Innovative color jet 3D printing of levetiracetam personalized paediatric preparations

3D printing is a promising technology used in the fabrication of complex oral dosage delivery pharmaceuticals.This study first reports an innovative color jet 3D printing(CJ-3DP)technology to produce colorful cartoon levetiracetam pediatric preparations with high accuracy and reproducibility.For this study,the ideal printing ink consisted of 40%(v/v)isopropanol aqueous solution containing 0.05%(w/w)polyvinylpyrrolidone and 4%(w/w)glycerin,which was satisfied with scale-up of the production.The external and internal spatial structures of the tablets were designed to control the appearance and release,and cartoon tablets with admirable appearances and immediate release characteristics were printed.The dosage model showed a good linear relationship between the model volume and the tablet strength(r>0.999),which proved the potential of personalized administration.The surface roughness indicated that the appearance of the CJ-3DP tablets was significantly better than the first listed 3D printed drug(Spritam R).Moreover,the scanning electron microscopy and porosity results further showed that the tablets have a structure of loose interior and tight exterior,which could ensure good mechanical properties and rapid dispersion characteristics simultaneously.In conclusion,the innovative CJ-3DP technology can be used to fabricate personalized pediatric preparations for improved compliance.Due to the stable formulation and fabrication process,this technology has the potential in scale-up production.

Cyanobacteria-based near-infrared light-excited self-supplying oxygen system for enhanced photodynamic therapy of hypoxic tumors

Tumor hypoxia has been considered to induce tumor cell resistance to radiotherapy and anticancer chemotherapy,as well as predisposing for increased tumor metastases.Therefore,strategies for the eradication of the hypoxic tumor are highly desirable.Photodynamic therapy(PDT)is a new technique that can be used to treat tumors using laser irradiation to photochemically activate a photosensitizer.Compared to traditional radiotherapy and chemotherapy,photodynamic therapy has many advantages,such as good selectivity,low toxicity,and less trauma and resistance.However,PDT is oxygen-dependent,and the lack of oxygen in hypoxic tumors renders photodynamic therapy ineffective.Cyanobacteria,the earliest photosynthetic oxygen-generating organisms,can utilize water as an electron donor to reduce CO_(2) into organic carbon compounds along with continuously releasing oxygen under sunlight.Inspired by this,herein,cyanobacteria were used as a living carrier of photosensitizer conjugated upconversion nanoparticles(UCNP)to construct a self-supplying oxygen PDT system.Improvement in the PDT efficiency for hypoxic tumors can be achieved as a result of in situ oxygen production by cyanobacteria under near-infrared(NIR)light using UCNP as a light harvesting antenna.A successful demonstration of this concept would be of great significance and could open the door to a new generation of carrier systems in the field of hypoxia-targeted drug transport platforms.

Anti-inflammatory and Anti-oxidant Effects of Licorice Flavonoids on Ulcerative Colitis in Mouse Model

Licorice（Glycyrrhizae Radix or Liquiritiae Radix） is traditionally used to treat various diseases including inflammation and gastric ulcers. Licorice is rich in flavonoid compounds and possesses anti-inflammatory activities. To investigate the protective effects of licorice flavonoids（LFs） in both acetic acid-induced and dextran sulphate sodium（DSS）-induced ulcerative colitis（UC） mouse model and its underlying mechanism. Acute UC was induced by intra-rectal acetic acid（4% v/v） after pretreatment with LFs（100, 200, and 400 mg/kg, p.o.）, 0.9% saline（20 mL/kg, p.o.） or Sulfasalazine（SASP）（600 mg/kg, p.o.） for 10 d. Quantitative analysis of chemical components of LFs was also conducted by HPLC. Our results showed that pre-treatment with LFs significantly reduced the wet weight/length ratio of colon, percentage of affected area, macroscopic and histological damage scores in acid-induced UC mice. LFs also significantly decreased the oxidative stress and pro-inflammatory cytokines, upregulated nuclear factor erythroid 2-related factor 2（Nrf2） pathway and downregulated nuclear transcription factor kappa B（NF-κB） pathway. At last, LFs also showed obvious antiulcer effect on the DSS-induced UC model. The major components of LFs were licochalcone A, glabrone, licoflavone, and licoflavone B. This study demonstrates that the protective effect of LFs may at least in part be due to its anti-oxidant activity through Nrf2 pathway and anti-inflammatory activity through NF-κB pathway.

