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Definitions

• the invention concerns to the synthesis of biocompatible hybride nanoparticles for medical applications, above all of magnetic fluid hyperthemia and magnetic resonance imaging.
• nanoparticles possess indeed a sufficiently high T2-relaxivity considerably increasing the contrast in MR image but in practice can be used only for MR imaging, perhaps even detection of marked cells. These nanoparticles appears to be usually superparamagnetic and thus does not allow MR navigated and controllable magnetic hyperthermia.
• Solution based on an employing of hybride nanoparticles of complex multicomponents metallic oxides, with an advantage grains of the perovskite phase La 1-x Sr x MnO 3 , provided with a coherent layer of hydrated silica oxide eliminates mentioned difficulties.
• the used synthesis procedure of the grains of magnetic oxides is based on a sol-gel citrate method where the prepared precursor is subsequently thermal treated usually at temperatures in the range of 650 0 C - 900 0 C. Under these conditions a tendency to sintering manifested by formation of connecting bridges between the arising grains of magnetic oxides grains leads to their agglomeration. Agglomeration of grains makes surface modification, overlaying by a continuous layer of hydrated silica oxide and thus their use in medicine considerably difficult.
• Grains of a high quality of coating have insulated cores whereby their exposition against organism is restricted. Therefore a mechanical treatment based on a combination of rolling and milling allowing a disruption of the synthesized agglomerates on the individual grains should be used. Links among the formed grains are broken by rolling in the first step, final separation of the individual grains and their dispersion in a liquid is achieved in the second step. A possibility to vary composition and size of the grains and adjust thus exactly magnetic properties critical for a given medical application is an expressive benefit of the described and proved procedure.
• Magnetic cores covered by a coherent layer of the hydrated silica oxide generates in a water medium of pH > 4 suspensions of a high stability.
• the formed silica shell restricts exposure of the organism against the magnetic core and an harmlessness of the nanoparticles is achieved.
• Surface of the synthesized grains is activated in an acidic medium and suspension is consequently stabilized by amonium citrate.
• Overlaying by the hydrated silica oxide is carried out in a medium of water, ethanol and ammonia under an increased temperature, employing substituted alkoxysilanes, like tetraethoxysilane.
• Hybrid nanoparticles carrying aminoalkyl chains and thus providing suitable groups for further derivatization can be obtained by the addition of an aminoalkylalkoxysilane to the encapsulation procedure. Therefore it is possible to attach on the surface of hybride nanoparticles additional molecules or entities and prepare complex nanoparticles with functional elements intended for a specific use like targeting to selected tissues or a combined therapy mediated by bonded molecules.
• Hydrophile coating of hydrated silica oxide provides a satisfactory biocompability thereby availibility for medical applications. Its thickness at least in the range of 5 run — 50 nm can be controlled by a selection of the reaction conditions, like temperature, time, composition of the reaction mixture.
• Heating efficiency up to 300 W/g Mn can be achieved by a suitable adjustment of the chemical composition of the magnetic cores (0.2 ⁇ x ⁇ 0,5) and their size (20 nm - 60 nm). Simultaneously the transition from the ferromagnetic to paramagnetic state can be set up in the temperature range of 40 0 C - 60 0 C, i.e. just above the temperature of healing. Self- controlled mechanisms of the magnetic heating restricting an overheating of the health tissue thus is applied.
• T2-relaxivity in the field of 0.5 T i.e. ability to shorten relaxation time of water and thus increase the contrast of the magnetic resonance imaging
• achieves for these hybride nanoparticles of the size 20 nm - 60 nm values of- 600 s ' VmM Mn i.e. markedly higher than the value of ