Fabrication of quantum dot-immobilized Y2O3 microspheres with effective photoluminescence for cancer radioembolization therapy.

Microspheres composed of Y-containing materials are effective agents for cancer radioembolization therapy using ß-rays. The distribution and dynamics of these microspheres in tissues can be easily determined by providing the microspheres with an imaging function. In addition, the use of quantum dots will enable the detection of microspheres at the individual particle level with high sensitivity. In this study, core - shell quantum dots were bound to chemically modified yttria microspheres under various conditions, and the effect of reaction conditions on the photoluminescence properties of the microspheres was investigated. The quantum dots were immobilized on the surfaces of the microspheres through dehydration - condensation reactions between the carboxy groups of quantum dots and the amino groups of silane-treated microspheres. As the reaction time increased, the photoluminescence peak blue shifted, and the photoluminescence intensity and lifetime decreased. Therefore, a moderate period of the immobilization process was optimal for imparting effective photoluminescence properties. This study is expected to facilitate particle-level tracking of microsphere dynamics in biological tissues for the development of minimally invasive cancer radiotherapy of deep-seated tumors.

We have established a method to immobilize quantum dots on yttria microspheres for cancer radiotherapy and revealed that photoluminescence intensity can be optimized by controlling the immobilization treatment time.

In vitro and in vivo pharmacological profile of OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan.

Tolvaptan is an orally active vasopressin V2 receptor antagonist and used for the treatment of volume overload in some disease as an aquaretic. Tolvaptan sodium phosphate (OPC-61815) is a pro-drug of tolvaptan that was designed to improve water solubility and enable intravenous use. The conversion of OPC-61815 to tolvaptan was evaluated for in vitro and in vivo pharmacokinetic studies. The pharmacodynamics of OPC-61815 were evaluated for in vitro receptor binding affinity, in vivo aquaretic and anti-edematous action. The solubility of OPC-61815 in water at 25 °C was 72.4 mg/mL and more than 100,000 times the solubility of tolvaptan. OPC-61815 was hydrolyzed to tolvaptan by human tissue S9 fractions and main enzyme of hydrolysis was alkaline phosphatase. After intravenous administration of OPC-61815 to rats and dogs, tolvaptan was detected in plasma within 5 min and the bioavailability of tolvaptan was 57.7% and 50.9%, respectively. Binding affinity of OPC-61815 for the human V2 receptor was 1/14 weaker than that of tolvaptan. OPC-61815 exerted dose-dependent aquaretic action in rats and dogs and a corresponding anti-edematous action in rat edema models. These results suggest that OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan, is an effective aquaretic by converting to tolvaptan after intravenous administration.

Compositional dependence of the apatite formation ability of Ti-Zr alloys designed for hard tissue reconstruction.

Ti-Zr alloys are expected to be novel biomaterials with low stress shielding owing to their lower Young's moduli than pure Ti. The drawback of metallic biomaterials is that their bone-bonding abilities are relatively low. NaOH and heat treatments have been performed to provide Ti-50Zr with apatite-forming ability in the body environment, which is essential for bone bonding. However, the systematic compositional dependence of apatite formation has not been revealed. In the present study, NaOH treatment of Ti-Zr alloys with various compositions and bone-bonding abilities was assessed in vitro by apatite formation in simulated body fluid (SBF). The corrosion current density in NaOH aqueous solution and the amount of Na incorporated into the surface tended to decrease with increasing Zr content. The apatite-forming ability of the treated alloy significantly decreased when the Zr content was ≥60 atom%. This phenomenon is attributed to the (1) low OH content on the surface, (2) low Na incorporation into the treated alloy surface, which enhances apatite formation, and (3) low ability of P adsorption to the Ti-Zr alloy in SBF following Ca adsorption to trigger apatite nucleation. Although the adhesion of the titanate/zirconate layer formed on the surfaces to the substrates increased as Zr content increased, the adhesion between the apatite and the substrate was still low.

Enhanced biosafety of silica coated gadolinium based nanoparticles.

