pH sensitive and controlled release system based on cellulose nanofibers-poly vinyl alcohol hydrogels for cisplatin delivery

Delivery of chemotherapy drugs, such as cisplatin, with controlled manner is a significant area of research in cancer treatment. The main purpose of this study was to investigate the in-vitro release of cisplatin from pH sensitive and controlled release hydrogels based on cellulose nanofibers (CNFs) and poly(vinyl alcohol) (PVA). Various hydrogels with different amounts of CNFs were prepared. This novel drug delivery system was characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and scanning electron microscopy (SEM) analyses. By in-vitro experiments the influence of CNFs contents and pH of the release media on the release rate of the drug were investigated. According to the results, the hydrogel containing 1 wt% CNFs in the release media with the pH of 7.4, efficiently sustained the drug release and so can cause to the reduction of side effects of drug. By fitting the experimental data with various kinetic models it was concluded that the release mechanism is best fitted by Korsmeyer-Peppas kinetic model suggesting the diffusion controlled release mechanism. The prepared hydrogel system is suitable for delivery of cisplatin in the small intestine with a controlled manner.     

Designing double-layered nanofibrous membranes as a wound dressing material

New generation wound dressings require the criteria that both bioactive and conventional wound dressing materials can recompense the fundamental properties like defense of wound from microbial invasion, dehydration during the wound care duration and mimic the healing process. In this study, functional double-layered nanofibrous composite membranes were fabricated via electrospinning method. The matrices consist of a sheet of ampicillin loaded poly(2-hydroxylethyl methacrylate/polyacrylic acid (pHEMA/pAA) nanofibers on the upper side (first layer: pH sensitive antibacterial barrier) and a sheet of poly(ε-caprolactone) (PCL)/gelatin nanofibers (second layer: bioactive part). Ampicillin was successfully incorporated to double-layered matrices which greatly changed the mechanical properties, biodegradability and water uptake ratios (up to 4 fold higher values). The success of the antimicrobial activity of ampicillin on Staphylococcus aureus and Escherichia coli was indicated by the inhibition zone test. pH sensitivity was confirmed by the swelling and ampicillin release studies by shifting pH value to basic environment. Thus, double-layered pHEMA-pAA nanofibers suggest as a potential wound dressing material for its pH sensitive drug delivery ability and its bioactive part.     

The Application of Mucoadhesive Chitosan Nanoparticles in Nasal Drug Delivery

Mucosal delivery of antigens can induce both humoral and cellular immune responses. Particularly, the nasal cavity is a strongly inductive site for mucosal immunity among several administration routes, as it is generally the first point of contact for inhaled antigens. However, the delivery of antigens to the nasal cavity has some disadvantages such as rapid clearance and disposition of inhaled materials. For these reasons, remarkable efforts have been made to develop antigen delivery systems which suit the nasal route. The use of nanoparticles as delivery vehicles enables protection of the antigen from degradation and sustains the release of the loaded antigen, eventually resulting in improved vaccine and/or drug efficacy. Chitosan, which exhibits low toxicity, biodegradability, good cost performance, and strong mucoadhesive properties, is a useful material for nanoparticles. The present review provides an overview of the mucosal immune response induced by nanoparticles, recent advances in the use of nanoparticles, and nasal delivery systems with chitosan nanoparticles.     

Novel Spray Dried Glycerol 2-Phosphate Cross-Linked Chitosan Microparticulate Vaginal Delivery System—Development,Characterization and Cytotoxicity Studies

Chitosan microparticulate delivery systems containing clotrimazole were prepared by a spray drying technique using glycerol 2-phosphate as an ion cross-linker. The impact of a cross-linking ratio on microparticle characteristics was evaluated. Drug-free and drug-loaded unmodified or ion cross-linked chitosan microparticles were examined for the in vitro cytotoxicity in VK2/E6E7 human vaginal epithelial cells. The presence of glycerol 2-phosphate influenced drug loading and encapsulation efficacy in chitosan microparticles. By increasing the cross-linking ratio, the microparticles with lower diameter, moisture content and smoother surface were observed. Mucoadhesive studies displayed that all formulations possessed mucoadhesive properties. The in vitro release profile of clotrimazole was found to alter considerably by changing the glycerol 2-phosphate/chitosan ratio. Results from cytotoxicity studies showed occurrence of apoptotic cells in the presence of chitosan and ion cross-linked chitosan microparticles, followed by a loss of membrane potential suggesting that cell death might go through the mitochondrial apoptotic pathway.     

