Enhanced Solubility and Bioavailability of Clotrimazole in Aqueous Solutions with Hydrophobized Hyperbranched Polyglycidol for Improved Antifungal Activity.

The poor solubility of clotrimazole in the aqueous medium and the uncontrolled removal of the drug-loaded suppository content limit its effectiveness in the treatment of vulvovaginal candidiasis. We present here the aqueous formulations of clotrimazole in the form of non-Newtonian structured fluids, i.e., Bingham plastic or pseudoplastic fluids constructed of hyperbranched polyglycidol, HbPGL, with a hydrophobized core with aryl groups such as phenyl or biphenyl. The amphiphilic constructs were obtained by the modification of linear units containing monohydroxyl groups with benzoyl chloride, phenyl isocyanate, and biphenyl isocyanate, while the terminal 1,2-diol groups in the shell were protected during the modification step, followed by their deprotection. The encapsulation of clotrimazole within internally hydrophobized HbPGLs using a solvent evaporation method followed by water addition resulted in structured fluids formation. Detailed Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analyses performed for aryl-HbPGLs with clotrimazole revealed the difference in drug compatibility among polymers. Clotrimazole in biphenyl-enriched HbPGL, unlike phenyl derivatives, was molecularly distributed in both the dry and the hydrated states, resulting in transparent formulations. The shear-thinning properties of the obtained fluid formulations make them injectable and thus suitable for the intravaginal application. Permeability tests performed with the usage of the Franz diffusion cell showed a 5-fold increase in the permeability constant of clotrimazole compared to drugs loaded in a commercially available disposable tablet and a 50-fold increase of permeability in comparison to the aqueous suspension of clotrimazole. Furthermore, the biphenyl-modified HbPGL-based drug liquid showed enhanced antifungal activity against both Candida albicans and Candida glabrata that was retained for up to 7 days, in contrast to the phenyl-HbPGL derivatives and the tablet. With their simple formulation, convenient clotrimazole/biphenyl-HbPGL formulation strategy, rheological properties, and enhanced antifungal properties, these systems are potential antifungal therapeutics for gynecological applications. This study points in the synthetic direction of improving the solubility of poorly water-soluble aryl-enriched pharmaceuticals.

"To Be or Not to Be" of a Polymer Nanogel-Unravelling the Relationship of Product Properties vs. Synthesis Conditions Governing the Radiation Crosslinking of Poly(acrylic acid) Using GPC/SEC-MALLS.

In this paper, a state-of-the-art multi-detection gel permeation chromatography/size exclusion chromatography (GPC/SEC) system including multi-angle laser light scattering (MALLS) is applied to monitor radiation-induced synthesis of internally crosslinked nanostructures from poly(acrylic acid) (PAA). The aim is to demonstrate that this modern tool yields a more detailed picture of reaction mechanism and product structure than the techniques used to date. The prevailing intramolecular crosslinking narrows the molecular weight distribution from Mw/Mn = 3.0 to 1.6 for internally crosslinked structures. A clear trend from over 0.7 to 0.5 in the Mark-Houwink exponent and a decrease in Rg/Rh from 1.7 to 1.0 point to the formation of nanogels, more rigid and less permeable than the starting coils. Changes in the coil contraction factor (g' = [η]irradiated/[η]linear) as a function of the radical density revealed the existence of two modes in intramolecular crosslinking, the initial one (up to 0.075 radicals per monomer unit) where the compactness of products changes strongly with progressing crosslinking and a second one where further compacting is suppressed by the lower flexibility of the partially crosslinked chain segments. This indicates a transition from soft, still internally crosslinkable nanogels to more rigid structures, less prone to further intramolecular loop formation. Our findings provide means for the tailored design of new PAA nanomaterials.

Laminar Biomaterial Composite of PVA Cryogel with Amnion as Potential Wound Dressing.

Gel dressings, composed of polymers both natural and synthetic, are successfully used in the treatment of burn wounds. They protect the burn wound site against adverse external factors, ensure an adequate level of tissue hydration, have soothing and pain-relieving properties, and also support the healing process and reduce the risk of pathological scars. Another promising material that can be used in the wound-healing process is an amnion membrane. Due to its valuable properties such as protecting the body against bacterial infections and permeability to nutrition, it has found usage in different brands of medicine. In this work, we have combined the beneficial properties of hydrogels and amnion in order to make the laminar dressing that may serve for wound healing. For that purpose, the physically crosslinked cryogel of poly(vinyl alcohol) (PVA) was covered with an amnion membrane. Subsequently, gamma irradiation was performed, leading to the simultaneous internal crosslinking of the hydrogel, its permanent bonding with the amnion, and dressing sterilization. The physicochemical properties of the dressing including gel fraction, swelling, and hardness were studied. Biological tests such as the MTT assay, antimicrobial activity, and histopathological examination confirmed that the obtained material constituted a promising candidate for further, more in-depth studies aiming at wound dressing application.

