Platelet-Drug Conjugates Engineered via One-step Fusion Approach for Metastatic and Postoperative Cancer Treatment.

The exploration of cell-based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one-step fusion process. We demonstrate doxorubicin (DOX)-encapsulated liposomes conjugated with interleukin-15 (IL-15) could fuse with platelets to achieve both cytoplasmic drug loading and surface cytokine modification with a loading efficiency of over 70 % within minutes. Due to their inherent targeting ability to metastatic cancers and postoperative bleeding sites, the engineered platelets demonstrated a synergistic therapeutic effect to suppress lung metastasis and postoperative recurrence in mouse B16F10 melanoma tumor models.

GSH-Activatable Aggregation-Induced Emission Cationic Lipid for Efficient Gene Delivery.

The key to gene therapy is the design of biocompatible and efficient delivery systems. In this work, a glutathione (GSH)-activated aggregation-induced-emission (AIE) cationic amphiphilic lipid, termed QM-SS-KK, was prepared for nonviral gene delivery. QM-SS-KK was composed of a hydrophilic biocompatible lysine tripeptide headgroup, a GSH-triggered disulfide linkage, and a hydrophobic AIE fluorophore QM-OH (QM: quinoline-malononitrile) tail. The peptide moiety could not only efficiently compact DNA but also well modulate the dispersion properties of QM-SS-KK, leading to the fluorescence-off state before GSH treatment. The cleavage of disulfide in QM-SS-KK by GSH generated AIE signals in situ with a tracking ability. The liposomes consisted of QM-SS-KK, and 1,2-dioleoylphosphatidylethanolamine (DOPE) (QM-SS-KK/DOPE) delivered plasmid DNAs (pDNAs) into cells with high efficiency. In particular, QM-SS-KK/DOPE had an enhanced transfection efficiency (TE) in the presence of 10% serum, which was two times higher than that of the commercial transfection agent PEI25K. These results highlighted the great potential of peptide and QM-based fluorescence AIE lipids for gene delivery applications.

[Effects of Three Illuminants on the Color of High Translucent Multilayered Zirconia].

OBJECTIVE: To evaluate the effects of three common illuminants on the color of four brands of high translucent multilayered zirconia (HTMZ) ceramics so as to provide reference for clinical practice and dental restoration fabrication, and to reduce the risks for illuminant change causing color mismatch between the natural teeth and the restorations made of HTMZ. METHODS: Four brands of commonly used HTMZ were selected and ten cuboid samples ( n=10/group) of 12 mm×10 mm×0.8 mm were prepared for each type of HTMZ. The L*, a*, and b* values of the samples were measured under D65, A and F2, three standard illuminants. Then, the L*, a*, and b* values were statistically analyzed by using factors of the type of the illuminant and the brand of the zirconia. Color difference (ΔE) of samples of the same brand under exposure to changed illuminants was also calculated. RESULTS: When the same samples were exposure to different illuminants, there was no significant difference in the L* value, the a* value for the different iluminants was shown to be illuminant A>illuminant F2>illuminant D65, and the b* value was shown to be illuminant F2>illuminant D65>illuminant A. The L*, a*, and b* values of samples of different brands showed statistically significant difference when they were exposed to the same illuminant ( P<0.0001). Samples of the same brand showed ΔE when they were under the three different illuninants, and all ΔE were clinically acceptable. CONCLUSION: The types of illuminant used, to a certain degree, affected the hue and chroma of HTMZ. There were colorimetric differences between restorations made of different brands of HTMZ ceramics of the same color. The types of illuminants most common to the daily life of patients and the color characteristics of materials of different brands should be taken into consideration to facilitate the selection of restoration materials and dental restoration fabrication, and to reduce the risks for color mismatch between the restorations and the adjacent teeth caused by the change of illuminants.

Design and Engineering of an Efficient Peroxidase Using Myoglobin for Dye Decolorization and Lignin Bioconversion.

The treatment of environmental pollutants such as synthetic dyes and lignin has received much attention, especially for biotechnological treatments using both native and artificial metalloenzymes. In this study, we designed and engineered an efficient peroxidase using the O2 carrier myoglobin (Mb) as a protein scaffold by four mutations (F43Y/T67R/P88W/F138W), which combines the key structural features of natural peroxidases such as the presence of a conserved His-Arg pair and Tyr/Trp residues close to the heme active center. Kinetic studies revealed that the quadruple mutant exhibits considerably enhanced peroxidase activity, with the catalytic efficiency (kcat/Km) comparable to that of the most efficient natural enzyme, horseradish peroxidase (HRP). Moreover, the designed enzyme can effectively decolorize a variety of synthetic organic dyes and catalyze the bioconversion of lignin, such as Kraft lignin and a model compound, guaiacylglycerol-ß-guaiacyl ether (GGE). As analyzed by HPLC and ESI-MS, we identified several bioconversion products of GGE, as produced via bond cleavage followed by dimerization or trimerization, which illustrates the mechanism for lignin bioconversion. This study indicates that the designed enzyme could be exploited for the decolorization of textile wastewater contaminated with various dyes, as well as for the bioconversion of lignin to produce more value-added products.