Fabrication of electrospun antimicrobial nanofibers containing metronidazole using nanospider technology

Nanospider technology as a modified electrospinning technique was used for the fabrication of electrospun nanofibers based on poly(vinyl alcohol) (PVA)/poly(ethylene oxide) (PEO) blend as drug delivery system (DDS) for metronidazole (MTZ) as an antimicrobial drug. Electrospun PVA/PEO/MTZ composite nanofibers were stabilized against disintegration in water by heating in oven at 110°C, or by soaking in isopropyl alcohol for 6 hrs. Incorporation of MTZ into electrospun nanofibers was confirmed by SEM, FT-IR spectra and TGA. The drug release results showed that the burst release was suppressed with stabilized electrospun nanofibers compared with non-stabilized ones. Electrospun PVA/PEO/MTZ composite nanofibers exhibited remarkable antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger, Penicillium notatum and Aspergillus flavus which varies with the species of the tested organisms.     

The effect of bentonite concentration on the drug delivery efficacy of a pH-sensitive alginate/bentonite hydrogel

We produced a protein loaded, pH-sensitive alginate-bentonite hydrogel for wound dressings. Alginate is a nontoxic polysaccharide with favorable pH-sensitive properties that make it useful for the intestinal delivery of protein drugs. However, the use of alginate for drug delivery is limited by drug leaching and rapid dissolution of alginate at the higher pH, which may result in lower entrapment efficiency and a burst in the release of entrapped protein drugs. To overcome these problems, we created a novel cross-linked alginate-bentonite hydrogel by combining mineral-rich bentonite with the alginate matrix along with an additive to ensure controlled release. We analyzed the gel in the drug loading process in an aqueous environment by looking at the release profiles of a model protein drug (BSA) from the hydrogel at pH values of 4.5, 5.2 (skin area) and 7.4, 9.2 (wound area). The swelling ratio decreased with bentonite concentration, but did not fall below 6. The rate of drug release was slowest at a pH value of 4.5 and fastest at a pH value of 9.2. The rate of drug release decreased with bentonite concentration. The presence of bentonite prevents the rapid dissolution of alginate at the higher pH, ensuring the controlled release of the entrapped drug.     

Montelukast incorporated poly(methyl vinyl ether-co-maleic acid)/poly(lactic-co-glycolic acid) electrospun nanofibers for wound dressing

The aim of the present study was to prepare nanofibers loaded with montelukast, a cysteinyl leukotrienes (CysLTs) inhibitor, with anti-inflammatory properties effective on wound healing. Polymeric nanofibers containing montelukast were spun by electrospinning method using different ratios of the blend of two biodegradable polymers of poly(methyl vinyl etherco-maleic acid) (PMVEMA) and poly(lactic-co-glycolic acid) (PLGA) at the total polymer concentration of 37 %, the distance of the needle to rotating screen of 19 cm, the voltage of 12 Kv and the rate of injection of 0.2 ml/h. The ratio of two polymers in the blend and the concentration of montelukast were optimized based on the diameter of the nanofibers, drug loading percent and release efficiency by a full factorial design. The morphology, diameter and diameter distribution of the nanofibers were studied by scanning electron microscopy (SEM). Drug loading percent in the nanofibers was determined by extracting the loaded drug from a specific surface of the nanofibers which was subsequently analyzed spectrophotometrically. The drug release rate from the nanofibers was studied in phosphate buffer solution (pH 7.4) containing 0.5 % Tween 20 at predetermined time intervals until 10 days. The cytotoxicity of the designed nanofibers was evaluated on mouse fibroblast cells using trypan blue method, their platelet adherence property was quantified by measuring the lactate dehydrogenase (LDH) activity and confirmed by SEM micrographs. The optimized ratio of PLGA/PMVEMA was 3:1 with the total concentration of polymers as 37 % loaded with 30 % of montelukast produced nanofibers with a diameter of 157.6 nm, drug loading percent of 43.7 % and release efficiency of 75 % after 10 days. The cell viability was similar in nanofibers and the negative control group. The platelets adhesion to the nanofibers was more than the negative control group (p<0.05).     