Neurotoxicity and brain localization of europium doped Gd2O3 nanotubes in rats after intranasal instillation

Europium doped Gd2O3nanotubes(Gd2O3:Eu3+NTs) were synthesized and characterized. Then,the neurotoxicity and brain localization of Gd2O3:Eu3+NTs were evaluated. All experimental rats were administered by intranasal instillation with 30 μL Gd2O3:Eu3+NTs suspension 3.0 and 15.0 mg/mL respectively every other day for 35 consecutive days, and the rats of control group were administered with an equal volume of physiological saline. The Morris water maze was used to assess the rats’ spatial learning and memory ability. The oxidative stress-related biomarkers and the activity of AChE in striatum and hippocampus were analyzed, and the histopathology of hippocampus and striatum was observed.The brain localization of gadolinium(Gd) was measured. The results showed that the escape latency of the rats in high-dose group prolonged significantly compared with that of control group after treatment of six weeks(p < 0.05), and the swimming time in D quadrant of high-dose group shortened significantly compared with the control group(p < 0.01). In addition, high-dose Gd2O3:Eu3+NTs could decrease the activity of GSH-Px and CAT in hippocampus and the activity of SOD in striatum(p < 0.05). MDA content in hippocampus and striatum of high-dose group increased(p < 0.05). High dose Gd2O3:Eu3+NTs could increase the activity of AChE in hippocampus(p < 0.05) and in striatum(p < 0.001). But there were no significant differences between the low-dose group and control group(p > 0.05). The results of Gd localization in brain showed that the ranking of Gd levels was olfactory bulb > striatum > hippocampus> cerebellum > brain stem > frontal cortex. The pathology results indicated that high dose Gd2O3:Eu3+NTs resulted in degeneration necrosis, nucleus pycnosis, and axons disappearance of the nerve cells at CA1, CA3 and DG area of hippocampus. Therefore, the results implied that Gd2O3:Eu3+NTs have the potential neurotoxicity and a possible danger in causing neurodegenerative disorders after intranasal instillation.

Liposome-coated CaO_(2)nanoblockers for enhanced checkpoint blockade therapy by inhibiting PD-L1 de novo biosynthesis

The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.

An Aptamer-based Colorimetric Sensor for Streptomycin and Its Application in Food Inspection

An aptamer-based colorimetric biosensor was developed, which could be used to detect residual strepto- mycin from food quickly and cost-effectively. The ssDNA aptamer target for streptomycin was obtained using sys- temic evolution of ligands by exponential enrichment through affinity chromatography. A total of 19 candidates were obtained after 10 rounds of selection and were grouped into 3 families according to their similarity of sequence and structure. Among them, aptamer A15 showed the highest affinity for streptomycin tested by fluorescence intensity analysis with a dissociation constant of 6.07 nmol/L. Aptamer A15 also exhibited a higher streptomycin specificity with the lowest detectable limit of 25 nmol/L according to the value of A620/A520 ratio with AuNP-based colorimetric assay. The method was specific and sensitive for the detection of streptomycin from simply-treated milk and honey at 100 and 125 nmol/L, respectively, and is a promising approach to monitor antibiotics or other small molecules ana- logues in food inspection.

1-(3-Aminopropyl)-3-butylimidazolium bromide for carboxyl group derivatization:potential applications in high sensitivity peptide identification by mass spectrometry

The cationic reagent 1-(3-aminopropyl)-3-butylimidazolium bromide(BAPI) was exploited for the derivatization of carboxyl groups on peptides.Nearly 100% derivatization efficiency was achieved with the synthetic peptide RVYVHPI(RI-7).Furthermore,the peptide derivative was stable in a 0.1% TFA/water solution or a 0.1%(v/v) TFA/acetonitrile/water solution for at least one week.The effect of BAPI derivatization on the ionization of the peptide RI-7 was further investigated,and the detection sensitivity was improved >42-fold via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF MS),thus outperforming the commercial piperazine derivatization approach.Moreover,the charge states of the peptide were largely increased via BAPI derivatization by electrospray ionization(ESI) MS.The results indicate the potential merits of BAPI derivatization for high sensitivity peptide analysis by MS.