One of the most important and novel approaches of biomedical engineering is the development of new, effective and non-invasive medical diagnosis abilities, and treatments that have such requirements as advanced technologies for tumor imaging. Gadolinium (Gd) compounds can be used as MRI contrast agents, however the release of Gd3+ ions presents some adverse side effects such as renal failure, pancreatitis or local necrosis. The main aim of the work was the development and optimization of Gadolinium based nanoparticles coated with silica to be used as bioimaging agent. Gd based nanoparticles were prepared through a precipitation method and afterwards, these nanoparticles were covered with silica, using Stöber method with ammonia and functionalized with 3-Aminopropyltriethoxysilane (APTES). Results showed that nanoparticles were homogeneous regarding chemical composition, silica layer thickness, total size and morphology. Also, silica coating was successfully not degraded after 4 weeks at pH 5.5, 6.0 and 7.4, contrary to GdOHCO3 nanoparticles that degraded. Regarding the in vitro cell tests, very good cell proliferation and viability were observed. In conclusion, the results showed that Gd based nanoparticles coated with silica for imaging applications were successfully obtained under a well-controlled method. Furthermore, silica coating may enhance magnetic nanoparticles biosafety because it avoids GdOHCO3 degradation into harmful products (such as Gd3+ ions) at physiological conditions.

Apatite-forming ability of vinylphosphonic acid-based copolymer in simulated body fluid: effects of phosphate group content.

Phosphate groups on materials surfaces are known to contribute to apatite formation upon exposure of the materials in simulated body fluid and improved affinity of the materials for osteoblast-like cells. Typically, polymers containing phosphate groups are organic matrices consisting of apatite-polymer composites prepared by biomimetic process using simulated body fluid. Ca(2+) incorporation into the polymer accelerates apatite formation in simulated body fluid owing because of increase in the supersaturation degree, with respect to apatite in simulated body fluid, owing to Ca(2+) release from the polymer. However, the effects of phosphate content on the Ca(2+) release and apatite-forming abilities of copolymers in simulated body fluid are rather elusive. In this study, a phosphate-containing copolymer prepared from vinylphosphonic acid, 2-hydroxyethyl methacrylate, and triethylene glycol dimethacrylate was examined. The release of Ca(2+) in Tris-NaCl buffer and simulated body fluid increased as the additive amount of vinylphosphonic acid increased. However, apatite formation was suppressed as the phosphate groups content increased despite the enhanced release of Ca(2+) from the polymer. This phenomenon was reflected by changes in the surface zeta potential. Thus, it was concluded that the apatite-forming ability of vinylphosphonic acid-2-hydroxyethyl methacrylate-triethylene glycol dimethacrylate copolymer treated with CaCl2 solution was governed by surface state rather than Ca(2+) release in simulated body fluid.

Adsorption characteristics of bovine serum albumin onto alumina with a specific crystalline structure.

Bone cement containing alumina particles with a specific crystalline structure exhibits the ability to bond with bone. These particles (AL-P) are mainly composed of delta-type alumina (δ-Al2O3). It is likely that some of the proteins present in the body environment are adsorbed onto the cement and influence the expression of its bioactivity. However, the effect that this adsorption of proteins has on the bone-bonding mechanism of bone cement has not yet been elucidated. In this study, we investigated the characteristics of the adsorption of bovine serum albumin (BSA) onto AL-P and compared them with those of its adsorption onto hydroxyapatite (HA), which also exhibits bone-bonding ability, as well as with those of adsorption onto alpha-type alumina (α-Al2O3), which does not bond with bone. The adsorption characteristics of BSA onto AL-P were very different from those onto α-Al2O3 but quite similar to those onto HA. It is speculated that BSA is adsorbed onto AL-P and HA by interionic interactions, while it is adsorbed onto α-Al2O3 by electrostatic attraction. The results suggest that the specific adsorption of albumin onto implant materials might play a role in the expression of the bone-bonding abilities of the materials.

In Situ Synthesis and Characterizations of a Strontium-Substituted Dicalcium Phosphate Anhydrous/Hydroxyapatite Biphasic Whisker and Its Properties Evaluation.