Chitosan in Mucoadhesive Drug Delivery: Focus on Local Vaginal Therapy

Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance in today’s drug development. Chitosan, due to its known biodegradability, bioadhesiveness and excellent safety profile offers means to improve mucosal drug therapy. We have used chitosan as mucoadhesive polymer to develop liposomes able to ensure prolonged residence time at vaginal site. Two types of mucoadhesive liposomes, namely the chitosan-coated liposomes and chitosan-containing liposomes, where chitosan is both embedded and surface-available, were made of soy phosphatidylcholine with entrapped fluorescence markers of two molecular weights, FITC-dextran 4000 and 20,000, respectively. Both liposomal types were characterized for their size distribution, zeta potential, entrapment efficiency and the in vitro release profile, and compared to plain liposomes. The proof of chitosan being both surface-available as well as embedded into the liposomes in the chitosan-containing liposomes was found. The capability of the surface-available chitosan to interact with the model porcine mucin was confirmed for both chitosan-containing and chitosan-coated liposomes implying potential mucoadhesive behavior. Chitosan-containing liposomes were shown to be superior in respect to the simplicity of preparation, FITC-dextran load, mucoadhesiveness and in vitro release and are expected to ensure prolonged residence time on the vaginal mucosa providing localized sustained release of entrapped model substances.     

Manufacturing and Optimization the Nanofibres Tissue of Poly(N-vinyl-2-pyrrolidone) - Poly(e-caprolactone) Shell/Poly(N-vinyl-2-pyrrolidone)-Amphotericin B Core for Controlled Drug Release System

Controlled release of drugs is important to reduce the amount of medication in treatment of any diseases and improves life quality. Poly(e-caprolactone) (PCL) has a low biodegradation rate that is a disadvantage in the biomedical and pharmaceutical fields. Poly(N-vinyl-2-pyrrolidone) (PVP) is a water-soluble polymer that to overcome of PCL low biodegradation rate, electrospinning of PCL blended with PVP was used for shell of nanofibers with controllable degradation rates and drug release rates. Oral and vaginal mucosal infections mainly caused by candida albicans. It is usually a harmless commensal organism; however it is known as an opportunistic pathogen for almost immunologically week and immune compromised people. Amphotericin-B (AmB) is a strong polyene antifungal antibiotic that has a significantly efficacy on candida albicans. This study is manufactured and optimized the PVP-PCL shell/PVP-AmB core nanofiberous tissue by working distance and feed flow rate for controlled drug release. AmB with PVP was successfully inserted into the core. PVPPCL shell (50/50)/PVP-AmB core nanofiberous were electrospinning with two optimum distances working and two flow rates. The mechanical properties of coaxial nanofibers were analyzed by instron machine. Scanning electron microscopy and transmission electron microscopy was used for analysis morphology. Further, drug release test were done for coaxial nanofibers with AmB different morphologies. The effect of flow rate and working distance on morphology and mechanical properties were evaluated by statistical two-way analysis of the variance (ANOVA). The diameter averages of nanofibers were decreased significantly by increasing working distance. Moreover, the stress and strain were increased by increasing working distance. Coaxial nanofibers biodegradability rate and drug release of nanofibers were increased also by increasing working distance and flow rate of core. Nanofibers drug release mechanism was indicated by Korsmeyer-Peppas which they followed fick′s lows and Higuchi model significantly. Also, results presented that biodegradability and drug release rate accelerate with increasing the working distance and increasing the amount of PVP in core.     

Design of Chitosan and Its Water Soluble Derivatives-Based Drug Carriers with Polyelectrolyte Complexes

Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail.     

