Infective Endocarditis in Cancer Patients　- Causative Organisms, Predisposing Procedures, and Prognosis Differ From Infective Endocarditis in Non-Cancer Patients.

BACKGROUND: Infective endocarditis (IE) in cancer patients is increasing, but because little is known about it in these patients, we analyzed patient characteristics and outcomes and compared these factors in IE patients with and without cancer. Methods and Results: This retrospective cohort study included 170 patients with IE newly diagnosed between January 2011 and December 2015. Among 170 patients, 30 (17.6%) had active cancer. The median age of IE patients with cancer was higher than that of non-cancer patients. Nosocomial IE was more common in cancer patients. Non-dental procedures, such as intravenous catheter insertion and invasive endoscopic or genitourinary procedures, were more frequently performed before IE developed in cancer patients. Staphylococcus was the most common pathogen in cancer patients, whereas Streptococcus was the most common in non-cancer patients. In-hospital mortality was significantly higher in cancer patients with IE (34.4% vs. 12.4%, P<0.001). IE was an important reason for discontinuing antitumor therapy and withholding additional aggressive treatment in nearly all deceased cancer patients. CONCLUSIONS: IE is common in cancer patients and is associated with poorer outcomes. Patients with IE and cancer have different clinical characteristics. Additional studies regarding antibiotic prophylaxis before non-dental invasive procedures in cancer patients are needed, as cancer patients are not considered to be at higher risk of IE.

Black Phosphorus-Based Reusable Biosensor Platforms for the Ultrasensitive Detection of Cortisol in Saliva.

A black phosphorus (BP)-based reusable biosensor platform is developed for the repeated and real-time detection of cortisol using antibody-conjugated magnetic particle (MP) structures as a refreshable receptor. Here, we took advantage of the low-noise characteristics of a mechanically exfoliated BP-based field-effect transistor (FET) and hybridized it with anti-cortisol antibody-functionalized MPs to build a highly sensitive cortisol sensor. This strategy allowed us to detect cortisol down to 1 aM in real time and discriminate cortisol from other hormones. In this case, we could easily remove MPs with used antibodies from the surface of a BP-FET and reuse the chip for up to eight repeated sensing operations. Moreover, since our platform could be fabricated using conventional photolithography techniques and the sensor can be reused multiple times, one should be able to significantly reduce operation costs for practical applications. Furthermore, this method could be utilized to detect different hormones with high sensitivity and selectivity in complex environments such as artificial saliva solutions. In this respect, our reusable BP-FET biosensing platform can be a powerful tool for versatile applications such as clinical diagnosis and basic biological analysis by conjugating various antibodies.

Arg-biodynamers as antibiotic potentiators through interacting with Gram-negative outer membrane lipopolysaccharides.

Antimicrobial resistance is becoming more prominent day after day due to a number of mechanisms by microbes, especially the sophisticated biological barriers of bacteria, especially in Gram-negatives. There, the lipopolysaccharides (LPS) layer is a unique component of the outer leaflet of the outer membrane which is highly impermeable and prevents antibiotics from passing passively into the intracellular compartments. Biodynamers, a novel class of dynamically bio-responsive polymers, may open new perspectives to overcome this particular barrier by accommodating various secondary structures and form supramolecular structures in such bacterial microenvironments. Generally, bio-responsive polymers are not only candidates as bio-active molecules against bacteria but also carriers via their interactions with the cargo. Based on their dynamicity, design flexibility, biodegradability, biocompatibility, and pH-responsiveness, we investigated the potential of two peptide-based biodynamers for improving antimicrobial drug delivery. By a range of experimental methods, we discovered a greater affinity of Arg-biodynamers for bacterial membranes than for mammalian membranes as well as an enhanced LPS targeting on the bacterial membrane, opening perspectives for enhancing the delivery of antimicrobials across the Gram-negative bacterial cell envelope. This could be explained by the change of the secondary structure of Arg-biodynamers into a predominant ß-sheet character in the LPS microenvironment, by contrast to the α-helical structure typically observed for most lipid membrane-permeabilizing peptides. In comparison to poly-L-arginine, the intrinsic antibacterial activity of Arg-biodynamers was nearly unchanged, but its toxicity against mammalian cells was >128-fold reduced. When used in bacterio as an antibiotic potentiator, however, Arg-biodynamers improved the minimum inhibitory concentration (MIC) against Escherichia coli by 32 times compared to colistin alone. Similar effect has also been observed in two stains of Pseudomonas aeruginosa. Arg-biodynamers may therefore represent an interesting option as an adjuvant for antibiotics against Gram-negative bacteria and to overcome antimicrobial resistance.

