Linezolid and Vancomycin Decrease the Therapeutic Effect of Methylene Blue‐Photodynamic therapy in a Mouse Model of MRSA Bacterial Arthritis

We previously reported that photodynamic therapy (PDT) using intra‐articular methylene blue (MB) could be used to treat arthritis in mice caused by bioluminescent methicillin‐resistant Staphylococcus aureus (MRSA) either in a therapeutic or in a preventative mode. PDT accumulated neutrophils into the mouse knee via activation of chemoattractants such as inflammatory cytokines or chemokines. In this study, we asked whether PDT combined with antibiotics used for MRSA could provide added benefit in controlling the infection. We compared MB‐PDT alone, systemic administration of either linezolid (LZD) alone or vancomycin (VCM) alone or the combination of PDT with either LZD or VCM. Real‐time noninvasive imaging was used to serially follow the progress of the infection. PDT alone was the most effective, whereas LZD alone was ineffective and VCM alone showed some benefit. Surprisingly the addition of LZD or VCM reduced the therapeutic effect of PDT alone (P < 0.05). Considering that PDT in this mouse model stimulates neutrophils to be antibacterial rather than actively killing the bacteria, we propose that LZD and VCM might inhibit the activation of inflammatory cytokines without eradicating the bacteria, and thereby reduce the therapeutic effect of PDT.     

Irradiance,Photofrin® Dose and Initial Tumor Volume are Key Predictors of Response to Interstitial Photodynamic Therapy of Locally Advanced Cancers in Translational Models

The objective of the present study was to develop a predictive model for Photofrin^®-mediated interstitial photodynamic therapy (I-PDT) of locally advanced tumors. Our finite element method was used to simulate 630-nm intratumoral irradiance and fluence for C3H mice and New Zealand White rabbits bearing large squamous cell carcinomas. Animals were treated with light only or I-PDT using the same light settings. I-PDT was administered with Photofrin^® at 5.0 or 6.6 mg kg⁻¹, 24 h drug-light interval. The simulated threshold fluence was fixed at 45 J cm⁻² while the simulated threshold irradiance varied, intratumorally. No cures were obtained in the mice treated with a threshold irradiance of 5.4 mW cm⁻². However, 20–90% of the mice were cured when the threshold irradiances were ≥8.6 mW cm⁻². In the rabbits treated with I-PDT, 13 of the 14 VX2 tumors showed either local control or were cured when threshold irradiances were ≥15.3 mW cm⁻² and fluence was 45 J cm⁻². No tumor growth delay was observed in VX2 treated with light only (n = 3). In the mouse studies, there was a high probability (92.7%) of predicting cure when the initial tumor volume was below the median (493.9 mm³) and I-PDT was administered with a threshold intratumoral irradiance ≥8.6 mW cm⁻².     

Infection Microenvironment-Sensitive Photothermal Nanotherapeutic Platform to Inhibit Methicillin-Resistant Staphylococcus aureus Infection

Methicillin-resistant Staphylococcus aureus (MRSA) can induce multiple inflammations. The biofilm formed by MRSA is resistant to a variety of antibiotics and is extremely difficult to cure, which seriously threatens human health. Herein, a nanoparticle encapsulating berberine with polypyrrole core and pH-sensitive shell to provide chemo-photothermal dual therapy for MRSA infection is reported. By integrating photothermal agent polypyrrole, berberine, acid-degradable crosslinker, and acid-induced charge reversal polymer, the nanoparticle exhibited highly efficient MRSA infection treatment. In normal uninfected areas and bloodstream, nanoparticles showed negatively charged, demonstrating high biocompatibility and excellent hemocompatibility. However, once arriving at the MRSA infection site, the nanoparticle can penetrate and accumulate in the biofilm within 2 h. Simultaneously, berberine can be released into biofilm rapidly. Under the combined effect of photothermal response and berberine inhibition, 88.7% of the biofilm is removed at 1000 µg mL⁻¹. Moreover, the nanoparticles have an excellent inhibitory effect on biofilm formation, the biofilm inhibition capacity can reach up to 90.3%. Taken together, this pH-tunable nanoparticle can be employed as a new generation treatment strategy to fight against the fast-growing MRSA infection.     