Towards Cancer Nanoradiopharmaceuticals-Radioisotope Nanocarrier System for Prostate Cancer Theranostics Based on Radiation-Synthesized Polymer Nanogels.

Despite the tremendous development of oncology, prostate cancer remains a debilitating malignancy. One of the most promising approaches to addressing this issue is to exploit the advancements of nanomedicine in combination with well-established nuclear medicine and radiotherapy. Following this idea, we have developed a radioisotope nanocarrier platform of electron-beam-synthesized nanogels based on poly(acrylic acid). We have developed a functionalization protocol, showing the very high (>97%) efficiency of the conjugation in targeting a ligand-bombesin derivative. This engineered peptide can bind gastrin-releasing peptide receptors overexpressed in prostate cancer cells; moreover, it bears a radioisotope-chelating moiety. Our nanoplatform exhibits very promising performance in vitro; the radiolabeled nanocarriers maintained high radiochemical purity of >90% in both the labeling buffer and human serum for up to 14 days. The application of the targeted nanocarrier allowed also effective and specific uptake in PC-3 prostate cancer cells, up to almost 30% after 4 h, which is a statistically significant improvement in comparison to carrier-free radiolabeled peptides. Although our system requires further studies for more promising results in vivo, our study represents a vital advancement in radionanomedicine-one of many steps that will lead to effective therapy for castration-resistant prostate cancer.

Mucoadhesive gellan gum-based and carboxymethyl cellulose -based hydrogels containing gemcitabine and papain for bladder cancer treatment.

Local treatment of bladder cancer faces several limitations such as short residence time or low permeation through urothelium tissue. The aim of this work was to develop patient-friendly mucoadhesive gel formulations combining gemcitabine and the enzyme papain for improved intravesical chemotherapy delivery. Hydrogels based on two different polysaccharides, gellan gum and sodium carboxymethylcellulose (CMC), were prepared with either native papain or papain nanoparticles (nanopapain) to explore for the first time their use as permeability enhancers through bladder tissue. Gel formulations were characterized regarding enzyme stability, rheological behavior, retention on bladder tissue and bioadhesion, drug release properties, permeation capacity, and biocompatibility. After 90 days of storage, the enzyme loaded in the CMC gels retained up to 83.5 ± 4.9 % of its activity in the absence of the drug, and up to 78.1 ± 5.3 with gemcitabine. The gels were mucoadhesive and the enzyme papain showed mucolytic action, which resulted in resistance against washing off from the urothelium and enhanced permeability of gemcitabine in the ex vivo tissue diffusion tests. Native papain shortened lag-time tissue penetration to 0.6 h and enhanced 2-fold drug permeability All formulations demonstrated pseudoplastic behavior and no irritability. Overall, the developed formulations have potential as an upgraded alternative to intravesical therapy for bladder cancer treatment.

Study of the Optimal Composition and Storage Conditions of the Fricke-XO-Pluronic F-127 Radiochromic Dosimeter.

This paper presents the results of research on the Fricke-XO-Pluronic F-127 dosimeter. It consists of a Fricke dosimetric solution and xylenol orange (XO), which are embedded in a matrix of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic F-127). Upon irradiation, Fe+2 ions transform into Fe+3, forming a colored complex with XO ([XO-Fe]+3). The color intensity is related to the dose absorbed. The optimal composition, storage conditions, and radiation-induced performance of the Fricke-XO-Pluronic F-127 dosimeter were investigated. The optimal composition was found to be 1 mM FAS, 50 mM sulfuric acid (H2SO4), 0.165 mM XO in 25% Pluronic F-127. The basic features of this dosimeter are discussed, such as dose sensitivity, linear and dynamic dose range, stability before and after irradiation, storage conditions, dose response for irradiation with 6 and 15 MV photons, and batch-to-batch reproducibility. The obtained results showed a certain potential of the Fricke-XO-Pluronic F-127 for radiotherapy dosimetry.