Biodynamer Nano-Complexes and -Emulsions for Peptide and Protein Drug Delivery.

Background: Therapeutic proteins and peptides offer great advantages compared to traditional synthetic molecular drugs. However, stable protein loading and precise control of protein release pose significant challenges due to the extensive range of physicochemical properties inherent to proteins. The development of a comprehensive protein delivery strategy becomes imperative accounting for the diverse nature of therapeutic proteins. Methods: Biodynamers are amphiphilic proteoid dynamic polymers consisting of amino acid derivatives connected through pH-responsive dynamic covalent chemistry. Taking advantage of the amphiphilic nature of the biodynamers, PNCs and DEs were possible to be prepared and investigated to compare the delivery efficiency in drug loading, stability, and cell uptake. Results: As a result, the optimized PNCs showed 3-fold encapsulation (<90%) and 5-fold loading capacity (30%) compared to DE-NPs. PNCs enhanced the delivery efficiency into the cells but aggregated easily on the cell membrane due to the limited stability. Although DE-NPs were limited in loading capacity compared to PNCs, they exhibit superior adaptability in stability and capacity for delivering a wider range of proteins compared to PNCs. Conclusion: Our study highlights the potential of formulating both PNCs and DE-NPs using the same biodynamers, providing a comparative view on protein delivery efficacy using formulation methods.

Bioactive polymeric metallosomes self-assembled through block copolymer-metal complexation.

Spontaneous formation of polymeric metallosomes with uniform size (~100 nm) was found to occur in aqueous medium through the reaction of an anticancer agent, (1,2-diaminocyclohexane)platinum(II) (DACHPt), with a Y-shaped block copolymer of ω-cholesteroyl-poly(L-glutamic acid) and two-armed poly(ethylene glycol) (PEGasus-PLGA-Chole). Circular dichroism spectrum measurements revealed that the PLGA segment forms an α-helix structure within the metallosomes, suggesting that secondary-structure formation of metallocomplexed PLGA segment may drive the self-assembly of the system into vesicular structure. These metallosomes can encapsulate water-soluble fluorescent macromolecules into their inner aqueous phase and eventually deliver them selectively into tumor tissues in mice, owing to the prolonged blood circulation. Accordingly, fluorescent imaging of the tumor was successfully demonstrated along with an appreciable antitumor activity by DACHPt moieties retained in the vesicular wall of the metallosomes, indicating the potential of metallosomes as multifunctional drug carriers.

Development of insect-proof starch adhesive containing encapsulated cinnamon oil for paper box adhesion to inhibit Plodia interpunctella larvae infestation.

The objectives of this study were to develop insect-resistant adhesives and apply them to a cardboard packaging system for preventing Plodia interpunctella (Hübner) (Lepidoptera: Pyralidae) larvae infestation. Cinnamon essential oil (CO), an insecticide, was encapsulated with maltodextrin (CS/MD/CO), ß-cyclodextrin (CS/ß-CD/CO), and polyvinyl alcohol (CS/PVA/CO) in corn starch (CS) paste. This resulted in a sustained and gradual release of CO from the starch-based insect-proof adhesives. Penetration pathways of insects into corrugated cardboard boxes were investigated through the use of a screening test for infestation profiling. Microscopic images of encapsulated CO in an oil in water (O/W) emulsion were observed to confirm the morphology of the adhesives. Adhesion forces of CS, CS/CO, CS/MD/CO, CS/ß-CD/CO, and CS/PVA/CO were determined to be 6.2 N, 4.0 N, 3.1 N, 6.0 N, and 5.8 N, respectively. Consequently, significant decreases of adhesion force in the CS/CO and CS/MD/CO were found to be due to the presence of the surfactant (Span® 80) and the low adhesive properties of MD. The duration of the insecticidal activities of the developed adhesives was evaluated by measuring their release rates for 14 days and repellent profiles up to 24 hr and 40 days. As a result, CS/ß-CD/CO and CS/PVA/CO were found to have an inhibited rapid release and sustained repellent profiles. In conclusion, CS/ß-CD/CO and CS/PVA/CO were determined to be suitable for encapsulation models and could be applied to industrial cardboard containers to prevent cases of insect invasion. PRACTICAL APPLICATION: Corn starch-based natural adhesives with an insect-proof property were applied to food containers consisted of corrugated cardboard boxes. Cornflake cereal packaging using insect-proof corrugated cardboard successfully prohibited pest invasion in commercial food distribution simulation model. Developed insecticidal adhesives are able to control insect penetration in distribution and storage steps.

