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Background Biofilm formation is one of the main reasons for persistent bacterial infections. Recently, pH-sensitive copolymers have fascinated incredible attention to tackle biofilm-related infections. However, the proper incorporation of pH-sensitive segments in the polymer chains, which could significantly affect the biofilms targeting ability, has not been particularly investigated. Herein, we synthesized three types of pH-sensitive copolymers based on poly (β-amino ester) (PAE), poly (lactic-co-glycolic acid) (PLA) and polyethylene glycol (PEG), PAE-PLA-mPEG (A-L-E), PLA-PAE-mPEG (L-A-E) and PLA-PEG-PAE (L-E-A) to address this issue. Results The three copolymers could self-assemble into micelles (M A-L-E , M L-A-E and M L-E-A ) in aqueous medium. Compared with M A-L-E and M L-A-E , placing the PAE at the distal PEG end of PLA-PEG to yield PLA-PEG-PAE (M L-E-A ) was characterized with proper triggering pH, fully biofilm penetration, and high cell membrane binding affinity. Further loaded with Triclosan (TCS), M L-E-A /TCS could efficiently kill the bacteria either in planktonic or biofilm mode. We reasoned that PAE segments would be preferentially placed near the surface and distant from the hydrophobic PLA segments. This would increase the magnitude of surface charge-switching capability, as the cationic PAE + would easily disassociate from the inner core without conquering the additional hydrophobic force arising from covalent linkage with PLA segments, and rapidly rise to the outermost layer of the micellar surface due to the relative hydrophilicity. This was significant in that it could enable the micelles immediately change its surface charge where localized acidity occurred, and efficiently bind themselves to the bacterial surface where they became hydrolyzed by bacterial lipases to stimulate release of encapsulated TCS even a relatively short residence time to prevent rapid wash-out. I n vivo therapeutic performance of M L-E-A /TCS was evaluated on a classical biofilm infection model, implant-related biofilm infection. The result suggested that M L-E-A /TCS was effective for the treatment of implant-related biofilm infection, which was proved by the efficient clearance of biofilm-contaminated catheters and the recovery of surrounding infected tissues. Conclusions In summary, elaboration on the architecture of pH-sensitive copolymers was the first step to target biofilm. The M L-E-A structure may represent an interesting future direction in the treatment of biofilm-relevant infections associated with acidity. Graphic abstract

Nanostructured lipid carriers (NLCs) are emerging as attractive drug carriers in transdermal drug delivery. The surface modification of NLCs with cell-penetrating peptides (CPPs) can enhance the skin permeation of drugs. The objective of the current study was to evaluate the ability of the cell-penetrating peptide (CPP) polyarginine to translocate NLCs loaded with lornoxicam (LN) into the skin layers and to evaluate its anti-inflammatory effect. The NLCs were prepared using an emulsion evaporation and low temperature solidification technique using glyceryl monostearates, triglycerides, DOGS-NTA-Ni lipids and surfactants, and then six histidine-tagged polyarginine containing 11 arginine (R11) peptides was modified on the surface of NLCs. The developed NLCs formulated with LN and R11 (LN-NLC-R11) were incorporated into 2% HPMC gels. NLCs were prepared with a particle size of (121.81±3.61)-(145.72±4.78) nm, and the zeta potential decreased from (-30.30±2.07) to (-14.66±0.74) mV after the modification of R11 peptides. The encapsulation efficiency and drug loading were (74.61±1.13) % and (7.92±0.33) %, respectively, regardless of the surface modification. Cellular uptake assays using HaCaT cells suggested that the NLC modified with R11 (0.02%, w/w) significantly enhanced the cell internalization of nanoparticles relative to unmodified NLCs ( <0.05 or <0.01). An in vitro skin permeation study showed better permeation-enhancing ability of R11 (0.02%, w/w) than that of other content (0.01% or 0.04%). In carrageenan-induced rat paw edema models, LN-NLC-R11 gels inhibited rat paw edema and the production of inflammatory cytokines compared with LN-NLC gels and LN gels ( <0.01). In our investigation, it was strongly demonstrated that the surface modification of NLC with R11 enhanced the translocation of LN across the skin, thereby alleviating inflammation.

