Platinum-Coordinated Dual-Responsive Nanogels for Universal Drug Delivery and Combination Cancer Therapy.

Developing a universal nanoplatform for efficient delivery of various drugs to target sites is urgent for overcoming various biological barriers and realizing combinational cancer treatment. Nanogels, with the advantages of both hydrogels and nanoparticles, may hold potential for addressing the above issue. Here, a dual-responsive nanogel platform (HPC nanogel) is constructed using ß-cyclodextrin-conjugated hyaluronic acid (HA-ßCD), polyethyleneimine (PEI), and cisplatin. HA-ßCD and PEI compose the skeleton of the nanogel, and cisplatin molecules provide the junctions inside the skeleton, thus affording a multiple interactions-based nanogel. Besides, HA endows the nanogel with hyaluronidase (HAase)-responsiveness, and cisplatin guarantees the glutathione (GSH)-responsive ability, which make the nanogel a dual-responsive platform that can degrade and release the loaded drugs when encountering HAase or GSH. Additionally, the HPC nanogel possesses excellent small-molecule drug and protein loading and intracellular delivery capabilities. Especially, for proteins, their intracellular delivery via nanogels is not hindered by serum proteins, and the enzymes delivered into cells still maintain their catalytic activities. Furthermore, the nanogel can codeliver different cargoes to achieve "cocktail" chemotherapeutic efficacy and realize combination cancer therapy. Overall, the HPC nanogel can serve as a multifunctional platform capable of delivering desired drugs to treat cancer or other diseases.

Mild heat stress limited the post-acidification caused by Lactobacillus rhamnosus hsryfm 1301 in fermented milk.

OBJECTIVE: Fermented milk is the optimal vehicle for delivering probiotic bacteria. However, the viable count of probiotic bacteria such as some lactic acid bacteria and the post-acidification of fermented milk are a contradiction. The objective of this study was to restrict the post-acidification of the fermented milk containing living Lactobacillus rhamnosus hsryfm 1301. RESULTS: Mild heat stress treatment (46 °C, 1 h) was chosen to help control the post-acidification caused by L. rhamnosus hsryfm 1301. When fermented milk was produced by single L. rhamnosus hsryfm 1301, the heat stress treatment reduced the post-acidification from 0.39 to 0.11% lactic acid, and the viable cells were maintained above 2.0 × 108 CFU mL-1 during 21 days of storage. Although the post-acidification limitation of heat treatment was relatively weak in fermented milk produced by L. rhamnosus hsryfm 1301 and S. thermophilus grx02 (from 0.26 to 0.10% lactic acid), this treatment was still effective. Furthermore, no whey separation in the fermented milk was caused by the treatment. CONCLUSIONS: Mild heat stress treatment could limit the post-acidification caused by L. rhamnosus hsryfm 1301 by decreasing its metabolism and proliferation. This treatment is a promising strategy to improve the shelf life of probiotic fermented milk.

Capsular polysaccharide-amikacin nanoparticles for improved antibacterial and antibiofilm performance.

Natural nanoscale polysaccharide and its application have attracted much attention in recent years. In this study, we report for the first time that a novel naturally occurring capsular polysaccharide (CPS-605) from Lactobacillus plantarum LCC-605, which can self-assemble into spherical nanoparticles with an average diameter of 65.7 nm. To endow CPS-605 with more functionalities, we develop amikacin-functionalized capsular polysaccharide (CPS) nanoparticles (termed CPS-AM NPs) with improved antibacterial and antibiofilm activities against both Escherichia coli and Pseudomonas aeruginosa. They also exhibit faster bactericidal activity than AM alone. The high local positive charge density of CPS-AM NPs facilitates the interaction between the NPs and bacteria, leading to extraordinary bactericidal efficiencies (99.9 % and 100 % for E. coli and P. aeruginosa, respectively, within 30 min) by damaging the cell wall. Very interestingly, CPS-AM NPs exhibit an unconventional antibacterial mechanism against P. aeruginosa, that is, they can induce plasmolysis, along with bacterial cell surface disruption, cell inclusion release and cell death. In addition, CPS-AM NPs exhibit low cytotoxicity and negligible hemolytic activity, showing excellent biocompatibility. The CPS-AM NPs provide a new strategy for the design of next-generation antimicrobial agents that can reduce the working concentration of antibiotics to fight against bacterial resistance.

Sorbicillinoids hyperproduction without affecting the cellulosic enzyme production in Trichoderma reesei JNTR5.

BACKGROUND: Microbial production of bioactive secondary metabolites is challenging as most of the encoding genes are silent; and even if they are activated, the biosynthetic pathways are usually complex. Sorbicillinoids with multifunctional bioactivities are examples of these problems, which if solved can result in a more sustainable, simple supply of these important compounds to the pharmaceutical industry. As an excellent producer of cellulosic enzymes, Trichoderma reesei can secrete various sorbicillinoids. RESULTS: Here, we obtained a T. reesei mutant strain JNTR5 from the random mutation during overexpression of gene Tr69957 in T. reesei RUT-C30. JNTR5 exhibited a significant constitutive increase in sorbicillinoids production without affecting the cellulosic enzyme production. Confocal laser scanning microscope (CLSM) results indicated that sorbicillinoids were distributed in both mycelium and spores of JNTR5 with blue and green fluorescence. Compared with RUT-C30, JNTR5 displayed different cell morphology, reduced growth rate, and increased sporulation, but a similar biomass accumulation. Furthermore, transcriptome analysis revealed that all genes belonging to the sorbicillinoid gene cluster were upregulated, while most cellulase-encoding genes were downregulated. The cell wall integrity of JNTR5 was damaged, which might benefit the cellulase secretion and contribute to the almost unchanged cellulase and hemicellulase activity given that the damaged cell wall can enhance the secretion of the enzymes. CONCLUSIONS: For the first time, we constructed a sorbicillinoids hyperproduction T. reesei platform with comparable cellulosic enzymes production. This outperformance of JNTR5, which is strain-specific, is proposed to be attributed to the overexpression of gene Tr69957, causing the chromosome remodeling and subsequently changing the cell morphology, structure, and the global gene expression as shown by phenotype and the transcriptome analysis of JNTR5. Overall, JNTR5 shows great potential for industrial microbial production of sorbicillinoids from cellulose and serves as an excellent model for investigating the distribution and secretion of yellow pigments in T. reesei.

Naturally occurring protein/polysaccharide hybrid nanoparticles for stabilizing oil-in-water Pickering emulsions and the formation mechanism.

In this study, we reported for the first time that the natural protein/polysaccharide hybrid nanoparticles (PPH NPs) with a diameter of âˆ¼ 129 nm, originating from Lactobacillus plantarum fermented cheese whey, could act as green-based NPs for stabilizing Pickering emulsions. Characterizations of PPH NPs showed that the negative-charged PPH NPs were composed of âˆ¼ 37.7% total protein and âˆ¼ 7.3% polysaccharide bearing several functional groups, such as -OH, -NH, -COOH, etc.; and displayed excellent emulsifying capacity in preparing oil-in-water Pickering emulsions. The obtained emulsions exhibited gel-like behavior with excellent stability against the variation of pH, ionic strength, and temperature. Confocal observations showed that PPH NPs effectively adsorbed and anchored at the oil-water interface, thus creating the steric hindrance to inhibit droplet coalescence. This research is of importance in developing novel and biocompatible Pickering stabilizers with outstanding performance, as well as enable a versatile design of stable Pickering emulsions suitable for food industries.