Predictors of 18F-sodium fluoride uptake in patients with stable coronary artery disease and adverse plaque features on computed tomography angiography.

AIMS: In patients with stable coronary artery disease (CAD) and high-risk plaques (HRPs) on coronary computed tomography angiography (CTA), we sought to define qualitative and quantitative CTA predictors of abnormal coronary 18F-sodium fluoride uptake (18F-NaF) by positron emission tomography (PET). METHODS AND RESULTS: Patients undergoing coronary CTA were screened for HRP. Those who presented with ≥3 CTA adverse plaque features (APFs) including positive remodelling; low attenuation plaque (LAP, <30 HU), spotty calcification; obstructive coronary stenosis ≥50%; plaque volume >100 mm3 were recruited for 18F-NaF PET. In lesions with stenosis ≥25%, quantitative plaque analysis and maximum 18F-NaF target to background ratios (TBRs) were measured. Of 55 patients, 35 (64%) manifested coronary 18F-NaF uptake. Of 68 high-risk lesions 49 (70%) had increased PET tracer activity. Of the APFs, LAP had the highest sensitivity (39.4%) and specificity (98.3%) for predicting 18F-NaF uptake. TBR values were higher in lesions with LAP compared to those without [1.6 (1.3-1.8) vs. 1.1 (1.0-1.3), P = 0.01]. On adjusted multivariable regression analysis, LAP (both qualitative and quantitative) was independently associated with plaque TBR [LAP qualitative: ß = 0.47, 95% confidence interval (CI) 0.30-0.65; P < 0.001] and (LAP volume: ß = 0.20 per 10 mm3, 95% CI 0.13-0.27; P < 0.001). CONCLUSION: In stable CAD patients with HRP, LAP is predictive of 18F-NaF coronary uptake, but 18F-NaF is often seen in the absence of LAP. If 18F-NaF uptake is shown to be associated with adverse outcomes and becomes clinically used, the presence of LAP may define patients who would not benefit from the added testing.

Improvement of the dissolution rate and bioavailability of fenofibrate by the supercritical anti-solvent process.

The purpose of this study was to improve solubility and oral bioavailability of fenofibrate via solid dispersion (SD) using a supercritical anti-solvent (SAS) process with amphipathic polymers P407 and TPGS. Solid dispersion techniques have been widely used to enhance the solubility and dissolution profiles of poorly soluble drugs. Fenofibrate is classified as a Biopharmaceutics Classification System class II compound because of its low solubility and high gastrointestinal permeability. Two copolymers were selected based on solubility and dissolution tests. Their physicochemical properties were compared with those prepared by conventional solvent evaporation (CSE). The SD formulations containing fenofibrate were successfully prepared using the SAS and CSE methods. The dissolution rate (%) of fenofibrate at 60 min was significantly improved compared with the solution of raw fenofibrate (19.5% ±â€¯3.7%) by 95.1% ±â€¯2.5% and 93.7% ±â€¯4.1% using the SAS and the CSE process, respectively. This approximately four-fold increase in dissolution rate indicates that oral bioavailability can be enhanced. In addition, pharmacokinetic study was analyzed using the area under the curve (AUC) and Cmax values of SAS-SD and CSE-SD in rats. The AUC was 2.1 times higher and Cmax was 1.9 times higher in SAS-SD, indicating higher concentrations of fenofibrate in the blood. In a pharmacodynamic study to evaluate the efficacy of the drug in hyperlipidemic rat models, SAS-SD showed strong lipid-lowering effects including cholesterol (1.9-fold) and triglycerides (3.3-fold), than CSE-SD. Taken together, these results suggested that SAS-SD has excellent potential as a formulation for the poorly soluble drug fenofibrate.