Chitosan and Kappa-Carrageenan Vaginal Acyclovir Formulations for Prevention of Genital Herpes. In Vitro and Ex Vivo Evaluation

Vaginal formulations for the prevention of sexually transmitted infections are currently gaining importance in drug development. Polysaccharides, such as chitosan and carrageenan, which have good binding capacity with mucosal tissues, are now included in vaginal delivery systems. Marine polymer-based vaginal mucoadhesive solid formulations have been developed for the controlled release of acyclovir, which may prevent the sexual transmission of the herpes simplex virus. Drug release studies were carried out in two media: simulated vaginal fluid and simulated vaginal fluid/simulated seminal fluid mixture. The bioadhesive capacity and permanence time of the bioadhesion, the prepared compacts, and compacted granules were determined ex vivo using bovine vaginal mucosa as substrate. Swelling processes were quantified to confirm the release data. Biocompatibility was evaluated through in vitro cellular toxicity assays, and the results showed that acyclovir and the rest of the materials had no cytotoxicity at the maximum concentration tested. The mixture of hydroxyl-propyl-methyl-cellulose with chitosan- or kappa-carrageenan-originated mucoadhesive systems that presented a complete and sustained release of acyclovir for a period of 8–9 days in both media. Swelling data revealed the formation of optimal mixed chitosan/hydroxyl-propyl-methyl-cellulose gels which could be appropriated for the prevention of sexual transmission of HSV.     

Synthesis and Characterization of 2-Decenoic Acid Modified Chitosan for Infection Prevention and Tissue Engineering

Chitosan nanofiber membranes are recognized as functional antimicrobial materials, as they can effectively provide a barrier that guides tissue growth and supports healing. Methods to stabilize nanofibers in aqueous solutions include acylation with fatty acids. Modification with fatty acids that also have antimicrobial and biofilm-resistant properties may be particularly beneficial in tissue regeneration applications. This study investigated the ability to customize the fatty acid attachment by acyl chlorides to include antimicrobial 2-decenoic acid. Synthesis of 2-decenoyl chloride was followed by acylation of electrospun chitosan membranes in pyridine. Physicochemical properties were characterized through scanning electron microscopy, FTIR, contact angle, and thermogravimetric analysis. The ability of membranes to resist biofilm formation by S. aureus and P. aeruginosa was evaluated by direct inoculation. Cytocompatibility was evaluated by adding membranes to cultures of NIH3T3 fibroblast cells. Acylation with chlorides stabilized nanofibers in aqueous media without significant swelling of fibers and increased hydrophobicity of the membranes. Acyl-modified membranes reduced both S. aureus and P. aeruginosa bacterial biofilm formation on membrane while also supporting fibroblast growth. Acylated chitosan membranes may be useful as wound dressings, guided regeneration scaffolds, local drug delivery, or filtration.     

Nano-sized albumin-copolymer micelles for efficient doxorubicin delivery

We present the discovery of a nano-sized protein-derived micellar drug delivery system based on the polycationic albumin precursor protein cBSA-147. The anticancer drug doxorubicin (DOX) was efficiently encapsulated into nanosized micelles based on hydrophobic interactions with the polypeptide scaffold. These micelles revealed attractive stabilities in various physiological buffers and a wide pH range as well as very efficient uptake into A549 cells after 1 h incubation time only. In vitro cytotoxicity was five-times increased compared to free DOX also indicating efficient intracellular drug release. In addition, multiple functional groups are available for further chemical modifications. Based on the hydrophobic loading mechanism, various classical anti-cancer drugs, in principle, could be delivered even synergistically in a single micelle. Considering these aspects, this denatured albumin-based drug delivery system represents a highly attractive platform for nanomedicine approaches towards cancer therapy.     

Enzyme-modified casein fibers and their potential application in drug delivery

Enzymatic crosslinking of casein fibers was done using Transglutaminase (TGase) to improve the mechanical properties, particularly the stability in aqueous conditions and make them suitable for controlled drug release application. Crosslinking casein with 5 U/g of TGase in the spinning dope for 60 min at 25 °C increased the tenacity and tensile strain of the fibers from 0.40 g/den and 4.2 % to 0.70 g/den and 23.1 %, respectively. The stability of the fibers in water at different pH levels was considerably improved after the enzymatic crosslinking. The SDS-PAGE electrophoresis confirmed that higher molecular weight proteins were formed in TGase-crosslinked fibers. Thermogravimetric analysis (TGA) showed that TGase treated fibers also had a higher thermal degradation temperature than the non-crosslinked fibers. Crosslinked fibers exhibited delayed and lower rate of drug release from the fibers suggesting their suitability for controlled drug release.     

