Triple branched RGD modification on liposomes: A prospective strategy to enhance the glioma targeting efficiency.

Glioma, as one of the most common primary intracranial tumors, is in an urgent need for specific targeting agents. Multi-branched RGD ligand is a promising alternative for liposome functionalization which combines the benefits of high affinity with αvß3 receptors and proper branching structure in response to the receptor clustering. Herein, we designed and synthesized single branched, double branched and triple branched RGD ligand (1RGD-Chol, 2RGD-Chol and 3RGD-Chol) respectively, which were then modified on the liposomes to prepare six different kinds of liposomes (including 1RGD-Lip, 2RGD-Lip, 3RGD-Lip, 2 × 1RGD-Lip, 3 × 1RGD-Lip and unmodified Lip). Subsequently, a series of assays were conducted. The results exhibited that the liposome decorated with 3RGD-Chol ligand possessed superior cellular internalization ability in C6 cells and bEnd.3 cells, suggesting the strongest ability of 3RGD-Lip to target the blood-brain barrier (BBB) and glioma cells. Besides, both the cytotoxicity and pro-apoptotic assays revealed that PTX-3RGD-Lip had the strongest ability to inhibit the survival of C6 cells. Moreover, the enrichment of liposomes at tumor site was 3RGD-Lip > 3 × 1RGD-Lip ≈ 2RGD-Lip ≈ 2 × 1RGD-Lip > 1RGD-Lip > Lip according to the in vivo imaging of C6-bearing mice, which was consistent with the result of in vitro targeting experiments. To sum up, the targeting efficiency of liposomes can be strongly promoted by improving the amount of targeting molecules, whereas the branching structure and spatial distance of RGD residues also accounted for the affinity between liposomes and αvß3 receptors. Collectively, PTX-3RGD-Lip would be a prospective strategy in glioma treatment.

Tumor bacterial markers diagnose the initiation and four stages of colorectal cancer.

Increasing evidence has supported dysbiosis in the faecal microbiome along control-adenoma-carcinoma sequence. In contrast, the data is lacking for in situ tumor bacterial community over colorectal cancer (CRC) progression, resulting in the uncertainties of identifying CRC-associated taxa and diagnosing the sequential CRC stages. Through comprehensive collection of benign polyps (BP, N = 45) and the tumors (N = 50) over the four CRC stages, we explored the dynamics of bacterial communities over CRC progression using amplicons sequencing. Canceration was the primarily factor governing the bacterial community, followed by the CRC stages. Besides confirming known CRC-associated taxa using differential abundance, we identified new CRC driver species based on their keystone features in NetShift, including Porphyromonas endodontalis, Ruminococcus torques and Odoribacter splanchnicus. Tumor environments were less selective for stable core community, resulting in heterogeneity in bacterial communities over CRC progression, as supported by higher average variation degree, lower occupancy and specificity compared with BP. Intriguingly, tumors could recruit beneficial taxa antagonizing CRC-associated pathogens at CRC initiation, a pattern known as "cry-for-help". By distinguishing age- from CRC stage-associated taxa, the top 15 CRC stage-discriminatory taxa contributed an overall 87.4% accuracy in diagnosing BP and each CRC stage, in which no CRC patients were falsely diagnosed as BP. The accuracy of diagnosis model was unbiased by human age and gender. Collectively, our findings provide new CRC-associated taxa and updated interpretations for CRC carcinogenesis from an ecological perspective. Moving beyond stratifying case-control, the CRC-stage discriminatory taxa could add the diagnosis of BP and the four CRC stages, especially the patients with poor pathological feature and un-reproducibility between two observers.

Multiple targeted doxorubicin-lonidamine liposomes modified with p-hydroxybenzoic acid and triphenylphosphonium to synergistically treat glioma.