Design of novel proliposome formulation for antioxidant peptide, glutathione with enhanced oral bioavailability and stability.

To develop proliposome formulations to improve the oral bioavailability of l-glutathione (GSH), GSH-loaded proliposomes were prepared using the granule method. Mannitol was selected as an effective excipient to achieve the desired particle size, entrapment efficiency (EE), and solubility for oral delivery of the final formulation. To evaluate the effect of surface charge of proliposomes on the oral bioavailability of GSH, negative (F1-F4) and positive proliposomes (F5-F9) were prepared. Particle size of F1 and F5 was 167.8 ± 0.9 and 175.9 ± 2.0 nm, and zeta potential of F1 and F5 was -8.1 ± 0.7 and 21.1 ± 2.0 mV, respectively. Encapsulation efficiency of F1 and F5 was 58.6% and 54.7%, respectively. Considering their particle size, zeta potential, and EE, the proliposomes F1 and F5 were adopted as the optimal formulations for further experiments. Solid state characterization of the proliposomes confirmed lipid coating on the surface of mannitol. The release of GSH from F1 and F5 formulations was prolonged until 24 h and pH independent. The total antioxidant capacity of GSH was concentration-dependent and maintained after formulation of GSH proliposomes. Circular dichroism spectroscopy confirmed that the molecular structure of GSH was maintained in the proliposome formulations. GSH proliposomes exhibited no significant changes in particle size and zeta potential for 4 weeks. An oral bioavailability study in rats revealed that F5 exhibited 1.05-, 1.08-, and 1.11-fold higher bioavailability than F1, commercial capsule formulation, and pure GSH, respectively. In conclusion, the prepared GSH proliposomes enhanced the poor bioavailability of GSH and prolonged its duration of action.

Three-Hour Delayed Imaging Improves Assessment of Coronary 18F-Sodium Fluoride PET.

Coronary 18F-sodium fluoride (18F-NaF) PET identifies ruptured plaques in patients with recent myocardial infarction and localizes to atherosclerotic lesions with active calcification. Most studies to date have performed the PET acquisition 1 h after injection. Although qualitative and semiquantitative analysis is feasible with 1-h images, residual blood-pool activity often makes it difficult to discriminate plaques with 18F-NaF uptake from noise. We aimed to assess whether delayed PET performed 3 h after injection improves image quality and uptake measurements. Methods: Twenty patients (67 ± 7 y old, 55% male) with stable coronary artery disease underwent coronary CT angiography (CTA) and PET/CT both 1 h and 3 h after the injection of 266.2 ± 13.3 MBq of 18F-NaF. We compared the visual pattern of coronary uptake, maximal background (blood pool) activity, noise, SUVmax, corrected SUVmax (cSUVmax), and target-to-background (TBR) ratio in lesions defined by CTA on 1-h versus 3-h 18F-NaF PET. Results: On 1-h PET, 26 CTA lesions with 18F-NaF PET uptake were identified in 12 (60%) patients. On 3-h PET, we detected 18F-NaF PET uptake in 7 lesions that were not identified on 1-h PET. The median cSUVmax and TBRs of these lesions were 0.48 (interquartile range [IQR], 0.44-0.51) and 1.45 (IQR, 1.39-1.52), respectively, compared with -0.01 (IQR, -0.03-0.001) and 0.95 (IQR, 0.90-0.98), respectively, on 1-h PET (both P < 0.001). Across the entire cohort, 3-h PET SUVmax was similar to 1-h PET measurements (1.63 [IQR, 1.37-1.98] vs. 1.55 [IQR, 1.43-1.89], P = 0.30), and the background activity was lower (0.71 [IQR, 0.65-0.81] vs. 1.24 [IQR, 1.05-1.31], P < 0.001). On 3-h PET, TBR, cSUVmax, and noise were significantly higher (respectively: 2.30 [IQR, 1.70-2.68] vs. 1.28 [IQR, 0.98-1.56], P < 0.001; 0.38 [IQR, 0.27-0.70] vs. 0.90 [IQR, 0.64-1.17], P < 0.001; and 0.10 [IQR, 0.09-0.12] vs. 0.07 [IQR, 0.06-0.09], P = 0.02). Median cSUVmax and TBR increased by 92% (range, 33%-225%) and 80% (range, 20%-177%), respectively. Conclusion: Blood-pool activity decreases on delayed imaging, facilitating the assessment of 18F-NaF uptake in coronary plaques. Median TBR increases by 80%, leading to the detection of more plaques with significant uptake than are detected using the standard 1-h protocol. A greater than 1-h delay may improve the detection of 18F-NaF uptake in coronary artery plaques.