Dicalcium phosphate anhydrous (DCPA) presents good biomineralization ability, the strontium element is known for superior bone affinity, and a whisker possesses good mechanical strength; all these are beneficial for improving the drawbacks of hydroxyapatite (HAP) like weaker mechanical properties, poor biomineralization, and slower degradation/absorption. Therefore, a homogeneous precipitation was adopted to synthesize Sr-substituted and DCPA and HAP coexisting whiskers. The composition, structure, and morphology based on urea dosage and substitution content were characterized, and the roles of DCPA, Sr, and whisker shape were investigated. It turned out that Sr-DCPA/HAP biphasic products contained about 19% DCPA and 81% HAP, and both phases occupied the outer and inner parts of the whisker, respectively. Increasing the urea dosage made the morphology transform from a sea urchin shape to fiber clusters and then whiskers, while Sr substitution brought the whisker back to the porous microsphere shape. Only 5% of Sr content and 15 g of urea could maintain the whisker shape. Sr could promote the proliferation of MC3T3-E1 cells even at a higher extract concentration of 10 mg/mL. The cells stayed in a healthy state whether cocultured with the whisker or the microsphere. The unstable DCPA combined with the decreased crystallinity brought by Sr doping contributed to shortening the apatite deposition period to within 7 days. The whisker morphology enhanced the compressive strength of acrylic resin, and the apatite layer helped to reduce the strength loss during soaking. The Sr-DCPA/HAP biphasic whisker with enhanced overall properties possessed more promising potential for biomedical application.

Preparation and characterizations of antibacterial poly(methyl methacrylate) bone cement via copolymerization with a quaternary ammonium monomer of dimethylaminotriclosan methacrylate.

Poly (methyl methacrylate) (PMMA) bone cement relies on the loaded antibiotic to realize the antibacterial purpose. But the exothermic behavior during setting often makes temperature-sensitive antibiotics inactivated. It is necessary to develop new material candidates to replace antibiotics. In this study, a new quaternary ammonium methacrylate (QAM) monomer called dimethylaminetriclosan methacrylate (DMATCM) was designed by the quaternization between 2-(Dimethylamino)ethyl methacrylate and triclosan, then employed as the modifier to explore the feasibility of equipping bone cement with antibacterial activity, and to investigate the variations on the physical and biological performances brought by the substitution ratio of DMATCM to MMA. Results showed that DMATCM opened its C=C bonding to participate in the MMA polymerization, and the quaternary ammonium group helped it to perform broad-spectrum antibacterial property against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. With an increased substitution ratio of DMATCM to MMA, the glass transition temperatures, the maximum exothermic temperatures, and the contact angles of bone cements declined, but the residual monomer contents, the fluid uptakes, and the setting times under Vical indentation increased. Long-term soaking made almost no changes to the weight loss and the mechanical properties of DMATCM-modified cements with lower substitution ratios of 0∼20%, and the activation rather enhanced the strengths of uncured AMBC-4 and AMBC-5 samples. Owing to more DMATCM exposed on the cement surface, the inhibition ring diameter produced by modified cement was improved to a maximum of 28.09 mm, and MC3T3-E1 cells performed the cell viabilities all beyond 70% and healthy adhesion after 72 h co-culturing. Taking all measured properties and ISO standards into account, the antibacterial bone cement under the ratio of 10% performed better, besides its good bactericidal effect, the other properties satisfied the requirements for clinical application.

Tolvaptan, an orally active non-peptide arginine vasopressin V2 receptor antagonist, reduces ascites in rats with chronic liver injury.

AIM: This is a non-clinical, proof of concept study, showing that tolvaptan has efficacy in reducing ascites in chronic liver injury, using a rat model induced by repeated dimethylnitrosamine (DMNA) injection. METHODS: A rat model of chronic liver injury was induced by 10 mg/kg of repeated i.p. injection with DMNA for 6-9 weeks. Tolvaptan was administrated to rats that showed obvious and stable ascites, and abdominal circumference was evaluated as a surrogate marker of ascites volume. Rats were placed in metabolic cages with free access to food and water to collect urine over a 24-h period. RESULTS: Oral tolvaptan (1 and 3 mg/kg) promoted a remarkable diuretic effect, decreasing bodyweight and abdominal circumference in a dose-dependent manner. Plasma sodium concentration was increased by tolvaptan due to the large amount of free-water excretion following tolvaptan administration. CONCLUSION: Tolvaptan had therapeutic efficacy in the reduction of ascites in rats with chronic liver injury. These results are consistent with the clinical data showing tolvaptan has therapeutic implications in the reduction of ascites in patients with decompensated cirrhosis.