Influences of organic-modified Fe-montmorillonite on structure, morphology and properties of polyacrylonitrile nanocomposite fibers

The Fe-montmorillonite (Fe-MMT) combined catalysis effects of Fe ion with barrier effects of silicate clays, was firstly synthesized by hydrothermal method, and then was modified by cetyltrimethyl ammonium bromide (CTAB). The organic-modified Fe-montmorillonite (Fe-OMT) was dispersed in the N, N-dimethyl formamide (DMF) and then compounded with polyacrylonitrile (PAN) solution which was dissolved in DMF. The composite solutions were electrospun to form PAN/Fe-OMT nanocomposite fibers. The influences of the Fe-OMT on the structure, morphology, thermal, flammability and mechanical properties of PAN nanocomposite fibers were respectively characterized by X-ray diffraction (XRD), High-resolution transmission electron microscopy (HRTEM), Scanning electron microscopy (SEM), Thermogravimetric analyses (TGA), Micro Combustion Calorimeter (MCC) and Electronic Single Yarn Strength Tester. It was found from XRD curves that there was not observable diffraction peak of silicate clay, indicating that the silicate clay layers were well dispersed within the PAN nanofibers. The HRTEM image indicated that the multilayer stacks of nanoclays could be found within the nanofibers and were aligned almost along the axis of the nanofibers. The SEM images showed that the diameters of nanocomposite fibers were decreased with the loading of the Fe-OMT. The TGA analyses revealed that the onset temperature of thermal degradation and charred residue at 700°C of PAN nanocomposite fibers were notably increased compared with the pure PAN nanofibers, contributing to the improved thermal stability properties. It was also observed from MCC analyses that the decreased peak of heat release rate (PHRR) of the PAN nanocomposite fibers reduced the flammability properties. The loadings of Fe-OMT increased the tensile strength of PAN nanocomposite fibers, but the elongation at break of PAN nanocomposite fibers was lower than that of the PAN nanofibers.     

Controlled release of diclofenac from matrix polymer of chitosan and oxidized konjac glucomannan

The controlled release of diclofenac sodium (DFNa) from a chitosan-oxidized konjac glucomannan (CTS-OKG) polymer film was studied. Konjac glucomannan (KGM) was initially oxidized by sodium periodate and then cross-linked to CTS via imine bonds (-C=N-) to form the new CTS-OKG copolymer. The DFNa loaded CTS-OKG polymers were characterized by Fourier transformed infrared spectroscopy (FT-IR) and X-ray diffractometry (XRD). Finally, the release profiles of DFNa from the CTS-OKG polymer matrices were evaluated in a simulated gastrointestinal fluid system comprised of two hours in simulated gastric fluid (SGF; pH 1.2) followed by 24 h in simulated intestinal fluid (SIF; pH 7.4). A 1:2:1 (w/w/w) ratio of CTS:OKG:DFNa prepared at room temperature for 3 hours gave the highest % encapsulation efficiency (EE) of 95.6 ± 0.6 and resulted in a minimal release of DFNa (<1% over 2 h) in SGF (pH 1.2) and a significantly improved sustained release in SIF (pH 7.4) with ~6% and 19% release over 8 and 24 h, respectively), some 15- and five-fold lower than that of the two commercial DFNa preparations, Diclosian and Voltaren. This formulation may be used for further study as a long term intestine controlled release drug model (at least 3 days).     