Peri-Coronary Adipose Tissue Density Is Associated With 18F-Sodium Fluoride Coronary Uptake in Stable Patients With High-Risk Plaques.

OBJECTIVES: This study aimed to assess the association between increased lesion peri-coronary adipose tissue (PCAT) density and coronary 18F-sodium fluoride (18F-NaF) uptake on positron emission tomography (PET) in stable patients with high-risk coronary plaques (HRPs) shown on coronary computed tomography angiography (CTA). BACKGROUND: Coronary 18F-NaF uptake reflects the rate of calcification of coronary atherosclerotic plaque. Increased PCAT density is associated with vascular inflammation. Currently, the relationship between increased PCAT density and 18F-NaF uptake in stable patients with HRPs on coronary CTA has not been characterized. METHODS: Patients who underwent coronary CTA were screened for HRP, which was defined by 3 concurrent plaque features: positive remodeling; low attenuation plaque (LAP) (<30 Hounsfield units [HU]) and spotty calcification; and obstructive coronary stenosis ≥50% (plaque volume >100 mm3). Patients with HRPs were recruited to undergo 18F-NaF PET/CT. In lesions with stenosis ≥25%, quantitative plaque analysis, mean PCAT density, maximal coronary motion-corrected 18F-NaF standard uptake values (SUVmax), and target-to-background ratios (TBR) were measured. RESULTS: Forty-one patients (age 65 ± 6 years; 68% men) were recruited. Fifty-one lesions in 23 patients (56%) showed increased coronary 18F-NaF activity. Lesions with 18F-NaF uptake had higher surrounding PCAT density than those without 18F-NaF uptake (-73 HU; interquartile range -79 to -68 HU vs. -86 HU; interquartile range -94 to -80 HU; p < 0.001). 18F-NaF TBR and SUVmax were correlated with PCAT density (r = 0.63 and r = 0.68, respectively; all p < 0.001). On adjusted multiple regression analysis, increased lesion PCAT density and LAP volume were associated with 18F-NaF TBR (ß = 0.25; 95% confidence interval: 0.17 to 0.34; p < 0.001 for PCAT, and ß = 0.07; 95% confidence interval: 0.03 to 0.11; p = 0.002 for LAP). CONCLUSIONS: In patients with HRP features on coronary CTA, increased density of PCAT was associated with focal 18F-NaF PET uptake. Simultaneous assessment of these imaging biomarkers by 18F-NaF PET and CTA might refine cardiovascular risk prediction in stable patients with HRP features.

Feasibility of Coronary 18F-Sodium Fluoride Positron-Emission Tomography Assessment With the Utilization of Previously Acquired Computed Tomography Angiography.