A type of pH-sensitive multi-targeted brain tumor site-specific liposomes (Lip-CTPP) co-modified with p-hydroxybenzoic acid (p-HA) and triphenylphosphonium (TPP) were designed and prepared to co-load doxorubicin (DOX) and lonidamine (LND). Lip-CTPP are promising potential carriers to exert the anti-glioma effect of DOX and LND collaboratively given the following features: 1) Lip-CTPP have a good pharmacokinetic behavior; 2) Lip-CTPP can cross the blood-brain barrier (BBB) and recognize tumor cells through the affinity of p-HA and dopamine/sigma receptors; 3) Lip-CTPP are highly positive charged once the acid-sensitive amide bonds are cleaved in endo/lysosomes to expose TPP and protonate amine groups; 4) the positive charged Lip-CTPP escape from endo/lysosomes and accumulate in mitochondria through electrostatic adsorption; 5) DOX and LND are released and synergistically increase anti-tumor efficacy. Our in vitro and in vivo results confirmed that Lip-CTPP could greatly elevate the inhibition rate of tumor cell proliferation, migration and invasion, promote apoptosis and necrosis, and interfere with mitochondrial function. In addition, Lip-CTPP could significantly prolong the survival time of glioma bearing mice, narrow the tumor region and inhibit the infiltration and metastasis capability of glioma cells. Collectively, Lip-CTPP are promising nano formulations to enhance the synergistic effect of DOX and LND in glioma treatment.

pH-redox responsive cascade-targeted liposomes to intelligently deliver doxorubicin prodrugs and lonidamine for glioma.

To synergistically treat glioma with a combination chemotherapy, we design and prepare novel cascade-targeted liposomes (Lip-TPGS) using glucose and triphenylphosphonium (TPP) as targeting moieties, which could intelligently deliver redox-sensitive doxorubicin (DOX) prodrugs (SDOX) and chemotherapeutic sensitizer lonidamine (LND). The pH-responsive ligand Chol-TPG modified by PEGylated glucose can overcome the blood-brain barrier and reach tumor cells. Combined with the modification of mitochondria targeting ligand (Chol-TPP), Lip-TPGS are endowed with pH-responsive charge regulation function and multi-stage targeting abilities. After triggered by the excessive glutathione in tumor cells, Lip-TPGS could sufficiently release the parent drugs DOX, which would significantly reduce side effects without compromising anti-glioma efficacy. Therefore, Lip-TPGS possess these characteristics: good pharmacokinetic behavior, superior brain targeting ability, specific tumor recognition and internalization capability, and strong endo/lysosome escaping and mitochondria targeting potential. Furthermore, Lip-TPGS exhibit significant advantages on anti-glioma by inhibiting proliferation, promoting apoptosis, inducing mitochondria dysfunction, inhibiting migration and invasion, prolonging the survival time, narrowing tumor areas, limiting lung metastasis, and reducing toxicity to normal organs. In summary, Lip-TPGS, with cascade targeting abilities from tissue/cell to organelle levels and highly controlled drug release properties, would become a promising drug delivery system for glioma treatment.

[Analysis of oral condition and caries related factors of 152 deaf-mute students in Jing'an district, Shanghai].

PURPOSE: To investigate the oral condition of deaf-mute students in Jing 'an district, Shanghai, and to analyze caries related factors among deaf-mute students. METHODS: Using general survey method, 152 students aging from 9 to 18 years old from two schools in Jing 'an district of Shanghai underwent oral examinations and questionnaire survey. SPSS 22.0 software package was used for statistical analysis of the data. RESULTS: Among the 152 deaf-mute students, caries rate was 53.3%, DMFT index was 1.80±2.66, detection rate of gingival bleeding was 65.8%, detection rate of calculus was 69.7%, caries rate of first molar was 36.2%, and percentage of pit and fissure sealant was 0.6%. Among children aging 12-15 years old, the caries rate was 50.0%, DMFT index was 1.69±3.13, detection rate of gingival bleeding was 68.5%, and the detection rate of calculus was 70.4%, all were significantly higher than those of urban group aging 12-15 years old during the Fourth National Oral Health Epidemiological Survey. According to logistic regression analysis, frequency of daily brushing（P=0.009）, dental surface of brushing（P<0.001）, brushing time（P=0.005）, frequency of drinking sweet drinks and carbonated drinks（P=0.003）, and the knowledge of oral health care（P=0.036） were all related factors affecting the occurrence of caries among deaf-mute students. CONCLUSIONS: For the prevention and control of caries in deaf-mute students, we should further strengthen oral health education and promote the implementation of intervention measures such as local fluoridation, pit and fissure sealant and early dental caries filling, so as to effectively control the occurrence and development of caries in deaf-mute students.