Optimal photosensitizers for photodynamic therapy of infections should kill bacteria but spare neutrophils

Photodynamic therapy (PDT) for localized microbial infections exerts its therapeutic effect both by direct bacterial killing and also by the bactericidal effects of host neutrophils stimulated by PDT. Therefore, PDT-induced damage to neutrophils must be minimized, while direct photoinactivation of bacteria is maintained to maximize the therapeutic efficacy of antimicrobial PDT in vivo. However, there has been no study in which the cytocidal effect of PDT on neutrophils was investigated. In this study, the cytocidal effects of PDT on neutrophils were evaluated using different antimicrobial photosensitizers to find suitable candidate photosensitizers for antimicrobial PDT. PDT on murine peripheral-blood neutrophils was performed in vitro using each photosensitizer at a concentration that exerted a maximum bactericidal effect on methicillin-resistant Staphylococcus aureus, and morphological alteration and viability of neutrophils were studied. Most neutrophils were viable (>80%) after PDT using toluidine blue-O (TB) or methylene blue (MB), while neutrophils showed morphological change and their viabilities were decreased (<70%) after PDT using other photosensitizers (erythrosine B, rose bengal, crystal violet, Photofrin, new methylene blue and Laserphyrin). These results suggest that PDT using TB or MB can preserve host neutrophils while exerting a significant therapeutic effect on in vivo localized microbial infection.     

Photodynamic therapy induces selective extravasation of macromolecules: Insights using intravital microscopy

Photodynamic therapy (PDT) with Visudyne^® acts by direct cellular phototoxicity and/or by an indirect vascular-mediated effect. Here, we demonstrate that the vessel integrity interruption by PDT can promote the extravasation of a macromolecular agent in normal tissue. To obtain extravasation in normal tissue PDT conditions were one order of magnitude more intensive than the ones in tissue containing neovessels reported in the literature.Fluorescein isothiocyanate dextran (FITC-D, 2000 kDa), a macromolecular agent, was intravenously injected 10 min before (LK0 group, n = 14) or 2 h (LK2 group, n = 16) after Visudyne^®-mediated PDT in nude mice bearing a dorsal skin fold chamber. Control animals had no PDT (CTRL group, n = 8). The extravasation of FITC-D from blood vessels in striated muscle tissue was observed in both groups in real-time for up to 2500 s after injection. We also monitored PDT-induced leukocyte rolling in vivo and assessed, by histology, the corresponding inflammatory reaction score in the dorsal skin fold chambers.In all animals, at the applied PDT conditions, FITC-D extravasation was significantly enhanced in the PDT-treated areas as compared to the surrounding non-treated areas (p < 0.0001). There was no FITC-D leakage in the control animals. Animals from the LK0 group had significantly less FITC-D extravasation than those from the LK2 group (p = 0.0002). In the LK0 group FITC-D leakage correlated significantly with the inflammation (p < 0.001).At the selected conditions, Visudyne^®-mediated PDT promotes vascular leakage and FITC-D extravasation into the interstitial space of normal tissue. The intensity of vascular leakage depends on the time interval between PDT and FITC-D injection. This concept could be used to locally modulate the delivery of macromolecules in vivo.     