BACKGROUND: We assessed the feasibility of utilizing previously acquired computed tomography angiography (CTA) with subsequent positron-emission tomography (PET)-only scan for the quantitative evaluation of 18F-NaF PET coronary uptake. METHODS AND RESULTS: Forty-five patients (age 67.1±6.9 years; 76% males) underwent CTA (CTA1) and combined 18F-NaF PET/CTA (CTA2) imaging within 14 [10, 21] days. We fused CTA1 from visit 1 with 18F-NaF PET (PET) from visit 2 and compared visual pattern of activity, maximal standard uptake (SUVmax) values, and target to background ratio (TBR) measurements on (PET/CTA1) fused versus hybrid (PET/CTA2). On PET/CTA2, 226 coronary plaques were identified. Fifty-eight coronary segments from 28 (62%) patients had high 18F-NaF uptake (TBR >1.25), whereas 168 segments had lesions with 18F-NaF TBR ≤1.25. Uptake in all lesions was categorized identically on coregistered PET/CTA1. There was no significant difference in 18F-NaF uptake values between PET/CTA1 and PET/CTA2 (SUVmax, 1.16±0.40 versus 1.15±0.39; P=0.53; TBR, 1.10±0.45 versus 1.09±0.46; P=0.55). The intraclass correlation coefficient for SUVmax and TBR was 0.987 (95% CI, 0.983-0.991) and 0.986 (95% CI, 0.981-0.992). There was no fixed or proportional bias between PET/CTA1 and PET/CTA2 for SUVmax and TBR. Cardiac motion correction of PET scans improved reproducibility with tighter 95% limits of agreement (±0.14 for SUVmax and ±0.15 for TBR versus ±0.20 and ±0.20 on diastolic imaging; P<0.001). CONCLUSIONS: Coronary CTA/PET protocol with CTA first followed by PET-only allows for reliable and reproducible quantification of 18F-NaF coronary uptake. This approach may facilitate selection of high-risk patients for PET-only imaging based on results from prior CTA, providing a practical workflow for clinical application.

Chemical amplification accelerates reactive oxygen species triggered polymeric degradation.

Chemical amplification is a known strategy for improving the sensitivity of stimuli-responsive polymers. However, the chemical amplification effect has never been fully examined. Many questions remain about its mechanism and efficacy, obstructing its further implementation. Here, we design and demonstrate a reactive oxygen species (ROS) responsive polymer (ROS-ARP) with a chemical amplification strategy to dismiss these concerns. The ROS-ARP is designed to change the hydrophilicity by ROS, revealing a carboxylic acid, which also catalyzes ketal hydrolysis along the polymer backbone. The chemical amplification strategy of ROS-ARP accelerated the polymer degradation up to 17 fold compared to a previously reported ROS-responsive polymer. To investigate the mechanism behind this increased acceleration, we compared the degradation kinetics in various environments. Additionally, other effects such as hydrophilicity changes were excluded. The accelerated degradation of ROS-ARP is evaluated as a potential drug delivery system, demonstrating on-demand cargo release from the formulated polymeric particles.

Biorthogonal click chemistry on poly(lactic-co-glycolic acid)-polymeric particles.

Biodegradable polymeric materials are a key area of investigation in drug delivery and disease treatment. This is due to their proven clinical potential for payload protection, responsivity, and surface modification imparted by the versatile array of polymers available for their formulation. Here, we employ a novel biodegradable azide containing polymer in the formulation of polymeric nanoparticles and show that these particles can then be functionalized, with biorthogonal click reactions, to alter their surface appearance and their ability to interact with biological systems.

Use of acidifier and solubilizer in tadalafil solid dispersion to enhance the in vitro dissolution and oral bioavailability in rats.