Organic-inorganic composites designed for biomedical applications.

Several varieties of ceramics, such as Bioglass-type glasses, sintered hydroxyapatite and glass-ceramic A-W, exhibit specific biological affinity, i.e., direct bonding to surrounding bone, when implanted in bony defects. These bone-bonding ceramics are called bioactive ceramics and are utilized as important bone substitutes in the medical field. However, there is a limitation to their clinical applications because of their inappropriate mechanical properties. Natural bone takes a kind of organic-inorganic composite, where apatite nanocrystals are precipitated on collagen fibers. Therefore, problems with the bioactive ceramics can be solved by material design based on the composites. In this paper, current research topics on the development of bioactive organic-inorganic composites inspired by actual bone microstructure have been reviewed in correlation with preparation methods and various properties. Several kinds of inorganic components have been found to exhibit bioactivity in the body environment. Combination of the inorganic components with various organic polymers enables the development of bioactive organic-inorganic composites. In addition, novel biomedical applications of the composites to drug delivery systems, scaffolds for tissue regeneration and injectable biomaterials are available by combining drugs or biological molecules with appropriate control of its microstructure.

Carboxymethyldextran/magnetite hybrid microspheres designed for hyperthermia.

Recently, organic-inorganic hybrids composed of derivatives of dextran, a polysaccharide, and magnetite nanoparticles have attracted much attention as novel thermoseeds. If they can be fabricated into microspheres of size 20-30 µm, they are expected to show not only hyperthermia effects but also embolization effects in human liver and kidney cancers. In this study, we examined the fabrication of carboxymethyldextran/magnetite microspheres using a water/oil emulsion as the reaction medium. Improvement of the chemical stability of the microcapsules by coating with silica using a sol-gel process was also investigated. The obtained hollow microspheres contained particles of size 20-30 µm. Silica coating using an appropriate catalyst for hydrolysis and polycondensation of alkoxysilanes was found to be effective for preventing dissolution and collapse in simulated body environments.

Enhancement of apatite formation on Ti-50Zr alloy in simulated body environment.

Ti-50Zr alloy is 2.5 times as strong as pure Ti and has a lower Young's modulus, making it a useful material for repairing bone and teeth. However, Ti-50Zr alloy has a limited ability to bond with bone in vivo. Under biological conditions, apatite formation at the surface of a Ti or alloy implant is necessary for its bonding with bone. Various approaches to surface modification have been proposed to impart bone-bonding ability to Ti-50Zr alloy; however, there remains a need for further improvements to the alloy's apatite-forming ability. Hence, in this study, we compared apatite formation at the surface of alloy substrates in simulated body fluid, after various surface treatments. Treatment with 5 M NaOH followed by 1 M CaCl2 was the most effective procedure, whereas a sample subjected to a hot water post-treatment formed less apatite. Notably, no apatite formed on samples treated with 10 M NaOH.

Anti-edematous effects of tolvaptan in experimental rodent models.

PURPOSE: The aim of this study was to evaluate the therapeutic efficacy of tolvaptan, a vasopressin V(2) receptor antagonist, on edema in two rat models: 1) histamine-induced vascular hyperpermeability of the dorsal skin and 2) carrageenan-induced paw edema. METHODS: In the skin vascular hyperpermeability model, 3 h after oral administration of tolvaptan or the natriuretic agent furosemide, rats were intravenously injected with Evans Blue (EB), followed by intradermal injection of 10 µg of histamine into the dorsal skin. One hour later, blood was collected to measure serum parameters. EB leakage area into the dorsal skin was also measured. Urine was collected for 4 h to determine urine parameters. In the paw edema model, edema was induced by injecting 1% w/v carrageenan into the right hind paw. Paw volume was measured hourly for 5 h. Tolvaptan or furosemide was orally administered 1 h before carrageenan injection. RESULTS: A single oral dose of tolvaptan (1-10 mg/kg) elicited marked and dose-dependent aquaresis, and improvements in edema. Similar effects were observed with furosemide (30 mg/kg). Tolvaptan tended to elevate the serum sodium level while furosemide caused a significant decrease. CONCLUSION: Tolvaptan had anti-edematous effects in two different rat models. By increasing free water excretion, tolvaptan may be more advantageous for certain patients than loop diuretics because it does not cause electrolyte loss, and may prevent electrolyte abnormities, such as hyponatremia. These results suggest that tolvaptan has potential clinical benefits for the treatment of edema.