Adsorptive decontamination of Cu2+-contaminated water and soil by carboxylated graphene oxide/chitosan/cellulose composite beads.

Graphene adsorbents have been applied to remove diverse pollutants from aqueous systems. However, the mechanical strength of most graphene adsorbents is low and the fragile graphene sheets are released into the environment. In this study, we prepared carboxylated graphene oxide/chitosan/cellulose (GCCSC) composite beads with good mechanical strength for the immobilization of Cu2+ from both water and soil. The proportional limit of GCCSC beads was 3.2 N, a much larger value than graphene oxide beads (0.2 N). The largest pressure for GCCSC beads recorded before brittle failure was 26 N. The Cu2+ adsorption capacity of GCCSC beads was 22.4 mg/g in aqueous systems at initial Cu2+ concentration of 40 µg/mL, which is competitive with many efficient adsorbents. The partition coefficient (PC) for the Cu2+ adsorption onto GCCSC beads was 1.12 mg/g/µM at Ce of 0.83 mg/L and qe of 14.3 mg/g. The PC decreased to 0.055 mg/g/µM at Ce of 26.0 mg/L and qe of 22.4 mg/g. The adsorption kinetics of Cu2+ on GCCSC beads were moderately fast and required approximately 3 h to reach equilibrium with a k2 of 0.0021 g/(mg·min). A lower temperature and higher pH slightly increased the adsorption capacity of GCCSC beads. The ionic strength did not influence the adsorption. The porous structure of GCCSC beads blocked the direct contact between soil and the graphene surface; thus, a high Cu2+ immobilization efficiency was achieved by GCCSC beads applied to soil. The implications for the design of high-performance graphene adsorbents for water and soil remediation are discussed.

Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation.

Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in lipid material structures and compositions to systematically achieve the pulmonary and hepatic (respectively) targeted mRNA distribution and expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation of LNP compositions. Contrary to current LNP paradigms, our findings demonstrate that cholesterol and phospholipid are dispensable for LNP functionality. Specifically, cholesterol-removal addresses the persistent challenge of preventing nanoparticle accumulation in hepatic tissues. By modulating and simplifying intrinsic LNP components, concurrent mRNA accumulation and translation is achieved in the lung and liver, respectively. This targeting strategy is applicable to existing LNP systems with potential to expand the progress of precise mRNA therapy for diverse diseases.

Glucose-responsive microneedle patch for closed-loop dual-hormone delivery in mice and pigs.

Insulin and glucagon secreted from the pancreas with dynamic balance play a vital role in regulating blood glucose levels. Although distinct glucose-responsive insulin delivery systems have been developed, the lack of a self-regulated glucagon release module limits their clinical applications due to the potential risk of hypoglycemia. Here, we describe a transdermal polymeric microneedle patch for glucose-responsive closed-loop insulin and glucagon delivery to achieve glycemic regulation with minimized risk of hypoglycemia. The glucose-responsive phenylboronic acid units can bind to glucose to reversibly shift the net charge (from positive to negative) of the entire polymeric matrix within microneedles. Therefore, the release ratio of the negatively charged insulin and the positively charged glucagon analog from the patch can be dynamically tuned upon the fluctuation of blood glucose levels to realize glycemic homeostasis. In both chemically induced type 1 diabetic mouse and minipig models, this glucose-responsive dual-hormone microneedle patch demonstrated tight long-term regulation in blood glucose levels (>24 hours in minipigs).

Toxicity and activity inhibition of metal-organic framework MOF-199 to nitrogen-fixing bacterium Azotobacter vinelandii.

Metal-organic framework (MOF) materials with fantastic properties have found important applications in various areas. Learning the lessons from plastics and microplastics, it is urgent to investigate the environmental impacts of emerging materials to avoid potential pollution. However, the environmental toxicity and risks of MOF materials are seldom reported. Herein, we studied the toxicity and activity inhibition of MOF-199 to nitrogen-fixing bacterium Azotobacter vinelandii. MOF-199 significantly suppressed the growth of A. vinelandii and led to cell death at 40 mg/L. MOF-199 penetrated the cell wall and induced the shrinking of bacterial cells. MOF-199 reduced the nitrogen fixation activity of A. vinelandii at 40 mg/L by decreasing the gene nifH levels and inhibiting the Ca2+Mg2+-ATPase activity, which was further confirmed by the changes in oxidative phosphorylation related genes. Complete growth inhibition and activity loss of A. vinelandii occurred at 60 mg/L of MOF-199. The toxicological mechanism of MOF-199 to A. vinelandii was assigned to the oxidative stress, which occurred at 20 mg/L and higher. Both Cu2+ release and particulates themselves contributed to the toxicity of MOF-199 to A. vinelandii. These findings highlighted the environmental hazards and risks of MOF materials to nitrogen-fixing bacteria and nitrogen fixation in the biogeochemical cycle.