Impact of Salt on Thermal Stability and Dose Response of the Fricke-XO-Pluronic F-127 3D Radiotherapy Dosimeter.

Fricke-XO-Pluronic F-127 has recently been proposed as a 3D dosimeter for radiotherapy. It contains the typical ingredients of the Fricke ionizing radiation dosimeter, which are embedded in a physical gel of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic F-127). The main reactions upon irradiation are the conversion of Fe+2 to Fe+3 and the formation of a colored complex with XO ([XO-Fe]+3). The study attempts to optimize the dosimeter in terms of its solution-to-gel transition temperature. In order to lower this temperature, the use of NaCl salt has been proposed. The new composition was characterized in order to obtain information on its thermal performance, storage stability, dose response to irradiation with a medical accelerator emitting different types of radiation, and tissue equivalence. The results obtained show an improvement in the sol-gel transition temperature and dose sensitivity compared to the composition without NaCl and broaden the knowledge of the Fricke-XO-Pluronic F-127.

Mucoadhesive Polymers and Their Applications in Drug Delivery Systems for the Treatment of Bladder Cancer.

Bladder cancer (BC) is the tenth most common type of cancer worldwide, affecting up to four times more men than women. Depending on the stage of the tumor, different therapy protocols are applied. Non-muscle-invasive cancer englobes around 70% of the cases and is usually treated using the transurethral resection of bladder tumor (TURBIT) followed by the instillation of chemotherapy or immunotherapy. However, due to bladder anatomy and physiology, current intravesical therapies present limitations concerning permeation and time of residence. Furthermore, they require several frequent catheter insertions with a reduced interval between doses, which is highly demotivating for the patient. This scenario has encouraged several pieces of research focusing on the development of drug delivery systems (DDS) to improve drug time residence, permeation capacity, and target release. In this review, the current situation of BC is described concerning the disease and available treatments, followed by a report on the main DDS developed in the past few years, focusing on those based on mucoadhesive polymers as a strategy. A brief review of methods to evaluate mucoadhesion properties is also presented; lastly, different polymers suitable for this application are discussed.

Synthesis and Properties of Targeted Radioisotope Carriers Based on Poly(Acrylic Acid) Nanogels.

Radiation crosslinking was employed to obtain nanocarriers based on poly(acrylic acid)-PAA-for targeted delivery of radioactive isotopes. These nanocarriers are internally crosslinked hydrophilic macromolecules-nanogels-bearing carboxylic groups to facilitate functionalization. PAA nanogels were conjugated with an engineered bombesin-derivative-oligopeptide combined with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate chelating moiety, aimed to provide selective radioligand transport. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium (DMTMM) toluene-4-sulfonate was used as the coupling agent. After tests on a model amine-p-toluidine-both commercial and home-synthesized DOTA-bombesin were successfully coupled to the nanogels and the obtained products were characterized. The radiolabeling efficiency of nanocarriers with 177Lu, was chromatographically tested. The results provide a proof of concept for the synthesis of radiation-synthesized nanogel-based radioisotope nanocarriers for theranostic applications.

An Updated Review of Macro, Micro, and Nanostructured Hydrogels for Biomedical and Pharmaceutical Applications.

Hydrogels are materials with wide applications in several fields, including the biomedical and pharmaceutical industries. Their properties such as the capacity of absorbing great amounts of aqueous solutions without losing shape and mechanical properties, as well as loading drugs of different nature, including hydrophobic ones and biomolecules, give an idea of their versatility and promising demand. As they have been explored in a great number of studies for years, many routes of synthesis have been developed, especially for chemical/permanent hydrogels. In the same way, stimuli-responsive hydrogels, also known as intelligent materials, have been explored too, enhancing the regulation of properties such as targeting and drug release. By controlling the particle size, hydrogel on the micro- and nanoscale have been studied likewise and have increased, even more, the possibilities for applications of the so-called XXI century materials. In this paper, we aimed to produce an overview of the recent studies concerning methods of synthesis, biomedical, and pharmaceutical applications of macro-, micro, and nanogels.

Amniotic Stem Cells Cultured on Thermoresponsive Polymers Allow Obtaining a Full Cell Sheet.

