Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases.

A cellular prion protein (PrPC) is a ubiquitous cell surface glycoprotein, and its physiological functions have been receiving increased attention. Endogenous PrPC is present in various kidney tissues and undergoes glomerular filtration. In prion diseases, abnormal prion proteins are found to accumulate in renal tissues and filtered into urine. Urinary prion protein could serve as a diagnostic biomarker. PrPC plays a role in cellular signaling pathways, reno-protective effects, and kidney iron uptake. PrPC signaling affects mitochondrial function via the ERK pathway and is affected by the regulatory influence of microRNAs, small molecules, and signaling proteins. Targeting PrPC in acute and chronic kidney disease could help improve iron homeostasis, ameliorate damage from ischemia/reperfusion injury, and enhance the efficacy of mesenchymal stem/stromal cell or extracellular vesicle-based therapeutic strategies. PrPC may also be under the influence of BMP/Smad signaling and affect the progression of TGF-ß-related renal fibrosis. PrPC conveys TNF-α resistance in some renal cancers, and therefore, the coadministration of anti-PrPC antibodies improves chemotherapy. PrPC can be used to design antibody-drug conjugates, aptamer-drug conjugates, and customized tissue inhibitors of metalloproteinases to suppress cancer. With preclinical studies demonstrating promising results, further research on PrPC in the kidney may lead to innovative PrPC-based therapeutic strategies for renal disease.

Enhanced Energy Storage Performance of Polymer/Ceramic/Metal Composites by Increase of Thermal Conductivity and Coulomb-Blockade Effect.

Polymer-based dielectrics have attracted considerable attention for a wide range of applications as energy storage devices with high power. However, high loss from low thermal conductivity (K) and leaky current may limit their practical utilization greatly. To overcome these issues, two-dimensional hexagonal boron nitride (h-BN) modified with polydopamine (PDA) and metal palladium nanoparticles (h-BN@PDA@Pd NPs) are introduced into a poly(vinylidene fluoride-hexafluoropropylene) P(VDF-HFP) copolymer matrix. The PDA coating improves the compatibility between the ceramic h-BN filler and the polymer matrix. Contrary to the general idea, the metallic Pd NPs enhance the breakdown strength of the polymer nanocomposites through the Coulomb-blockade effect. The nanocomposite film filled with 6 vol % h-BN@PDA@Pd NPs exhibits significantly improved recoverable energy density (Urec) of 58.6 J cm-3, which is increasedby 496% compared to pure P(VDF-HFP) film, maintaining an efficiency of 65%, even under a high voltage of 500 MV m-1. The in-plane thermal conductivity of the nanocomposites was improved from 0.21 to 1.02 W m-1 K-1 with increasing ceramic h-BN content. This study suggests that a dielectric polymer with surface-engineered ceramic h-BN fillers through a Coulomb-blockade effect of metal Pd NPs might be a promising strategy for high energy storage devices.

Enhanced transdermal drug delivery of zaltoprofen using a novel formulation.

Zaltoprofen is a non-steroidal anti-inflammatory drug (NSAID) belonging to the propionic acid class. It has strong inhibitory effects on acute and chronic inflammation. Although zaltoprofen is well tolerated orally compared to other NSAIDs, it has to be administered in three to four doses per day and was associated with ulcerogenicity, bellyache and indigestion. This makes administration of zaltoprofen unsuitable for patients with gastric ulcer and is also associated with drug interactions. Therefore, it is important to develop an alternative dosage form which is easier to administer and avoids first-pass metabolism. The transdermal route meets all the above advantages. In this study, zaltoprofen gels were prepared using carbomer with mixture solution of polyethylene glycol (PEG) 400, Tween 80 and (2-hydroxypropyl)-ß-cyclodextrin (HPCD) (called as T2), subsequently oleic acid as a penetration enhancer was added. Zaltoprofen gel containing T2 and oleic acid could promote the percutaneous absorption of zaltoprofen and increase AUC by 183% compared to zaltoprofen gel without T2 and oleic acid. Also, there was a finding zaltoprofen gel containing T2 and oleic acid did not cause dermal irritations in an experimental animal.

Surface-modified gemcitabine with mucoadhesive polymer for oral delivery.