Magnetic NiFe2O4/MWCNTs functionalized cellulose bioadsorbent with enhanced adsorption property and rapid separation.

Magnetic NiFe2O4 nanoparticles and multi-walled carbon nanotubes functionalized cellulose composite (m-NiFe2O4/MWCNTs@cellulose) as a magnetic bioadsorbent was prepared and used for effectively removing Congo Red (CR) from aqueous solution. The chemical and physical properties of the prepared m-NiFe2O4/MWCNTs@cellulose were characterized by XRD, TGA, FT-IR, VSM, SEM and TEM. Batch experiments were carried out to investigate the adsorption capacity and mechanisms. Effects of different adsorption parameters such as initial CR concentration, adsorbent dosage and temperature were studied. Results demonstrated that m-NiFe2O4/MWCNTs@cellulose had high adsorption capacity for CR from aqueous solution. The obtained experimental data fitted well with the pseudo-second-order equation and followed the Langmuir isotherm model with a maximum adsorption capacity of 95.70 mg g-1 for CR. The m-NiFe2O4/MWCNTs@cellulose with rapid magnetic separation and high adsorption capacity can be a promising and recyclable engineering biomaterials for purification and treatment of practical wastewater.

Biodefunctionalization of functionalized single-walled carbon nanotubes in mice.

Chemically modified carbon nanotubes with hydrophilic functionalities such as polyethylene glycols (PEGs) are widely pursued for potential biological and biomedical applications. In this study, PEGylated single-walled carbon nanotubes (PEG-SWNT) were intravenously administrated into mice to study their biodefunctionalization in vivo by using complementary Raman and photoluminescence measurements. There was meaningful defunctionalization of PEG-SWNT in liver over time, but not in spleen under similar conditions. The evidence from spectroscopic characterization and analyses is presented, and mechanistic implications are discussed.

Mechanical properties and degradation of drug eluted bioresorbable vascular scaffolds prepared by three-dimensional printing technology.

Bioresorbable vascular scaffolds are expected to replace the traditional metal stent, avoiding the long-term complications of metal stents. However, it is hard for the traditional scaffold manufacturing process to meet the requirements of individualized treatment for vascular lesions, which requires different morphologies. Here, we used a new method of scaffold manufacturing, three-dimensional printing technology, to prepare bioresorbable vascular scaffolds. The fabricated scaffold was loaded with sirolimus mixed with scaffold preparation material for slow drug release. The engineered, drug- loaded, bioresorbable vascular scaffold (BVS) was analyzed and tested in vivo. The scaffolds produced by three-dimensional printing technology exhibited good mechanical properties and in vitro degradation performance. The results also suggested that these scaffolds could maintain effective radial strength after long-term degradation and sustained release of the drug. As a new scaffold preparation method, it may provide a promising idea for developing bioresorbable vascular scaffold technology.

Blood Clearance, Distribution, Transformation, Excretion, and Toxicity of Near-Infrared Quantum Dots Ag2Se in Mice.

As a novel fluorescent probe in the second near-infrared window, Ag2Se quantum dots (QDs) exhibit great prospect in in vivo imaging due to their maximal penetration depth and negligible background. However, the in vivo behavior and toxicity of Ag2Se QDs still largely remain unknown, which severely hinders their wide-ranging biomedical applications. Herein, we systematically studied the blood clearance, distribution, transformation, excretion, and toxicity of polyethylene glycol (PEG) coated Ag2Se QDs in mice after intravenous administration with a high dose of 8 µmol/kg body weight. QDs are quickly cleared from the blood with a circulation half-life of 0.4 h. QDs mainly accumulate in liver and spleen and are remarkably transformed into Ag and Se within 1 week. Ag is excreted from the body readily through both feces and urine, whereas Se is excreted hardly. The toxicological evaluations demonstrate that there is no overt acute toxicity of Ag2Se QDs to mice. Moreover, in regard to the in vivo stability problem of Ag2Se QDs, the biotransformation and its related metabolism are intensively discussed, and some promising coating means for Ag2Se QDs to avert transformation are proposed as well. Our work lays a solid foundation for safe applications of Ag2Se QDs in bioimaging in the future.