Amniotic stem cells promote adhesion and migration of epithelial cells. Obtaining a full sheet containing amniotic stem cells seems to be the best solution for the treatment of burn wounds. The main advantage of this method is obtaining a full sheet of cells by lowering the temperature below the transition temperature, which does not affect extracellular matrix. The purpose of this work was to produce a skin substitute-a full sheet consisting of amniotic mesenchymal stem cells-and compare with well-known fibroblast sheet. Amniotic membrane cells revealed better tendency to full sheet detachment than fibroblasts. Confluence after 24 hours was always higher on polymer-coated dishes than on normal polypropylene dishes. Also viability was higher than on the control culture dish, while the number of apoptotic cells was always highest on polypropylene (control). Ile-Lys-Val-ala-Val (IKVAV) 0.28 addition to poly (poly [ethylene glycol] ethyl methacrylate) (PTEGMA) caused best cell confluence and highest percentage of cells in mitosis phase of cell cycle, but also worst cell detachment was observed in both cell types on PTEGMA IKVAV 0.28. Viability of cells transferred in cell sheet form onto a new culture dish was higher than when detached as suspension enzymatically. Additionally, percentage of apoptotic cells transferred in cell sheet form onto a new culture dish was always lower than when detached as suspension enzymatically. Culturing of PTEGMA, PTEGMA IKVAV 0.28 and PTEGMA IKVAV 0.14 have a stimulating effect on number of cells in mitosis in amniotic cell culture even after cell sheet transfer onto a new dish, whereas such effect with fibroblast was not observed.

Leuco crystal violet-Pluronic F-127 3D radiochromic gel dosimeter.

This work reports results related to the manufacturing and optimisation of a leuco crystal violet (LCV)-Pluronic F-127 radiochromic gel dosimeter suitable for 3D radiotherapy dosimetry. A feature of this gel is that the natural gelatine polymer, which is most often used as a matrix in 3D dosimeters, is substituted with Pluronic F-127 synthetic copolymer (poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide). Pluronic F-127 ensures a higher transparency than gelatine, which may be beneficial for optical computed tomography readout, and improves the thermal properties in the temperature range above ~30 °C at which the gelatine physical gel converts to a solution. The optimal composition obtained comprises 2 mM LCV, 4 mM 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol (Triton X-100), 17 mM trichloroacetic acid (TCAA) and 25% Pluronic F-127. Its main dose-response features are 4‒150 Gy linear dose range (150 Gy was the maximal dose applied to gels in this work), 0.0070 Gy-1 cm-1 dose sensitivity (derived from absorbance (600 nm) = f (dose) for 6 MeV electrons, 0.88(3) Gy s-1 and 0.0156 Gy-1 cm-1 derived from optical density (Δµ) = f (dose) for 6 MV x-rays, 0.1010 Gy s-1), low initial colour (initial absorbance = 0.0429) and a diffusion coefficient of crystal violet (CV) in LCV-Pluronic of 0.054 ± 0.023 mm2 h-1. Raman spectroscopy was used to characterize LCV-Pluronic chemical changes after irradiation. Differential scanning calorimetry (DSC) revealed that LCV-Pluronic is stable in temperatures between approximately 11 °C and 56 °C. Irradiation of LCV-Pluronic gel impacts on its first sol-gel transition temperature and the thermal effect of this process-both increased with absorbed dose, which might be related to the degradation of Pluronic. LCV-Pluronic is a promising 3D dosimeter for ionising radiation applications. Further work is needed to improve LCV-Pluronic response in the low dose region, and characterize potential effects of pH, temperature during irradiation, and radiation quality/dose rate on dose response characteristics.

Tetrazolium salts-Pluronic F-127 gels for 3D radiotherapy dosimetry.

This work is a follow-up study for a recently-proposed 3D radiochromic gel dosimeter that contains a tetrazolium salt and a physical gel matrix made of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic F-127). Several tetrazolium salts were examined in this work, including tetrazolium violet, blue tetrazolium chloride, nitro blue tetrazolium chloride (NBT), tetranitro blue tetrazolium chloride (tNBT) and thiazolyl blue tetrazolium bromide (TBTB). The salt-containing gel dosimeters were compared with the first Pluronic gel composition that contained 2,3,5-triphenyltetrazolium chloride (TTC) as the radiation-sensitive component (dose sensitivity of 0.0023 (Gy cm)-1). The Pluronic gels with NBT and tNBT outperformed the other gels, including the TTC-containing gel, with respect to their dose sensitivity and low dose-response. The NBT gels were found to have better stability over time than tNBT gels. Sensitization of the gels to ionizing radiation was examined by addition of tert-butyl alcohol and sodium formate. The best composition was 0.0818% NBT (1 mM), 25% Pluronic F-127 and 0.136 × 10-2% sodium formate. This gel dosimeter was insensitive to changes in dose rate for photons of different energies. The mean dose sensitivity amounted to 0.0047 ± 0.1 × 10-4 (Gy cm)-1. A diversion in the dose-response was observed for the gel irradiated with electrons. Additional characteristics of the NBT gel were a linear-dose range and a dynamic-dose range between <1 and ⩾150 Gy and a dose threshold of <1 Gy. The dose distribution registered for the NBT-Pluronic gel was stable after irradiation for over 7 d with no visible diffusion of the irradiated part, which is analogous to the original TTC-Pluronic gel.