Preparation and characterization of electrospun polyvinyl alcoholstyrylpyridinium/<Emphasis Type="Italic">β</Emphasis>-cyclodextrin composite nanofibers: Release behavior and potential use for wound dressing

Biocompatible polyvinyl alcohol (PVA)-styrylpyridinium (SbQ)/β-cyclodextrin (β-CD) composite nanofibers were obtained by electrospinning in this study. PVA-SbQ was used as the foundation polymer as well as crosslinking agent, β-CD was incorporated to achieve expected properties such as improved mechanical properties and thermal stability. The Fourier transform infrared spectroscopy (FTIR) spectra confirmed the existence of β-CD, and the morphologies and average fiber diameters of the electrospun composite nanofibers were also analyzed by SEM. X-ray diffraction patterns (XRD) of PVA-SbQ/β-CD composite nanofibers revealed that the inclusion of β-CD in the nanofibers affected the ordered phase of PVA. Besides, the thermal analyses revealed the improvement in the thermal properties for PVA-SbQ/β-CD composite nanofibers. It was found that the crosslinked composite nanofibers showed a clear higher tensile strength (TS) as well as a greater elongation at break (EB). Eventually, antifungal drug griseofulvin (GSV) has been loaded into the composite nanofibers by formation of its inclusion complex with β-CD in aqueous solution, ultraviolet light (UV-Vis) spectral analysis showed that the drug-loading nanofibers had certain sustained release effect.     

Fabrication of electrospun meta-aramid nanofibers in different solvent systems

Meta-aramid fibers were dissolved in four different solvent systems (DMAc, DMF, NMP, and DMSO) and two kinds of salts (LiCl and CaCl₂) were also introduced in this paper. Meta-aramid fibers had a limited solubility in above four solvents, however, fast dissolution could be obtained after adding a certain amount of salt (LiCl or CaCl₂). The concentration of salts was found to be an important role in affecting meltaging, dissolving time and viscosity of electrospun solution. Electrospun meta-aramid nanofibers mats were successfully prepared. A series of characterizations had been carried out by using SEM. The results shows the diameter of meta-aramid nanofibers ranging from 100 to 500 nm. The average diameter of the nanofibers increased with the concentration of meta-aramid fiber solution and the salt solution. A preferable morphology of meta-aramid nanofibers could be obtained under LiCl/DMAc system. While the electrospun nanofibers made in CaCl₂/DMAc solvent system had a better performance in thermal stability than that prepared in LiCl/DMAc system. Among the four kinds of prepared nanofibers, the nanofibersmat electrospun in LiCl/DMAc system with a concentration of meta-aramid solution at 11 wt% exhibit the best mechanical properties.     

Effects of ferric chloride on structure, surface morphology and combustion property of electrospun polyacrylonitrile composite nanofibers

In this work, the pure polyacrylonitrile (PAN) nanofibers and PAN/FeCl₃ composite nanofibers were prepared by an electrospinning process. Electrospinning solution properties including viscosity, surface tension and conductivity, had been measured and combined with the results of Scanning electron microscopy (SEM), Atomic force microscope (AFM) and Micro Combustion Calorimeter (MCC) to investigate the effects of FeCl₃ on the structure, surface morphology and combustion property of electrospun PAN nanofibers, respectively. It was found from SEM images that the diameters of composite nanofibers were decreased with the addition of FeCl₃, which was attributed predominantly to the increased conductivity of the polymer solutions compared to viscosity and surface tension. The AFM analyses revealed that the surface morphology of electrospun nanofibers changed from smooth and wrinkle-like structure (without FeCl₃) to rough and ridge-like structure (with FeCl₃). The results characterized by MCC showed that the loading of FeCl₃ decreased the heat release rate (HRR) and improved the combustion property of composite nanofibers.     

Preparation of inorganic silica nanofibers containing silver nanoparticles

Silica nanofibers containing silver nanoparticles were successfully prepared using sol-gel chemistry and electro-spinning technique. Solution of tetraethly orthosilicate in ethanol containing silver nitrate was aged to have sufficient viscosity and electrospun to form nanofibers. Upon thermal treatment, the gelation reaction between silanols was completed in the prepared silica nanofibers, and at the same time, silver ions in the nanofiber changed to metallic silver or silver oxides. The reduction of silver ions could be also achieved by UV irradiation, and the generated silver nanoparticles were present preferentially on the surface of the silica nanofibers. On testing release behavior of silver ions, it was found that most of silver remained in the silica nanofiber. The silica nanofibers containing silver nanoparticles exhibited excellent antibacterial and deodorant properties.