Synthesis of the <Superscript>99m</Superscript>Tc(CO)<Subscript>3</Subscript>–trovafloxacin dithiocarbamate complex and biological characterization in artificially methicillin-resistant <Emphasis Type="Italic">Staphylococcus aureus</Emphasis> infected rats model

The radiolabeling of trovafloxacin dithiocarbamate (TVND) with technetium-99m using [^99mTc-N]²⁺ core was investigated and biologically assessed as prospective infection imaging agent. The achievability of the ^99mTcN-TVND complex as a future MRSA infection radiotracer was investigated in artificially methicillin-resistant Staphylococcus aureus (MRSA) infected male Sprague–Dawley rats (MSDR). Radiochemically the ^99mTcN-TVND complex was characterized in terms of radiochemical purity (RCP) in saline, in vitro permanence in serum, in vitro binding with MRSA and biodistribution in living and heat killed MRSA infected MSDR. Radiochemically the complex showed stability in saline with a 97.90 ± 0.22% yield and serum at 37 °C up to 4 h. The ^99mTcN-TVND complex showed saturated in vitro binding with MRSA. Normal in vivo uptake in the MRSA infected MDRS was observed with a five fold uptake in the infected muscle as compared to inflamed and normal muscles. The high RCP values, in vitro permanence in serum, better in vitro binding with MRSA, biodistribution behavior and the target to non-target (infected to inflamed muscle) ratios posed the ^99mTcN-TVND complex as a promising MRSA infection radiotracer.     

Interaction of Liposomal Formulations of Meta-tetra(hydroxyphenyl)chlorin (Temoporfin) with Serum Proteins: Protein Binding and Liposome Destruction

mTHPC is a non polar photosensitizer used in photodynamic therapy. To improve its solubility and pharmacokinetic properties, liposomes were proposed as drug carriers. Binding of liposomal mTHPC to serum proteins and stability of drug carriers in serum are of major importance for PDT efficacy; however, neither was reported before. We studied drug binding to human serum proteins using size‐exclusion chromatography. Liposomes destruction in human serum was measured by nanoparticle tracking analysis (NTA). Inclusion of mTHPC into conventional (Foslip^®) and PEGylated (Fospeg^®) liposomes does not affect equilibrium serum protein binding compared with solvent‐based mTHPC. At short incubation times the redistribution of mTHPC from Foslip^® and Fospeg^® proceeds by both drug release and liposomes destruction. At longer incubation times, the drug redistributes only by release. The release of mTHPC from PEGylated vesicles is delayed compared with conventional liposomes, alongside with greatly decreased liposomes destruction. Thus, for long‐circulation times the pharmacokinetic behavior of Fospeg^® could be influenced by a combination of protein‐ and liposome‐bound drug. The study highlights the modes of interaction of photosensitizer‐loaded nanovesicles in serum to predict optimal drug delivery and behavior in vivo in preclinical models, as well as the novel application of NTA to assess the destruction of liposomes.     

Synthesis of a Rare Water-Soluble Silver(II)/Porphyrin and Its Multifunctional Therapeutic Effect on Methicillin-Resistant Staphylococcus aureus

Porphyrin derivatives are popular photodynamic therapy (PDT) agents; however, their typical insolubility in water has made it challenging to separate cells of organisms in a liquid water environment. Herein, a novel water-soluble 5,10,15,20-tetrakis(4-methoxyphenyl-3-sulfonatophenyl) porphyrin (TMPPS) was synthesized with 95% yield by modifying the traditional sulfonation route. The reaction of TMPPS with AgNO₃ afforded AgTMPPS an unusual Ag(II) oxidation state (97% yield). The free base and Ag(II) complex were characterized by matrix-assisted laser desorption ionization-mass spectroscopy, and ¹H nuclear magnetic resonance, Fourier-transform infrared, UV-vis, fluorescence, and X-ray photolectron spectroscopies. Upon 460 nm laser irradiation, AgTMPPS generated a large amount of ¹O₂, whereas no ⦁OH was detected. Antibacterial experiments on methicillin-resistant Staphylococcus aureus (MRSA) revealed that the combined action of Ag^Ⅱ ions and PDT could endow AgTMPPS with a 100% bactericidal ratio for highly concentrated MRSA (10⁸ CFU/mL) at a very low dosage (4 μM) under laser irradiation at 360 J/cm². Another PDT response was demonstrated by photocatalytically oxidizing 1,4-dihydronicotinamide adenine dinucleotide to NAD⁺ with AgTMPPS. The structural features of the TMPPS and AgTMPPS molecules were investigated by density functional theory quantum chemical calculations to demonstrate the efficient chemical and photodynamical effects of AgTMPPS for non-invasive antibacterial therapy.     