Glucose and Triphenylphosphonium Co-Modified Redox-Sensitive Liposomes to Synergistically Treat Glioma with Doxorubicin and Lonidamine.

Glioma is one of the most lethal and complex tumors, and thus, an effective drug delivery system must selectively target the tumor sites and release its cargos in a controlled manner. For the first time, we combined chemotherapeutic agent doxorubicin (DOX) and chemosensitizer lonidamine (LND) to synergistically treat glioma. We also designed and prepared multitargeted redox-sensitive liposomes (Lip-SPG) co-modified with glucose and triphenylphosphonium (TPP) to effectively deliver DOX and LND for anti-glioma therapy. The anti-glioma evaluation shows that DOX and LND have a synergistic effect and Lip-SPG could further enhance their cooperation. In vitro, Lip-SPG could increase the cellular uptake and mitochondrial uptake on bEnd.3 cells and C6 cells with multitargeting ability on the brain, tumor, and mitochondria mediated by glucose and TPP. Lip-SPG can also escape from lysosomes before entering the mitochondria. The anti-glioma efficacy in vitro shows that Lip-SPG can inhibit tumor cell proliferation and induce apoptosis. In addition, Lip-SPG have a remarkable interference to mitochondria, such as reducing intracellular ATP production, inducing ROS generation, and promoting mitochondrial membrane potential depolarization. Furthermore, in vivo, the introduction of PEGylation via glutathione-sensitive disulfide bonds endows Lip-SPG with favorable pharmacokinetic properties, brain targeting ability, low toxicity to normal tissues, and great anti-glioma efficacy with the survival time extended from 19 to 39 days. In conclusion, Lip-SPG are an effective delivery system for synergistically treating glioma with DOX and LND.

Engineering of Ribosome-inactivating Proteins for Improving Pharmacological Properties.

Ribosome-inactivating proteins (RIPs) are N-glycosidases, which depurinate a specific adenine residue in the conserved α-sarcin/ricin loop (α-SRL) of rRNA. This loop is important for anchoring elongation factor (EF-G for prokaryote or eEF2 for eukaryote) in mRNA translocation. Translation is inhibited after the attack. RIPs therefore may have been applied for anti-cancer, and anti-virus and other therapeutic applications. The main obstacles of treatment with RIPs include short plasma half-life, non-selective cytotoxicity and antigenicity. This review focuses on the strategies used to improve the pharmacological properties of RIPs on human immunodeficiency virus (HIV) and cancers. Coupling with polyethylene glycol (PEG) increases plasma time and reduces antigenicity. RIPs conjugated with antibodies to form immunotoxins increase the selective toxicity to target cells. The prospects for future development on the engineering of RIPs for improving their pharmacological properties are also discussed.

Separation mechanism of polyvinyl chloride and copper components from swollen electric cables by mechanical agitation.

In this study, a high-accuracy separation process is proposed for recycling pure polyvinyl chloride (PVC) and Cu from the thin electric cables of electrical, electronic, and automotive wastes by PVC swelling and mechanical agitation in hydrophobic organic solvent mixed with water. The high stirring speed and low blade height combined with proper blade type and reactor tank shape ensure a separation rate of over 98%. By conducting computational fluid dynamic and discrete element model simulations, quantitative force, fluid velocity, and data visualization analyses were performed. The obtained separation rate exhibited strong positive correlations with the resultant, drag, and centripetal forces at various stirring speeds and blade heights. Using the experimental and simulation data, a plausible separation mechanism was suggested. It was found that Cu pieces could slip out from swollen PVC covers under the action of external forces, while the stirring speed should be high enough to apply sufficient external forces to cables via either blade-to-cable collisions or fluid drag. Furthermore, the vertical motion of cables induced by the low blade height was essential because the rotation in the bottom reactor part inhibited the slipping of Cu pieces.