Gemcitabine (GEM) and paclitaxel (PTX) are effective combination anticancer agents against non-small-cell lung cancer (NSCLC). At the present time, a main challenge of combination treatment is the precision of control that will maximize the combined effects. Here, we report a novel method to load GEM (hydrophilic) and PTX (hydrophobic) into simplex tumor-targeted nanostructured lipid carriers (NLCs) for accurate control of the ratio of the two drugs. We covalently preconjugated the dual drugs through a hydrolyzable ester linker to form drug conjugates. -acetyl-d-glucosamine (NAG) is a glucose receptor-targeting ligand. We added NAG to the formation of NAG-NLCs. In general, synthesis of poly(6- -methacryloyl-d-galactopyranose)-GEM/PTX (PMAGP-GEM/PTX) conjugates was demonstrated, and NAG-NLCs were prepared using emulsification and solvent evaporation. NAG-NLCs displayed sphericity with an average diameter of 120.3±1.3 nm, a low polydispersity index of 0.233±0.04, and accurate ratiometric control over the two drugs. A cytotoxicity assay showed that the NAG-NLCs had better antitumor activity on NSCLC cells than normal cells. There was an optimal ratio of the two drugs, exhibiting the best cytotoxicity and combinatorial effects among all the formulations we tested. In comparison with both the free-drug combinations and separately nanopackaged drug conjugates, PMAGP-GEM/PTX NAG-NLCs (3:1) exhibited superior synergism. Flow cytometry and confocal laser scanning microscopy showed that NAG-NLCs exhibited higher uptake efficiency in A549 cells via glucose receptor-mediated endocytosis. This combinatorial delivery system settles problems with ratiometric coloading of hydrophilic and hydrophobic drugs for tumor-targeted combination therapy to achieve maximal anticancer efficacy in NSCLC.

Sequential treatment with paclitaxel (PTXL) and gemcitabine (GEM) is considered clinically beneficial for non-small-cell lung cancer. This study aimed to investigate the effectiveness of a nano-system capable of sequential release of PTXL and GEM within cancer cells. PTXL-ss-poly(6- -methacryloyl-d-galactopyranose)-GEM (PTXL-ss-PMAGP-GEM) was designed by conjugating PMAGP with PTXL via disulfide bonds (-ss-), while GEM via succinic anhydride (PTXL:GEM=1:3). An amphiphilic block copolymer N-acetyl-d-glucosamine(NAG)-poly(styrene-alt-maleic anhydride) -b-polystyrene acted as a targeting moiety and emulsifier in formation of nanostructures (NLCs). The PTXL-ss-PMAGP-GEM/NAG NLCs (119.6 nm) provided a sequential in vitro release of, first PTXL (redox-triggered), then GEM (pH-triggered). The redox- and pH-sensitive NLCs readily distributed homogenously in the cytoplasm. NAG augmented the uptake of NLCs by the cancer cells and tumor accumulation. PTXL-ss-PMAGP-GEM/NAG NLCs exhibited synergistic cytotoxicity in vitro and strongest antitumor effects in tumor-bearing mice compared to NLCs lacking pH/redox sensitivities or free drug combination. This study demonstrated the abilities of PTXL-ss-PMAGP-GEM/NAG NLCs to achieve synergistic antitumor effect by targeted intracellularly sequential drug release.

The increasing prevalence of systemic fungal infections, especially among immunocompromised individuals, highlights the need for advancements in targeted and effective antifungal treatments. This study presents a novel nanomaterial, CFW-phosphatidylethanolamine conjugate (CFW-PEc), designed to enhance the delivery and efficacy of antifungal agents by targeting fungal cell walls through specific chitin binding. Ethosomes, lipid-based nanocarriers known for their ability to improve drug delivery across skin and cell membranes, were utilized in this study. The physicochemical characteristics of voriconazole-loaded CFW-PEc ethosomes (CFW-PEc-VRC-ethosomes) were examined, including particle size, zeta potential, and entrapment efficiency. Antifungal efficacy of CFW-PEc-VRC-ethosomes was evaluated, including antifungal activity in vitro, CFW-PEc-ethosomes cellular uptake, and models of animal infection and imaging analyses. In vitro experiments demonstrated a concentration-dependent inhibition of growth by CFW-PEc, with cell inhibition rates reaching nearly 100% at 256 μM. In vivo investigations confirmed a 5-fold reduction in fungal burden in the liver and a 7.8-fold reduction in the kidney compared to the control group following treatment with CFW-PEc (0.1 μM)-VRC-ethosomes. Imaging analyses also confirmed the extended tissue retention of fluorescent dye-loaded CFW-PEc-ethosomes in mice, further underscoring their potential for clinical use. The targeted delivery of antifungal medications via ethosomes coated with CFW-PEc presents a promising strategy to improve antifungal effectiveness while reducing adverse effects, marking a significant advancement in fungal infection therapy.

commonly adheres to implanted medical devices and forms biofilms. Due to the minimal activity of current antifungals against biofilms, new drugs or drug-delivery systems to treat these persistent infections are urgently needed. In the present investigation, voriconazole-loaded nanostructured lipid carriers (Vrc-NLCs) were formulated for enhanced drug-delivery efficiency to to increase the antifungal activity of Vrc and to improve the treatment of infectious diseases. Vrc-NLCs were prepared by a hot-melt, high-pressure homogenization method, and size distribution, ζ-potential, morphology, drug-encapsulation efficiency, drug loading, and physical stability were characterized. The antifungal activity of Vrc-NLCs in vitro was tested during planktonic and biofilm growth in . The mean particle size of the Vrc-NLCs was 45.62±0.53 nm, and they exhibited spheroid-like morphology, smooth surfaces, and ζ-potential of -0.69±0.03 mV. Encapsulation efficiency and drug loading of Vrc-NLCs were 75.37%±2.65% and 3.77%±0.13%, respectively. Physical stability results revealed that despite the low measured ζ-potential, the dispersion of the Vrc-NLCs was stable during their 3-week storage at 4°C. The minimum inhibitory concentration of Vrc-NLCs was identical to that of Vrc. However, the inhibition rate of Vrc-NLCs at lower concentrations was significantly higher than that of Vrc during planktonic growth in in yeast-extract peptone dextrose medium. Surprisingly, Vrc-NLCs treatment reduced cell density in biofilm growth in and induced more switches form hyphal cells to yeast cells compared with Vrc treatment. In conclusion, Vrc-NLCs maintain antifungal activity of Vrc and increase antifungal drug-delivery efficiency to . Therefore, Vrc-NLCs will greatly contribute to the treatment of infectious diseases caused by .