Photodynamic Synovectomy Using Benzoporphyrin Derivative in an Antigen-induced Arthritis Model for Rheumatoid Arthritis

Experimental photodynamic therapy (PDT) has recently been adapted for the treatment of inflammatory and rheumatoid arthritis. The biodistribution of benzoporphyrin derivative monoacid ring A (BPD-MA) and the effect of percutaneous light activation via intra-articular bare cleaved optical fibers was investigated using a rabbit-antigen-induced arthritis model. Qualitative evaluation of intra-articular photosensitizer clearance was performed with laser-induced fluorescence from 0 to 6 h following intravenous injection. The compound was rapidly taken up within the joint and then cleared steadily over the 6 h interval. Biodistribution was determined by fluorescence microscopy and spectrofluoroscopic extraction techniques 3 h following intravenous injection of 2 mg/kg BPD-MA. The biodistribution study demonstrated elevated levels of BPD-MA in synovium (0.35 μg/g) and muscle (0.35μg/g). Fluorescence microscopy demonstrated presence of the compound within pathologic synovium but absence of the photosensitizer within meniscus, ligament, bone and articular cartilage. Tissue effects were evaluated histologically at 2 and 4 weeks posttreatment. BPD-MA-mediated PDT caused synovial necrosis in the region of light activation in 50% of treatment knees at 2 weeks and 43% at 4 weeks. No damage to nonpathologic tissues was observed. These studies indicate that selective destruction of synovium can be achieved by the light-activated photosensitizing agent BPD-MA without damage to articular cartilage or periarticular soft tissues. PDT needs to be further evaluated to optimize treatment parameters to provide for a new minimally invasive synovectomy technique.     

Bioorthogonal Turn-On BODIPY-Peptide Photosensitizers for Tailored Photodynamic Therapy

Photodynamic therapy (PDT) leads to cancer remission via the production of cytotoxic species under photosensitizer (PS) irradiation. However, concomitant damage and dark toxicity can both hinder its use. With this in mind, we have implemented a versatile peptide-based platform of bioorthogonally activatable BODIPY-tetrazine PSs. Confocal microscopy and phototoxicity studies demonstrated that the incorporation of the PS, as a bifunctional module, into a peptide enabled spatial and conditional control of singlet oxygen (¹O₂) generation. Comparing subcellular distribution, PS confined in the cytoplasmic membrane achieved the highest toxicities (IC₅₀=0.096±0.003 μm ) after activation and without apparent dark toxicity. Our tunable approach will inspire novel probes towards smart PDT.     

Synthesis and effect on SMMC-7721 cells of new benzo[c,d]indole rhodanine complex merocyanines as PDT photosensitizers

Photodynamic therapy (PDT) represents a modern and noninvasive therapeutic approach, however, it relies on the development of photosensitizers. Here five new benzo[c,d]indole rhodamine complex merocyanines (BIRCM) D1-D5, displaying low dark toxicity and significant photo toxicity, were synthesized as PDT photosensitizers, and characterized by ¹H NMR, IR, UV–Vis and HRMS. The investigation of their absorption spectra in different solvents showed that the absorption maxima and molar extinction coefficient were in the region 507–679 nm and 0.21 × 10⁴–1.27 × 10⁵ L · mol^?1cm^?1, respectively. The evaluation of PDT activity showed that only irradiation could not kill SMMC-7721 cells, and the cell survival rate and inhibition rate at the application dose and duration was 92%–87% and 78%–49%, respectively. Especially, using D2, absorbed in the red zone, as photosensitizer for PDT analyzed its effect on SMMC-7721 cells survival, it could be found that the cell survival rate was 92% without irradiating and the cell inhibited rate was 78% under irradiating at concentrations of 2.5 × 10^?6 mol/L, displaying low dark toxicity and high photo toxicity, which was valuable for PDT of some microvascular diseases or other superficial diseases.     