Fabrication and properties of alginate/calcium phosphate hybrid beads: A comparative study.

BACKGROUND: Microbeads for bone repair have been widely studied because they can be conveniently used in clinical applications. OBJECTIVE: This study concerns the preparation, physical properties and in vitro characterisation of different types of alginate/calcium phosphate (CaP) ceramic microbeads, which were designed for use as drug delivery systems and bone-regeneration matrices. METHODS: Hybrid microbeads were successfully prepared from sodium alginate and various CaP, namely 𝛼-tricalcium phosphate, 𝛽-tricalcium phosphate and hydroxyapatite using the liquid droplet method. RESULTS: Porosity, swelling properties and in vitro degradation of the microbeads in the aqueous environment were significantly changed by the added CaP. The compressive strength of the blocks fabricated from the beads was around 120 MPa irrespective of the type of CaP. The initial release rate of the model drug methylene blue was suppressed by the addition of CaP. CONCLUSION: The alginate-CaP composite beads hold promising potential as an encapsulation carrier of drugs and component of bone substitutes.

Preparation of bioactive and antibacterial PMMA-based bone cement by modification with quaternary ammonium and alkoxysilane.

Bone cement based on poly(methyl methacrylate) (PMMA) powder and methyl methacrylate (MMA) liquid is a very popular biomaterial used for the fixation of artificial joints. However, there is a risk of this cement loosening from bone because of a lack of bone-bonding bioactivity. Apatite formation in the body environment is a prerequisite for cement bioactivity. Additionally, suppression of infection during implantation is required for bone cements to be successfully introduced into the human body. In this study, we modified PMMA cement with γ-methacryloxypropyltrimetoxysilane and calcium acetate to introduce bioactive properties and 2-(tert-butylamino)ethyl methacrylate (TBAEMA) to provide antibacterial properties. The long-term antibacterial activity is attributed to the copolymerization of TBAEMA and MMA. As the TBAEMA content increased, the setting time increased and the compressive strength decreased. After soaking in simulated body fluid, an apatite layer was detected within 7 days, irrespective of the TBAEMA content. The cement showed better antibacterial activity against Gram-negative E. Coli than Gram-positive bacteria; however, of the Gram-positive bacteria investigated, B. subtilis was more susceptible than S. aureus.

Preparation of porous yttrium oxide microparticles by gelation of ammonium alginate in aqueous solution containing yttrium ions.

Porous Y2O3 microparticles 500 microm in size were obtained, when 1 wt%-ammonium alginate aqueous solution was dropped into 0.5 M-YCl3 aqueous solution by a Pasteur pipette and the resultant gel microparticles were heat-treated at 1100 degrees C. Small pores less than 1 microm were formed in the microparticles by the heat treatment. The bulk density of the heat-treated microparticle was as low as 0.66 g cm(-3). The chemical durability of the heat-treated microparticles in simulated body fluid at pH = 6 and 7 was high enough for clinical application of in situ radiotherapy. Although the size of the microparticles should be decreased to around 25 microm using atomizing device such as spray gun for clinical application, we found that the porous Y2O3 microparticles with high chemical durability and low density can be obtained by utilizing gelation of ammonium alginate in YCl3 aqueous solution in this study.

Structural control of magnetite nanoparticles for hyperthermia by modification with organic polymers: effect of molecular weight.

Hyperthermia treatment using appropriate magnetic materials in an alternating magnetic field to generate heat has been recently proposed as a low-invasive cancer treatment method. Magnetite (Fe3O4) nanoparticles are expected to be an appropriate type of magnetic thermal seed for this purpose, and the addition of organic substances during the synthesis process has been studied for controlling particle size and improving biological functions. However, the role of the properties of the organic polymer chosen as the modifier in the physical properties of the thermal seed has not yet been comprehensively revealed. Therefore, this study clarifies these points in terms of the molecular weight and the charge of the functional groups of the added polymers. Excepting polyethyleneimine, the Fe3O4 crystallite size decreased with increasing polymer molecular weight. Neutral polymers did not suppress the Fe3O4 formation regardless of the difference in molecular weight, while suppression of the Fe3O4 formation was observed for low molecular weight anionic polymers and high molecular weight cationic polymers. Samples with a small amount of Fe3O4 or with crystallite size less than 10 nm induced low heat generation under an alternating magnetic field.

