Vesicular IFN-γ as a cooperative attacker to enhance anti-cancer effect of 5-fluorouracil via thymidine phosphorylase upregulation and tumor microenvironment normalization.

On the basis of immuno-modulating effect and upregulating the activity of thymidine phosphorylase (TP), interferon-γ (IFN-γ) as a cooperative attacker was explored to enhance the anticancer activity of 5-fluorouracil (5-FU). We designed and prepared a self-assembled nano-vesicular system IFN-γ-EDP formulated by amphiphilic poly((polyethylene glycol)(dodecylphosphoethanolamine)phosphazene) (EDP) to entrap IFN-γ in the hydrophilic cavity. The IFN-γ-EDP vesicles allowed IFN-γ to accumulate at the tumor site and be taken up by tumor cells, resulting in significantly upregulated expression level of TP, distinct inhibition of cell growth, more cellular apoptosis and more serious cell cycle arrest when administrated combined with 5-FU. Moreover, IFN-γ-EDP could normalize the tumor microenvironment by enhancing the CD4+ and CD8+ T cell populations, promoting the IL-12 secretion and suppressing the IL-10 secretion in tumor. As a consequence, the combination therapy of IFN-γ-EDP with 5-FU achieved remarkably enhanced tumor inhibition rate of 56.9% against CT26 colorectal cancer.

Differences in the gut microbiomes of dogs and wolves: roles of antibiotics and starch.

BACKGROUND: Dogs are domesticated wolves. Change of living environment, such as diet and veterinary care may affect the gut bacterial flora of dogs. The aim of this study was to assess the gut bacterial diversity and function in dogs compared with captive wolves. We surveyed the gut bacterial diversity of 27 domestic dogs, which were fed commercial dog food, and 31 wolves, which were fed uncooked meat, by 16S rRNA sequencing. In addition, we collected fecal samples from 5 dogs and 5 wolves for shotgun metagenomic sequencing to explore changes in the functions of their gut microbiome. RESULTS: Differences in the abundance of core bacterial genera were observed between dogs and wolves. Together with shotgun metagenomics, the gut microbiome of dogs was found to be enriched in bacteria resistant to clinical drugs (P < 0.001), while wolves were enriched in bacteria resistant to antibiotics used in livestock (P < 0.001). In addition, a higher abundance of putative α-amylase genes (P < 0.05; P < 0.01) was observed in the dog samples. CONCLUSIONS: Living environment of dogs and domestic wolves has led to increased numbers of bacteria with antibiotic resistance genes, with exposure to antibiotics through direct and indirect methods. In addition, the living environment of dogs has allowed the adaptation of their microbiota to a starch-rich diet. These observations align with a domestic lifestyle for domestic dogs and captive wolves, which might have consequences for public health.

Polymeric nano-vesicles via intermolecular action to load and orally deliver insulin with enhanced hypoglycemic effect.

To date few polymeric vesicles have been investigated to improve oral insulin (INS) absorption due to their limited loading capacity. Therefore, an amphiphilic polyphosphazene (PEOP) containing lipid-like octadecylphosphoethanolamine (OPA) groups and amino-modified poly(ethylene glycol) at the proper ratio was designed and synthesized in this study. It was found that PEOP can self-assemble into nano-vesicles, which displayed considerable loading capability for INS by taking advantage of the synergetic effect of the interaction between OPA and INS and the physical encapsulation by the aqueous lumen of the vesicles. Furthermore, PEOP vesicles can promote INS absorption across the subsequent lymphatic transport of PEOP vesicles after their uptake by the enterocytes in the gastrointestinal tract, and consequently achieve better hypoglycemic effects in vivo. These results suggested that PEOP vesicles have great potential as oral INS carriers for diabetes therapy.

Nano-vesicles based on phospholipid-like amphiphilic polyphosphazenes to orally deliver ovalbumin antigen for evoking anti-tumor immune response.

Aimed at evoking an adequate anti-tumor immune response via oral administration route, this study constructed functionally and structurally mimicking-bacteria-membrane (MBM) nano-vesicle (RGD-PEOP) to orally deliver ovalbumin (OVA) antigen. In terms of simulating bacterial membrane structure, we creatively designed this nano-vesicle to have phospholipid-like octadecylphosphoethanolamine groups in vesicle membrane to improve OVA loading by means of specific interactions including salt bridge and hydrogen bond interaction. For simulating bacterial membrane function, the RGD peptide was modified onto the nano-vesicle surface, and the resulting vector displayed a good transport ability with a 3.4-fold higher than free OVA. In vitro and in vivo assay showed that the expression of co-stimulatory molecules and MHC class II complexes was significantly enhanced by MBM nano-vesicle. IFN-γ and IL-4 levels also increased several folds in the MBM nano-vesicle group. Consequently, MBM nano-vesicle achieved the highest in vivo inhibition rate of 69% against E.G7-OVA tumors among all the oral groups. These results suggest that this MBM nano-vesicle may be a promising vector to orally deliver OVA antigen for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Developing an effective non-bacterial carrier for oral cancer immunotherapy remains challenging. This work constructed a mimicking-bacteria-membrane nano-vesicle based on phospholipid-like amphiphilic polyphosphazenes for oral delivery of ovalbumin antigen. With the considerable capability to load ovalbumin antigen and target M cells, the nano-vesicle produced remarkable tumor suppression in vivo by evoking anti-tumor immune response.

Polymersomes: Preparation and Characterization.

Polymersomes, also called polymeric vesicles, are self-assembled by amphiphilic copolymers. Due to their unique characters, polymersomes are attracting more and more interest as an important class of vehicles for nanopharmaceuticals. In this chapter, various methods to prepare and characterize polymersomes are introduced systematically with several applicable examples. In addition, the advantages and disadvantages of each method were compared and analyzed with the aim to help readers choose the appropriate method in the process of experiments. Although some methods we introduced here are effective in preparing and characterizing polymersomes, the remaining challenge in this filed is to develop new tools. The reason is that polymersome is a kind of complex nanostructure, and some minor factors can affect the formation of polymersome. Meanwhile, more advanced technology should be developed to precisely determine the structure of some complex polymersomes such as multilayer polymersomes.