A Targeting Singlet Oxygen Battery for Multidrug-Resistant Bacterial Deep-Tissue Infections

Traditional photodynamic therapy (PDT) is dependent on externally applied light and oxygen, and the depth of penetration of these factors can be insufficient for the treatment of deep infections. The short half-life and short diffusion distance of reactive oxygen species (ROS) also limit the antibacterial efficiency of PDT. Herein, we designed a targeting singlet oxygen delivery system, CARG-Py, for irradiation-free and oxygen-free PDT. This system was converted to the “singlet oxygen battery” CARG-¹O₂ and released singlet oxygen without external irradiation or oxygen. CARG-¹O₂ is composed of pyridones coupled to a targeting peptide that improves the utilization of singlet oxygen in deep multidrug-resistant bacterial infections. CARG-¹O₂ was shown to damage DNA, protein, and membranes by increasing the level of reactive oxygen inside bacteria; the attacking of multiple biomolecular sites caused the death of methicillin-resistant Staphylococcus aureus (MRSA). An in vivo study in a MRSA-infected mouse model of pneumonia demonstrated the potential of CARG-¹O₂ for the efficient treatment of deep infections. This work provides a new strategy to improve traditional PDT for irradiation- and oxygen-free treatment of deep infections while improving convenience of PDT.     

Structure and Biodistribution Relationships of Photodynamic Sensitizers*

Abstract— Photodynamic therapy (PDT) has, during the last quarter century, developed into a fully fledged biomedical field with its own association, the International Photodynamic Association (IPA) and regular conferences devoted solely to this topic. Recent approval of the first PDT sensitizer, Photofrin® (porfimer sodium), by health boards in Canada, Japan, the Netherlands and United States for use against certain types of solid tumors represents, perhaps, the single most significant indicator of the progress of PDT from a laboratory research concept to clinical reality. The approval of Photofrin® will undoubtedly encourage the accelerated development of second-generation photo-sensitizers, which have recently been the subject of intense study. Many of these second-generation drugs show significant differences, when compared to Photofrin®, in terms of treatment times postinjection, light doses and drug doses required for optimal results. These differences can ultimately be attributed to variations in either the quantum efficiency of the photosensitizer in situ, which is in turn affected by aggregation state, localized concentration of endogenous quenchers and primary photophysics of the dye, or the intratumoral and intracellular localization of the photosensitizer at the time of activation with light. The purpose of this review is to bring together data relating to the biodistribution and pharmacokinetics of second-generation sensitizers and attempt to correlate this with structural and electronic features of these molecules. As this requires a clear knowledge of photosensitizer structure, only chemically well-characterized compounds are included, e.g. Photofrin® and crude sulfonated phthal-ocyanines have been excluded as they are known to be complex mixtures. Nonporphyrin-based photosensitizers, e.g. rose bengal and the hypericins, have also been omitted to allow meaningful comparisons to be made between different compounds. As the intracellular distribution of photosensitizers to organelles and other subcellular structures can have a large effect on PDT efficacy, a section will be devoted to this topic.     

The Effect of Fluence Rate on Tumor and Normal Tissue Responses to Photodynamic Therapy

