic therapeutic effects.