Effect of Calcium Acetate Content on Apatite-Forming Ability and Mechanical Property of PMMA Bone Cement Modified with Quaternary Ammonium.

Polymethyl methacrylate (PMMA)-based bone cement is a popular biomaterial used for fixation of artificial joints. A next-generation bone cement having bone-bonding ability, i.e., bioactivity and antibacterial property is desired. We previously revealed that PMMA cement added with 2-(tert-butylamino)ethyl methacrylate, γ-methacryloxypropyltrimethoxysilane and calcium acetate showed in vitro bioactivity and antibacterial activity. This cement contains calcium acetate at 20% of the powder component. Lower content of the calcium acetate is preferable, because the release of a lot of calcium salt may degrade mechanical properties in the body environment. In the present study, we investigate the effects of calcium acetate content on the setting property and mechanical strength of the cement and apatite formation in simulated body fluid (SBF). The setting time increased and the compressive strength decreased with an increase in calcium acetate content. Although the compressive strength decreased after immersion in SBF for 7 d, all the cements still satisfied the requirements of ISO5833. Apatite was formed in SBF within 7 d on the samples where the calcium acetate content was 5% or more. Therefore, it was found that PMMA cement having antibacterial properties and bioactivity can be obtained even if the amount of the calcium acetate is reduced to 5%.

Setting behavior, apatite-forming ability, mechanical strength of polymethylmethacrylate bone cement through bioactivity modification of phosphate functional groups combined with Ca2+ ions.

Bioactivity modification helps polymethylmethacrylate (PMMA) bone cement to reinforce its interfacial adhesion to bone tissues through the chemical bonding of apatite. Since Si-OH groups combined with Ca2+ ions have succeeded in inducing apatite formation, more combinations of functional groups and active ions are being explored. In this study, Bis[2-(methacryloyloxy)ethyl] phosphate (B2meP) containing phosphate (=PO4H) groups and Ca(CH3COO)2 supplying Ca2+ ion were adopted to investigate the feasibility of equipping PMMA bone cement with apatite-forming ability in vitro, more effects under designed contents on setting behavior, injectability, contact angle, cytotoxicity and mechanical strength were also investigated. Results showed B2meP copolymerized with MMA and became one section of PMMA chains, surface = PO4H groups and released Ca2+ ions pushed spherical apatite individuals nucleating and agglomerating into layer horizontally, Increasing B2meP content lowered the contact angle and the peak temperature, enhanced the cell viability of MC3T3-E1, but prolonged apatite forming period. Injectability rate performed a similar trend to setting time. Lower adding content and deposited apatite layer contributed to reduce the strength loss in soaking. Taking biological performance and other properties into balance, cement added with B2meP of 10 wt% in MMA and Ca(CH3COO)2 of 20 wt% in PMMA performed better.

Synthesis of bioactive HEMA-MPS-CaCl2 hybrid gels: effects of catalysts in the sol-gel processing on mechanical properties and in vitro hydroxyapatite formation in a simulated body fluid.

We investigated synthetic conditions for the fabrication of bioactive hybrid gels from monomers of 2-hydroxyethylmethacrylate (HEMA) and 3-methacryloxypropyltrimethoxysilane (MPS) in combination with CaCl(2), at a starting molar ratio of HEMA: MPS : CaCl(2) of 9 : 1 : 1. Hydroxyapatite formation, essential to show bone bonding, was observed on the HEMA- MPS-CaCl( 2) hybrid gels with the added catalysts NH(3) or HCl with a molar ratio to MPS of 0.1, but not on the hybrid gel with HCl at a molar ratio to MPS of 1. The mechanical properties of the gels were dependent on the catalysts, which may affect the microstructures that develop during sol-gel processing.