Photodynamic therapy (PDT), carried out at low fluence rates, may enhance tumor response as well as affect treatment selectivity. We have studied the effects of fluence rate on the response of the murine radiation-induced fibrosarcoma (RIF) to PDT using Photofrin® (5 mg/kg). Tumor response was tested over a large range of fluence rates (10-200 mW/cm²) and fluences (25-378 J/ cm²). Low fluence rates were more efficient; -60 J/cm2 at 10 mW/cm² was needed to achieve the same tumor growth delay as -100 J/cm² at 150 mW/cm² and -150 J/cm2 at 200 mW/cm². Despite this increased efficiency, lower fluence rates still required longer treatment times for equivalent anti-tumor effects: 95 min for 57 J/cm² at 10 mW/cm²versus 11 min for 100 J/cm² at 150 mW/cm². Effects of fluence rate on the PDT toxicity to normal tissue were examined through the response of the murine (C311) foot to Photofrin® PDT. Treatment with conditions that produced equivalent tumor responses, i.e. 57 J/cm² at 10 mW/cm² and 100 J/cm² at 150 mW/cm², resulted in a more severe foot response at the higher fluence rate (median peak response: 0.9 at 10 mW/cm², 1.5 at 150 mW/cm²) with more time required for tissue to return to normal (8 days at 10 mW/cm², at least 30 days at 150 mW/cm²). However, when feet were treated with an equal fluence of 100 J/cm2 at various fluence rates, longer healing times accompanied the lower fluence rate treatments. Overall, this paper demonstrates that lower PDT fluence rates are associated with increased efficiency of tumor response. If this increased efficiency is accounted for by lowering treatment fluence, lower fluence rates also may result in a more favorable normal tissue response to treatment.     

Inhibition of human neutrophil elastase activity by encapsulated serum (serumsome™) therapy

In order to inhibit human leukocyte proteolytic activity as a means of arresting the inflammatory response in tissues in vivo, we have designed a novel antiprotease carrier named serumsomes^™. Stabilized human serum was added to a flask containing a film of dried, purified lipids (phosphatidylcholine/dicetyl phosphate/cholesterol, 70∶20∶10) and hand-shaken for 10 min. Equal volumes of human neutrophils, and either serumsomes^™ (in stabilized human serum) or stabilized human serum alone were mixed together. Following 2 h of incubation at 37°C, the total elastase content of the neutrophils was reduced to 60±15% and 83±7% of the original activity by serumsomes^™ and stabilized human serum, respectively. Analysis of β-glucuronidase activity, a nonproteolytic lysosomal marker enzyme, revealed no diminution of activity during either of these incubations. These experiments demonstrate that human neutrophils are capable of interacting with serumsomes^™ in vitro, selectively inhibiting the lysosomal protease elastase. By administering serumsomes^™ in vivo, one may potentially preload blood leukocytes with serum antiproteases prior to their migration to inflammatory sites and thus possibly reduce the extent of tissue injury.     

Chiral Separation of 4-Iminoflavan Derivatives on Several Polysaccharide-Based Chiral Stationary Phases by HPLC

The HPLC enantiomeric separation of seven 4-iminoflavans was successfully accomplished in the normal phase mode using six polysaccharide-based chiral stationary phases namely, Chiralcel^®OD-H, Chiralcel^®OD, Chiralcel^®OJ, Chiralpak^®AD, Chiralpak^®IA and Chiralpak^®IB under normal and polar organic phase modes. The resolution depended on nature and concentration of alcoholic modifier. The results demonstrate clearly that the chromatographic system based on the coated and immobilized type Chiralpak^®IB and Chiralcel^®OD-H CSPs provide a powerful analytical tool for enantiomeric separation of all the 4-iminoflavans used in this study.

     

Induction of systemic neutrophil response in mice by photodynamic therapy of solid tumors.

Photodynamic therapy (PDT) of solid tumors elicits a strong, acute inflammatory response characterized by a rapid and massive infiltration of activated neutrophils into the tumor. The present study investigated the impact of PDT on the systemic and local (treatment site) kinetics of neutrophil trafficking and activity in mouse SCCVII and EMT6 tumor models. Differential leukocyte counts in the peripheral blood of treated mice revealed a pronounced neutrophilia developing rapidly after Photofrin porfimer sodium (Photofrin)- or tetra(m-tetrahydroxyphenyl)chlorin (mTHPC)-based PDT. Significant neutrophilia was also observed upon PDT treatment of normal dorsal skin but not on the footpad of tumor-free mice. The changes in circulating neutrophil numbers were accompanied by an efflux of these cells from the bone marrow. An increased proportion of cells with high L-selectin (CD62L antigen) expression was found among bone-marrow-residing neutrophils 6-24 h after PDT, and in neutrophils in the peripheral circulation and treated tumors 24 h after therapy. Complement inhibition completely prevented the development of PDT-induced neutrophilia. The results of the present study demonstrate that treatment of solid tumors by PDT induces a strong and protracted increase in systemic neutrophil numbers mediated by complement activation. This reaction reflects rapid and massive mobilization and activation of neutrophils for the destruction of PDT-treated tumor tissue.     