The purpose of this study is to improve the solubility, in vitro dissolution, and oral bioavailability in rats of tadalafil (TDF) by using SD technique with a weak acid and a copolymer. TDF-SD was prepared via solvent evaporation, coupled with the incorporation of an acidifier and solubilizer. Tartaric acid enhanced the solubility of TDF over 5-fold in DW, and Soluplus® enhanced the solubility of TDF over 8.7-fold and 19.2-fold compared to that of TDF (pure) in DW and pH 1.2 for 1h, respectively. The optimal formulation of TDF-SD3 was composed of TDF vs Tartaric acid vs Soluplus® vs Aerosil=1:1:3:3. The in vitro dissolution rate of TDF-SD3 in DW, pH 1.2 and pH 6.8 buffer (51.5%, 53.3%, and 33.2%, respectively) was significantly higher than that of the commercial product (Cialis®) powder (16.5%, 15.2%, and 14.8%, respectively). TDF was completely transformed to an amorphous form as shown in SEM, DSC and PXRD data. The stability of TDF-SD3 included drug contents and in vitro dissolution for 1 month were similar to those of Cialis®, and the amorphous form of TDF-SD3 was well maintained for 6 months. The TDF-SD3 formulation improved the relative bioavailability (BA) and peak plasma concentration (Cmax) compared to that of Cialis® powder after oral administration in rats as 117.3% and 135.7%, respectively. From the results, we found that the acidifier increased the wettability of TDF, and the solubilizer improved solubility through hydrogen bonding with TDF, thereby increasing the solubility, dissolution and oral bioavailability of TDF in TDF-SD3.

Enhancing the in vitro anticancer activity of albendazole incorporated into chitosan-coated PLGA nanoparticles.

To improve the solubility and anticancer activity of albendazole (ABZ), chitosan (CS)-coated poly-dl-lactic-co-glycolic acid (PLGA) nanoparticles were developed. CS was used to coat ABZ-loaded PLGA nanoparticles to enhance both mucoadhesiveness and colloidal stability. CS-coated PLGA nanoparticles were prepared by suspending the nanoparticles in CS solution after solvent diffusion. The CS-coated PLGA nanoparticles were characterized, and ABZ release was studied in vitro from various formulations. The mucoadhesive properties and in vitro anticancer activities of CS-coated PLGA nanoparticles were investigated by measurement of zeta potentials and the MTT assay, respectively. Spherical nanoparticles below 500nm in diameter were successfully prepared; the particle size distribution was narrow. Complete encapsulation of ABZ in CS-coated PLGA nanoparticles was confirmed by SEM, FTIR, DSC, and XRD. The particle sizes of CS-coated PLGA nanoparticles were in the range of 260-480nm; the encapsulation efficiency was 43.4-54.6%; and the yield 58.5-67.8%. The zeta potential of CS-coated nanoparticles was above +27mV and stability was maintained for 4 weeks. At pH 7.4, the in vitro release of ABZ from nanoparticles (P188-5) was 200-fold higher than that from untreated ABZ; this persisted for 12h. Moreover, ABZ release from CS-coated PLGA nanoparticles (P188-CS0.5) was 1.5-fold higher than that from untreated ABZ at pH 1.2. Additionally, the ABZ-loaded CS-coated nanoparticles exhibited superior mucoadhesion and improved cytotoxicity. The results show that CS coating of PLGA nanoparticles may improve the anticancer effect and the mucoadhesive properties of ABZ-loaded nanoparticles.

Atomic force microscopy observation of highly arrayed phospholipid bilayer vesicle on a gold surface.

Tapping mode atomic force microscopy (TM-AFM) imaging of a phospholipid bilayer vesicle (liposome) immobilized on a gold surface was performed to investigate morphologies of the electrode surfaces produced through application of three different sample preparation methods. We compared both methods from a morphological viewpoint using TM-AFM images. Liposomes, composed of zwitterionic and anionic phospholipids, were prepared by extrusion. Results indicate that the surface with immobilized L1-liposome, which was fabricated by the amino coupling method, seemed to form large amounts of aggregated or fused liposomes. In contrast, L2-liposome-containing 1-octadecanthiol that was directly attached on the gold surface using thiol-gold binding force was immobilized as a uniform surface topology without liposome aggregation. Finally, we attempted to arrange individual L3-liposome, prepared by mixing zwitterionic and anionic phospholipids, onto the gold layer by electron-beam (e-beam) lithography technique. A third method, L3-liposome formation on the sensor surface, is greatly anticipated for biosensor applications.

The use of laryngeal mask airway in dental treatment during sevoflurane deep sedation.