Poly(ethylene glycol)-poly(D,L-lactide) (PEG-PLA), a type of copolymer widely used for drug delivery, was synthesized in the present work based on previous studies, which is used for bovine serum albumin (BSA)-loaded micelle formulation. The micelles exhibited less than 100 nm in size with narrow polydispersity indices (PDI) of smaller than 0.3, and showed an encapsulation efficiency of 69%. BSA was encapsulated in the PEG-PLA micelle successfully exhibiting intact structure indicated by native polyacrylamide gel electrophoresis (Native-PAGE), fluorescence spectroscopy and fourier transform infrared spectroscopy (FTIR) analysis methods. It investigated the effects of freeze-drying, varying amount of cryoprotectants (sucrose, mannitol and lactose), and ultrasonication treatment on the size, and size distribution. The micelles were agglomerated in the freeze-drying process demonstrated by transmission electron microscope (TEM) and dynamic light scattering (DLS) analysis. Five percent of mannitol and ultrasonication for 90 s were found producing a significant reduction in agglomeration as well as a sharp decrease in size. The results demonstrated suitable cryoprotectant, and ultrasonication are beneficial to control the size and distribution of protein-loaded PEG-PLA micelle.

Gemcitabine (GEM) and paclitaxel (PTX) are effective combination anticancer agents against non-small-cell lung cancer (NSCLC). At the present time, a main challenge of combination treatment is the precision of control that will maximize the combined effects. Here, we report a novel method to load GEM (hydrophilic) and PTX (hydrophobic) into simplex tumor-targeted nanostructured lipid carriers (NLCs) for accurate control of the ratio of the two drugs. We covalently preconjugated the dual drugs through a hydrolyzable ester linker to form drug conjugates. V-acetyl-D-glucosamine (NAG) is a glucose receptor-targeting ligand. We added NAG to the formation of NAG-NLCs. In general, synthesis of poly(6-0-methacryloyl-D-galactopyranose)-GEM/PTX (PMAGP-GEM/PTX) conjugates was demonstrated, and NAG-NLCs were prepared using emulsification and solvent evaporation. NAG-NLCs displayed sphericity with an average diameter of 120.3[+ or -]1.3 nm, a low polydispersity index of 0.233[+ or -]0.04, and accurate ratiometric control over the two drugs. A cytotoxicity assay showed that the NAG-NLCs had better antitumor activity on NSCLC cells than normal cells. There was an optimal ratio of the two drugs, exhibiting the best cytotoxicity and combinatorial effects among all the formulations we tested. In comparison with both the free-drug combinations and separately nanopackaged drug conjugates, PMAGP-GEM/PTX NAG-NLCs (3:1) exhibited superior synergism. Flow cytometry and confocal laser scanning microscopy showed that NAG-NLCs exhibited higher uptake efficiency in A549 cells via glucose receptor-mediated endocytosis. This combinatorial delivery system settles problems with ratiometric coloading of hydrophilic and hydrophobic drugs for tumor-targeted combination therapy to achieve maximal anticancer efficacy in NSCLC. Keywords: polymer-drug conjugate, nanostructured lipid carriers, combination treatment, ratiometric drug loading, cancer targeting

Biochar application as a soil amendment has been proposed as a strategy to improve soil fertility and increase crop yields. However, the effects of successive biochar applications on cotton yields and nutrient distribution in soil are not well documented. A three-year field study was conducted to investigate the effects of successive biochar applications at different rates on cotton yield and on the soil nutrient distribution in the 0-100 cm soil profile. Biochar was applied at 0, 5, 10, and 20 t ha-1 (expressed as Control, BC5, BC10, and BC20, respectively) for each cotton season, with identical doses of chemical fertilizers. Biochar enhanced the cotton lint yield by 8.0-15.8%, 9.3-13.9%, and 9.2-21.9% in 2013, 2014, and 2015, respectively, and high levels of biochar application achieved high cotton yields each year. Leaching of soil nitrate was reduced, while the pH values, soil organic carbon, total nitrogen (N), and available K content of the 0-20 cm soil layer were increased in 2014 and 2015. However, the changes in the soil available P content were less substantial. This study suggests that successive biochar amendments have the potential to enhance cotton productivity and soil fertility while reducing nitrate leaching.