Solubilization and Release of a Model Drug Nimesulide from PEO–PPO–PEO Block Copolymer Core–Shell Micelles: Effect of Size of PEO Blocks

The commercially available polypropylene oxide (PPO)–polyethylene oxide (PEO) symmetrical triblock copolymers (Pluronics^®) have been recognized as pharmaceutical excipients and used in a variety of applications. This paper reports studies on micellar and solubilization behavior of three PEO–PPO–PEO block copolymers, viz. P103, P104 and P105 (same PPO mol. wt = 3250 g·mol^?1 but different  % PEO = 30, 40 and 50 %, respectively) in aqueous solutions. Critical micellization concentrations (CMCs), critical micellization temperatures (CMTs), and micelle size/polydispersity for copolymers with and without the drug, nimesulide (NIM), are reported. The solubilization of NIM is significantly enhanced with increasing hydrophobicity (P103 > P104 > P105), concentration, temperature and in the presence of added salt. The copolymer hydrophobicity, temperature and the drug loading strongly affect micelle behavior. The micelle–water partition coefficient (P) and thermodynamic parameters of solubilization, viz. Gibbs energy ( $ \Updelta G_{s}^{\text{o}} $ ), enthalpy ( $ \Updelta H_{s}^{\text{o}} $ ) and entropy ( $ T\Updelta S_{s}^{\text{o}} $ ), were calculated. The solubilization site of the drug in different micellar solutions and its release from Pluronics^® micelles in phosphate buffer saline (PBS) solution at 37 °C were examined. The kinetics of NIM exhibits burst release characteristics, which are believed to be controlled by degradation of the copolymers. These studies were carried out to investigate the feasibility of using Pluronics^® as a release vehicle of nimesulide in vitro. From the results, it was concluded that Pluronic^® based formulations might be practical for drug delivery.     

Thickness dependence of thermally induced changes in surface and bulk properties of Nafion® nanofilms

Thermally induced changes in surface wettability, dewetting behavior, and proton transport of “self‐assembled” nanothin Nafion^® films (4–300 nm) on SiO₂ substrate is reported. Thermal annealing induces switching of the surface wettability of 55 nm and thinner films from hydrophilic to super‐hydrophobic. Thickness dependence of this behavior is observed with higher annealing temperature required for lower thickness films, indicating highly restrictive mobility of Nafion^® ionomer as film thickness decreases. Dewetting is only observed for 4‐nm thin film. Significant suppression in proton conductivity upon thermal annealing was noted. Similarly, two other bulk properties, water uptake and swelling, were found to decrease upon annealing. This work reports a systematic examination of the thickness dependence of thermally induced changes in both surface and bulk properties of ultra‐thin Nafion^®. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 1267–1277     

Chiral Separation of 4-Iminoflavan Derivatives on Several Polysaccharide-Based Chiral Stationary Phases by HPLC

The HPLC enantiomeric separation of seven 4-iminoflavans was successfully accomplished in the normal phase mode using six polysaccharide-based chiral stationary phases namely, Chiralcel^®OD-H, Chiralcel^®OD, Chiralcel^®OJ, Chiralpak^®AD, Chiralpak^®IA and Chiralpak^®IB under normal and polar organic phase modes. The resolution depended on nature and concentration of alcoholic modifier. The results demonstrate clearly that the chromatographic system based on the coated and immobilized type Chiralpak^®IB and Chiralcel^®OD-H CSPs provide a powerful analytical tool for enantiomeric separation of all the 4-iminoflavans used in this study.