BACKGROUND: General anesthesia is frequently considered for pediatric patients, as they often find it difficult to cooperate and stay calm during administration of potentially painful treatments. Sedation can overcome these adversities; however, this is challenging while maintaining unobstructed airways. METHODS: The study involved 11 pediatric dental patients treated with LMA under deep sedation with sevoflurane, from 2011 through 2015. LMA size, sevoflurane concentration, and the vital signs of patients were assessed through a chart review. RESULTS: The age distribution of the patients ranged from 6 to 10 years old. A total of 3 patients underwent mesiodens extraction, while the remaining 8 underwent an surgically assisted orthodontic forced tooth eruption The average sedation period was approximately 45 minutes and the LMA size was 2½. The sevoflurane concentration was maintained at 2% on average, and overall, the measurements of vital signs were within the normal range; the patients had an average blood pressure of 98/49 mmHg, breathing rate of 26 times/min, pulse frequency of 95 times/min, SpO2s level of 99 mmHg, and ETCO2 level of 41.2 mmHg. CONCLUSIONS: Deep sedation with sevoflurane coupled with LMA may be applied successfully in pediatric patients who undergo mesiodens extraction or a surgically assisted orthodontic forced tooth eruption.

Solubilization and formulation of chrysosplenol C in solid dispersion with hydrophilic carriers.

We investigated how to overcome problems associated with the solubility, dissolution, and oral bioavailability of the poorly water-soluble drug compound, chrysosplenol C (CRSP), as well as the effects of single and binary hydrophilic polymers (PVP K-25 and/or PEG 6000) on the solubility and dissolution parameters of CRSP. Then an optimized formulation was further developed with a surfactant. To select a surfactant suitable for a CRSP-loaded solid dispersion (SD), the solubility of CRSP in distilled water containing 1% surfactant was compared with the solubilities in other surfactants. Sodium lauryl sulfate (SLS) showed the highest drug solubility. Overall, a formulation containing CRSP, binary hydrophilic polymers (PVP and PEG 6000), and SLS at a ratio of 2.0/0.2/1.1/0.7 showed the optimum in vitro release profile. This optimized formulation had better safety properties than pure CRSP in cell viability examinations. SD formulations were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and Fourier-transform infrared (FT-IR) spectroscopy. Our optimized SD formulation is expected to improve the bioavailability of CRPS because it improves the solubility and dissolution rate of CRSP.

Thermosensitive and mucoadhesive sol-gel composites of paclitaxel/dimethyl-ß-cyclodextrin for buccal delivery.

The purpose of this study was to develop a buccal paclitaxel delivery system using the thermosensitive polymer Pluronic F127 (PF127) and the mucoadhesive polymer polyethylene oxide (PEO). The anticancer agent paclitaxel is usually used to treat ovarian, breast, and non-small-cell lung cancer. To improve its aqueous solubility, paclitaxel was incorporated into an inclusion complex with (2,6-di-O-methyl)-ß-cyclodextrin (DMßCD). The formation of the paclitaxel inclusion complex was evaluated using various techniques, including x-ray diffractometry (XRD), Fourier-transform infrared (FT-IR) spectrophotometry, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Hydrogels were prepared using a cold method. Concentrations of 18, 20, and 23% (w/v) PF127 were dissolved in distilled water including paclitaxel and stored overnight in a refrigerator at 4 °C. PEO was added at concentrations of 0.1, 0.2, 0.4, 0.8, and 1% (w/v). Each formulation included paclitaxel (0.5 mg/mL). The sol-gel transition temperature of the hydrogels was measured using the tube-inverting method. Drug release from the hydrogels was measured using a Franz diffusion cell containing pH 7.4 phosphate-buffered solution (PBS) buffer at 37 °C. The cytotoxicity of each formulation was measured using the MTT assay with a human oral cancer cell (KB cell). The sol-gel transition temperature of the hydrogel decreased when PF127 was present and varied according to the presence of mucoadhesive polymers. The in vitro release was sustained and the release rate was slowed by the addition of the mucoadhesive polymer. The cytotoxicity of the blank formulation was low, although the drug-loaded hydrogel showed acceptable cytotoxicity. The results of our study suggest that the combination of a PF 127-based mucoadhesive hydrogel formulation and inclusion complexes improves the in vitro release and cytotoxic effect of paclitaxel.