Recent developments in Pickering emulsions for biomedical applications

Pickering emulsions, stabilised by organic or inorganic particles, offer long-term dispersibility of liquid droplets and resistance to coalescence. The versatility of stabilising particles and their ability to encapsulate and release cargo with high internal payload capacity makes them attractive in a wide variety of applications, ranging from catalysis to the cosmetic and food industry. While these properties make them an equally promising material platform for pharmaceutical and clinical applications, the development of Pickering emulsions for healthcare is still in its infancy. Herein, we summarise and discuss recent progress in the development of Pickering emulsions for biomedical applications, probing their design for passive diffusion-based release as well as stimuli-responsive destabilisation. We further comment on challenges and future directions of this exciting and rapidly expanding area of research.     

Characterizations of modalities and lex modalities

A reflective subuniverse in homotopy type theory is an internal version of the notion of a localization in topology or in the theory of ∞-categories. Working in homotopy type theory, we give new characterizations of the following conditions on a reflective subuniverse L: (1) the associated subuniverse $L^{\prime }$ of L-separated types is a modality; (2) L is a modality; (3) L is a lex modality; and (4) L is a cotopological modality. In each case, we give several necessary and sufficient conditions. Our characterizations involve various families of maps associated to L, such as the L-étale maps, the L-equivalences, the L-local maps, the L-connected maps, the unit maps ${\eta }_X$, and their left and/or right orthogonal complements. More generally, our main theorem gives an overview of how all of these classes related to each other. We also give examples that show that all of the inclusions we describe between these classes of maps can be strict.     

Methods for engineering therapeutic peptides

This review discussed recent advancements related to therapeutic peptide engineering.     

Swellable polymer films containing Au nanoparticles for point-of-care therapeutic drug monitoring using surface-enhanced Raman spectroscopy

Large (10 × 10 cm) sheets of surface-enhanced Raman spectroscopy (SERS) active polymer have been prepared by stabilising metal nanoparticle aggregates within dry hydroxyethylcellulose (HEC) films. In these films the aggregates are protected by the polymer matrix during storage but in use they are released when aqueous analyte droplets cause the films to swell to their gel form. The fact that these “Poly-SERS” films can be prepared in bulk but then cut to size and stored in air before use means that they provide a cost effective and convenient method for routine SERS analysis. Here we have tested both Ag and Au Poly-SERS films for use in point-of-care monitoring of therapeutic drugs, using phenytoin as the test compound. Phenytoin in water could readily be detected using Ag Poly-SERS films but dissolving the compound in phosphate buffered saline (PBS) to mimic body fluid samples caused loss of the drug signal due to competition for metal surface sites from Cl⁻ ions in the buffer solution. However, with Au Poly-SERS films there was no detectable interference from Cl⁻ and these materials allowed phenytoin to be detected at 1.8 mg L⁻¹, even in PBS. The target range of detection of phenytoin in therapeutic drug monitoring is 10–20 mg L⁻¹. With the Au Poly-SERS films, the absolute signal generated by a given concentration of phenytoin was lower for the films than for the parent colloid but the SERS signals were still high enough to be used for therapeutic monitoring, so the cost in sensitivity for moving from simple aqueous colloids to films is not so large that it outweighs the advantages which the films bring for practical applications, in particular their ease of use and long shelf life.     

Simultaneous determination of ten antiepileptic drugs in human plasma by liquid chromatography and tandem mass spectrometry with positive/negative ion‐switching electrospray ionization and its application in therapeutic drug monitoring

A simple, rapid, and high‐throughput liquid chromatography with tandem mass spectrometry method for the simultaneous quantitation of ten antiepileptic drugs in human plasma has been developed and validated. The method required only 10 μL of plasma. After simple protein precipitation using acetonitrile, the analytes and internal standard diphenhydramine were separated on a Zorbax SB‐C₁₈ column (50 × 4.6 mm, 2.7 μm) using acetonitrile/water as the mobile phase at a flow rate of 0.9 mL/min. The total run time was 6 min for each sample. The validation results of specificity, matrix effects, recovery, linearity, precision, and accuracy were satisfactory. The lower limit of quantification was 0.04 μg/mL for carbamazepine, 0.02 μg/mL for lamotrigine, 0.01 μg/mL for oxcarbazepine, 0.4 μg/mL for 10‐hydroxycarbazepine, 0.1 μg/mL for carbamazepine‐10,11‐epoxide, 0.15 μg/mL for levetiracetam, 0.06 μg/mL for phenytoin, 0.3 μg/mL for valproic acid, 0.03 μg/mL for topiramate, and 0.15 μg/mL for phenobarbital. The intraday precision and interday precision were less than 7.6%, with the accuracy ranging between –8.1 and 7.9%. The method was successfully applied to therapeutic drug monitoring of 1237 patients with epilepsy after administration of standard antiepileptic drugs. The method has been proved to meet the high‐throughput requirements in therapeutic drug monitoring.     

Therapeutic drug monitoring of cefepime with micellar electrokinetic capillary chromatography: Assay improvement,quality assurance,and impact on patient drug levels

The improvement and performance of a micellar electrokinetic capillary chromatography assay for cefepime in human serum and plasma with a 50 μm id fused‐silica capillary elongated from 40 to 60 cm is reported. Sample preparation with dodecylsulfate protein precipitation at pH 4.5, the pH 9.1 separation medium, and the applied voltage were as reported previously [16]. The change resulted in a significant lower current, higher resolution, and increased detection time intervals. The performance of the assay with multilevel internal calibration was assessed with calibration and control samples. Quality assurance data of a 2‐year period assessed under the new conditions demonstrated the robustness of the assay. In serum samples of patients who received both cefepime and sulfamethoxazole, cefepime could not be detected due to the inseparability of the two compounds. The presence of an interference can be recognized by an increased peak width (width > 0.2 min), the appearance of a shoulder or an unresolved double peak. The patient data gathered during a 3‐year period reveal that introduction of therapeutic drug monitoring led to a 50% reduction of the median drug level. The data suggest that therapeutic drug monitoring can help to minimize the risk of major adverse reactions and to increase drug safety on an individual basis.     