Gemcitabine microparticles were prepared using chitosan, polyethylene oxide or carbopol as the mucoadhesive polymer and eudragit L100-55 as the enteric polymer by a double emulsion method. The particle size and zeta potential changed from 1338.3 ± 254.1 nm to 2459.4 ± 103.6 nm and -5.16 ± 1.62 mV to 2.84 ± 0.65 mV, respectively, with increasing chitosan to gemcitabine weight ratio from 0.25 to 1. The gemcitabine-loaded microparticles without mucoadhesive polymer (F50) showed the particle size and zeta potential of 671.3 ± 58.3 nm and - 16.7 ± 1.82 mV, respectively. The cellular uptake of gemcitabine into Caco-2 cells from gemcitabine-loaded microparticles with chitosan increased with increasing incubation time in Caco-2 cells compared to that of gemcitabine-loaded microparticles with polyethylene oxide or carbopol, suggesting that chitosan might be the optimal mucoadhesive polymer. Gemcitabine microparticles will be tested to identify whether the oral absorption could be increased in the future.

Preparation and evaluation of polymeric microparticulates for improving cellular uptake of gemcitabine.

BACKGROUND: Gemcitabine must be administered at high doses to elicit the required therapeutic response because of its very short plasma half-life due to rapid metabolism. These high doses can have severe adverse effects. METHODS: In this study, polymeric microparticulate systems of gemcitabine were prepared using chitosan as a mucoadhesive polymer and Eudragit L100-55 as an enteric copolymer. The physicochemical and biopharmaceutical properties of the resulting systems were then evaluated. RESULTS: There was no endothermic peak for gemcitabine in any of the polymeric gemcitabine microparticulate systems, suggesting that gemcitabine was bound to chitosan and Eudragit L100-55 and its crystallinity was changed into an amorphous form. The polymeric gemcitabine microparticulate system showed more than 80% release of gemcitabine in 30 minutes in simulated intestinal fluid. When mucin particles were incubated with gemcitabine polymeric microparticulates, the zeta potential of the mucin particles was increased to 1.57 mV, indicating that the polymeric gemcitabine microparticulates were attached to the mucin particles. Furthermore, the F53 polymeric gemcitabine microparticulates having 150 mg of chitosan showed a 3.8-fold increased uptake of gemcitabine into Caco-2 cells over 72 hours compared with gemcitabine solution alone. CONCLUSION: Overall, these results suggest that polymeric gemcitabine microparticulate systems could be used as carriers to help oral absorption of gemcitabine.

Practical preparation procedures for docetaxel-loaded nanoparticles using polylactic acid-co-glycolic acid.

BACKGROUND: Nanoparticles fabricated from the biodegradable and biocompatible polymer, polylactic-co-glycolic acid (PLGA), are the most intensively investigated polymers for drug delivery systems. The objective of this study was to explore fully the development of a PLGA nanoparticle drug delivery system for alternative preparation of a commercial formulation. In our nanoparticle fabrication, our purpose was to compare various preparation parameters. METHODS: Docetaxel-loaded PLGA nanoparticles were prepared by a single emulsion technique and solvent evaporation. The nanoparticles were characterized by various techniques, including scanning electron microscopy for surface morphology, dynamic light scattering for size and zeta potential, x-ray photoelectron spectroscopy for surface chemistry, and high-performance liquid chromatography for in vitro drug release kinetics. To obtain a smaller particle, 0.2% polyvinyl alcohol, 0.03% D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), 2% Poloxamer 188, a five-minute sonication time, 130 W sonication power, evaporation with magnetic stirring, and centrifugation at 8000 rpm were selected. To increase encapsulation efficiency in the nanoparticles, certain factors were varied, ie, 2-5 minutes of sonication time, 70-130 W sonication power, and 5-25 mg drug loading. RESULTS: A five-minute sonication time, 130 W sonication power, and a 10 mg drug loading amount were selected. Under these conditions, the nanoparticles reached over 90% encapsulation efficiency. Release kinetics showed that 20.83%, 40.07%, and 51.5% of the docetaxel was released in 28 days from nanoparticles containing Poloxamer 188, TPGS, or polyvinyl alcohol, respectively. TPGS and Poloxamer 188 had slower release kinetics than polyvinyl alcohol. It was predicted that there was residual drug remaining on the surface from x-ray photoelectron spectroscopy. CONCLUSION: Our research shows that the choice of surfactant is important for controlled release of docetaxel.