TTC-Pluronic 3D radiochromic gel dosimetry of ionizing radiation.

This work reports the first results obtained using a new 3D radiochromic gel dosimeter. The dosimeter is an aqueous physical gel matrix made of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic F-127, PEO-PPO-PEO) doped with a representative of tetrazolium salts, 2, 3, 5-triphenyltetrazolium chloride (TTC). There were several reasons for the choice of Pluronic as a gel forming substrate: (i) the high degree of transparency and colourlessness; (ii) the possibility of gel dosimeter preparation at both high and low temperatures due to the phase behaviour of Pluronic; (iii) the broad temperature range over which the TTC-Pluronic dosimeter is stable; and (iv) the non-toxicity of Pluronic. A reason for the choice of TTC was its ionising radiation-induced transformation to water-insoluble formazan, which was assumed to impact beneficially on the spatial stability of the dose distribution. If irradiated, the TTC-Pluronic gels become red but transparent in the irradiated part, while the non-irradiated part remains crystal clear. The best obtained composition is characterised by <4 Gy dose threshold, a dose sensitivity of 0.002 31 (Gy × cm)-1, a large linear dose range of >500 Gy and a dynamic dose response much greater than 500 Gy (7.5% TTC, 25% Pluronic F-127, 50 mmol dm-3 tetrakis). Temporal and spatial stability studies revealed that the TTC-Pluronic gels (7.5% TTC, 25% Pluronic F-127) were stable for more than one week. The addition of compounds boosting the gels' dose performance caused deterioration of the gels' temporal stability but did not impact the stability of the 3D dose distribution. The proposed method of preparation allows for the repeatable manufacture of the gels. There were no differences observed between gels irradiated fractionally and non-fractionally. The TTC-Pluronic dose response might be affected by the radiation source dose rate-this, however, requires further examination.

Determination of Propagation Rate Coefficient for the Polymerization of N-Vinylpyrrolidone in Aqueous Solution by Pulsed Electron Polymerization and Size Exclusion Chromatography.

A new method for determination of a propagation rate coefficient in radical polymerization, pulsed electron polymerization-size exclusion chromatography (PEP-SEC), has been tested on N-vinylpyrrolidone in water and shown to yield results very similar to those obtained by the well-established pulsed laser polymerization-size exclusion chromatography (PLP-SEC). A potential advantage of PEP-SEC is its applicability to studying polymerizations in nontransparent systems and lack of any additives. Series of nanosecond pulses of high-energy electrons from an accelerator generate radicals which initiate polymerization. Further analysis of the samples and data processing are the same as in PLP-SEC. The described technique can be potentially developed into a method complementary and/or comparative to PLP-SEC.

Poly(vinyl methyl ether) hydrogels at temperatures below the freezing point of water-molecular interactions and states of water.

Water interacting with a polymer reveals a number of properties very different to bulk water. These interactions lead to the redistribution of hydrogen bonds in water. It results in modification of thermodynamic properties of water and the molecular dynamics of water. That kind of water is particularly well observable at temperatures below the freezing point of water, when the bulk water crystallizes. In this work, we determine the amount of water bound to the polymer and of the so-called pre-melting water in poly(vinyl methyl ether) hydrogels with the use of Raman spectroscopy, dielectric spectroscopy, and calorimetry. This analysis allows us to compare various physical properties of the bulk and the pre-melting water. We also postulate the molecular mechanism responsible for the pre-melting of part of water in poly(vinyl methyl ether) hydrogels. We suggest that above -60 °C, the first segmental motions of the polymer chain are activated, which trigger the process of the pre-melting.