Tumor‐Targeting W18O49 Nanoparticles for Dual‐Modality Imaging and Guided Heat‐Shock‐Response‐Inhibited Photothermal Therapy in Gastric Cancer

Photothermal therapy (PTT) is an emerging noninvasive and precise localized therapeutic modality; however, it is deeply limited by its poor tumor accumulation, inadequate photothermal conversion efficiency, and the thermoresistance of cancer cells. Aimed at these shortcomings, tumor‐targeting nanoparticles (iRGD‐W₁₈O₄₉‐17AAG) comprising carboxyl‐group‐functionalized W₁₈O₄₉ nanoparticles, integrin‐targeting peptide iRGD, and HSP90‐inhibitor 17AAG are developed. The W₁₈O₄₉ nanoparticles act as excellent PTT carriers and computed tomography (CT) imaging contrast agents. The ring type polypeptide iRGD promotes the accumulation of nanoparticles in the tumour and further penetration into cancer cells. The introduction of 17AAG can inhibit the heat‐shock response and overcome the thermoresistance, thus increasing the curative effect of PTT and reducing the chance of tumor recurrence. The W₁₈O₄₉ nanoparticles can also be used to monitor and guide the phototherapeutic through CT and near‐infrared fluorescence imaging after modification with Cy5.5. In addition, superior biosafety is also indicated in both preliminary in vitro and in vivo assessments. The potential of iRGD‐W₁₈O₄₉‐17AAG in tumor targeting, dual modality imaging‐guided and remarkable enhanced PTT of gastric cancer with ignorable side effect both in vitro and in vivo, which may be further applied in clinic, is highlighted.     

The universal modality, the center of a Heyting algebra, and the Blok–Esakia theorem

We introduce the bimodal logic , which is the extension of Bennett’s bimodal logic by Grzegorczyk’s axiom □(□(p→□p)→p)→p and show that the lattice of normal extensions of the intuitionistic modal logic WS5 is isomorphic to the lattice of normal extensions of , thus generalizing the Blok–Esakia theorem. We also introduce the intuitionistic modal logic WS5.C, which is the extension of WS5 by the axiom (p¬p)→(p→p), and the bimodal logic , which is the extension of Shehtman’s bimodal logic by Grzegorczyk’s axiom, and show that the lattice of normal extensions of WS5.C is isomorphic to the lattice of normal extensions of .     

Short-Term Therapeutic Trial of Proton Pump Inhibitors in Suspected Extraesophageal Reflux

Pharyngoesophageal gastric acid reflux is thought to initiate chronic posterior laryngitis. The gold standard for measuring gastric reflux is dual-channel 24-hour pH monitoring. This is a time-consuming, inconvenient, expensive method that is not available in all areas. New therapeutic regimes that make use of proton pump inhibitors (PPIs) have proven to be therapeutically efficient for control of acid reflux. Twenty-four consecutive patients with chronic voice disorders and signs of posterior laryngitis were selected for therapy. Twenty-four hour pH monitoring was performed independently before the therapy. The trial therapy consisted of all patients receiving pantoprazole, 40 mg once daily for 6 weeks. Immediately following the therapy a statistically significant (p < 0.05) improvement was observed in all patients. This improvement was analyzed retrospectively by comparison with the results of 24-hour pH monitoring. In 71% of the patients the 24-hour pH-monitoring gave a positive result showing a high number of patients with extraesophageal reflux in our study group. Patients with positive results of pH-monitoring responded in a statistically significant manner (p < 0.05) to the pantoprazole therapy, whereas those patients without detected reflux did not. A 3-month follow-up of the patients with a positive result of the pH-monitoring confirmed the improvement. No patients reported adverse effects. A 6-week treatment with pantoprazole can be clinically justified. It helps to save time and reduce costs, allows for selection of reflux-negative patients for alternative therapy, and may prevent inadequate treatment of patients with false-negative pH monitoring. Twenty-four hour pH monitoring is still recommended for patients unresponsive to this trial therapy.     

Rapid high-performance liquid chromatography determination of lopinavir, a novel HIV-1 protease inhibitor, in human plasma

Summary Lopinavir is a new specific and potent HIV-1 protease inhibitor. A rapid high-performance liquid chromatographic method using UV detection, has been developed and validated for the analysis of lopinavir in plasma. This involved a single liquid-solid extraction on an OASIS^? HLB column in the presence of an internal standard. Separation was achieved on a Xterra^?, C₈ (150×3.9 mm I.D.) column with a mobile phase consisting of acetonitrile and water (41∶59, v/v). The detection wavelength was 210 nm. The assay was linear from 0.187 to 10.0 μg.mL⁻¹ and the limit of quantification was 0.187 μg.mL⁻¹. Mean recovery was ranged from 90.7% to 97.8% for lopinavir and 97.1% for the internal standard. Day to day precision and accuracy were less than 9.6% and 7.3% respectively. This rapid and simple method can readily be used for drug monitoring of lopinavir, in HIV-1 infected patients.