Practical dechlorination of polyvinyl chloride wastes in NaOH/ethylene glycol using an up-scale ball mill reactor and validation by discrete element method simulations.

To avoid the formation of undesired Cl compounds during polyvinyl chloride (PVC) wastes treatment and facilitate the recycling of valuable NaCl and dechlorinated hydrocarbons as feedstocks, advanced dechlorination (de-Cl) process should be developed. Here, an up-scale ball mill reactor was established for the de-Cl of real PVC wastes, including sealing strips from waste refrigerators and crushed cable coverings from waste cables. The effects of NaOH on de-Cl were validated with lab-scale studies and the influences of mechanical conditions were innovatively investigated. A maximum de-Cl degree of 99% was obtained with 1 M NaOH in ethylene glycol for sealing strips, whereas a maximum de-Cl degree of 92% was obtained with Φ1.27 cm stainless steel balls at a moderate rotation speed for cable coverings. The remaining Cl content in the sample residues was small and decreased with decreasing residue size, resulting in minimum contents of 0.49% and 0.61% for sealing strips and cable coverings, respectively. The de-Cl behavior was consistent with a shrinking-core model and the meaning of kinetic parameters was illustrated. The ball milling process was simulated by discrete element method (DEM). A positive correlation was observed between the apparent rate constant of the experimental de-Cl process and the specific impact energy calculated using DEM simulations. The combined experimental and simulation approach suggested that the surface of PVC is first dechlorinated and then crushed into fine particles by ball milling to expose the inner unreacted surface. For industrial application, the balance of chemical and mechanical conditions should be optimized.

Validation of a deplasticizer-ball milling method for separating Cu and PVC from thin electric cables: A simulation and experimental approach.

There is increasing demand in the electronics recycling industry for an effective method to separate polyvinyl chloride (PVC) and Cu from thin electric cable waste. Herein, a novel separation technique involving PVC embrittlement via plasticizer extraction and crushing by ball milling is proposed. The method was developed by varying the size, quantity, and hardness of the cables, as well as the size and quantity of the milling balls, to determine a combination that resulted in complete separation of PVC and high-purity Cu (>99.9%) from thin electric cables. The experimental crushing behavior was demonstrated via a sphere-to-cylinder discrete element model combined with a statistical approach. The mechanism of PVC crushing generated cracks from the edge to the center of the cable via ball impacts that were strong enough to overcome the elastic repulsion force of the PVC. The resulting method was found to be effective at separating PVC and high-purity Cu (>99.9%) from de-plasticized thin electric cables with diameters of 1.5-2.7 mm.

Anti-bacterial properties of ultrafiltration membrane modified by graphene oxide with nano-silver particles.

To improve the anti-biofouling properties of PVDF membranes, GO-Ag composites were synthesized and used as membrane antibacterial agent by a simple and environmentally friendly method. As identified by XRD, TEM and FTIR analysis, AgNPs were uniformly assembled on the synthesized GO-Ag sheets. The membranes were prepared by phase inversion method with different additional amounts (0.00-0.15wt%) of GO-Ag composites. The GO-Ag composites modified membranes show improved hydrophilicity, mechanical property and permeability than unmodified PVDF membrane. Specially, the antibacterial properties and inhibition of biofilm formation were greatly enhanced based on conventional inhibition zone test and anti-adhesion of bacterial experiment. The modified membranes also reveal a remarkable long-term continuous antimicrobial activity with slower release rate of Ag+ compared to AgNPs/PVDF membrane.