Removal of carbon nanotubes from aqueous environment with filter paper.

The potential health and environmental hazards of carbon nanotubes (CNTs) have been a concerned issue. However, in contrast to the wide recognition of the toxicity of CNTs, little attention has been paid to the decontamination/remediation of CNT pollution. In this study, we report that CNTs can be removed from aqueous environment. In the presence of Ca²(+), CNTs aggregate quickly to micron size and then enable easy and effective removal via normal filtration. After filtration, CNT suspension becomes colorless with the remnant CNT concentration less than 0.5 µg mL⁻¹, a safe dose based on the published data. The filtration approach also works well in the presence of typical surfactant and dissolved organic matter. The removal efficiency is Ca²(+) concentration-dependent and regulated by the initial pH value and ionic strength. Our study is helpful for future decontamination of CNTs from aqueous environment.

In vitro toxicity evaluation of graphene oxide on A549 cells.

Graphene and its derivatives have attracted great research interest for their potential applications in electronics, energy, materials and biomedical areas. However, little information of their toxicity and biocompatibility is available. Herein, we performed a comprehensive study on the toxicity of graphene oxide (GO) by examining the influences of GO on the morphology, viability, mortality and membrane integrity of A549 cells. The results suggest that GO does not enter A549 cell and has no obvious cytotoxicity. But GO can cause a dose-dependent oxidative stress in cell and induce a slight loss of cell viability at high concentration. These effects are dose and size related, and should be considered in the development of bio-applications of GO. Overall, GO is a pretty safe material at cellular level, which is confirmed by the favorable cell growth on GO film.

Increased urinary 8-hydroxy-2'-deoxyguanosine levels in workers exposed to di-(2-ethylhexyl) phthalate in a waste plastic recycling site in China.

BACKGROUND: Di-(2-ethylhexyl) phthalate (DEHP) is a common plasticizer used in industrial and diverse consumer products. Animal studies indicate DEHP caused developmental, reproductive, and hepatic toxicities. However, human studies of the potential effects of DEHP are limited. METHODS: The exposed site with a history of over 20 years of waste plastic recycling was located in Hunan Province, China. The reference site without known DEHP pollution source was about 50 km far away from the exposed site. In this study, 181 workers working in plastic waste recycling and 160 gender-age matched farmers were recruited. DEHP concentrations in water and cultivated soil samples, serum thyroid-stimulating hormone, malondialdehyde (MDA), superoxide dismutase (SOD), urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), and micronuclei frequency in human capillary blood lymphocytes were analyzed. RESULTS: Mean levels of DEHP were greater in environment at the recycling site than at reference site (industry wastewater for the exposed: 42.43 µg/l; well water: 14.20 vs. 0.79 µg/l, pond water: 135.68 vs. 0.37 µg/l, cultivated soil: 13.07 vs. 0.81 mg/kg, p < 0.05 for all). The workers had higher median levels of MDA (3.80 vs. 3.14 nmol/ml) and urinary 8-OHdG (340.37 vs. 268.18 µmol/mol creatinine) and decreased SOD activities (112.15 vs. 123.82 U/ml) than the reference group (p < 0.01 for all). Multivariate analysis revealed that the history of working in waste plastic recycling was an independent risk factor for the increased urinary 8-OHdG levels in the male workers (p < 0.01). CONCLUSIONS: The occupational DEHP exposure might contribute to oxidative deoxyribonucleic acid damage in the male workers.

[Analysis of solid-liquid oxidizing poly silicic ferric sulfate (PSF-I)].

A new type of inorganic coagulant, solid-liquid oxidative poly silicic ferric sulfate (PSF-I), was prepared by adding KMnO4 and stabilizer M to poly silicic ferric sulfate (PSF). The species characteristics of PSF-I, the filtrate of PSF-I and PSF with spectrophotometer, and coagulation performance of PSF-I and the filtrate of PSF-I with jar tests were explored, respectively. Coagulation efficiency of PSF-I was studied compared to that of PSF and poly ferric sulfate (PFS), and the effect of storage time on coagulation performance of PSF-I was investigated. The results show that KMnO4 added to PSF modifies the microstructure of PSF, increasing species size of PSF and making UVA characteristic peaks of Fe3+ ion in PSF-I higher than that in PSF. There exists KMnO4 unattached in PSF-I. The solid phase in PSF-I is a kind of primary nucleus for building up flocs. The optimal dosage with PSF-I is 9 mg x L(-1), in comparison with 12 mg x L(-1) by PSF-I filtrate. The removal of natural organic matters (NOM) is not only caused by adsorption/charge-neutralization and co-precipitation but also by oxidization using PSF-I as coagulant, while to PSF and PFS, adsorption/charge-neutralization and co-precipitation is the only coagulation mechanism.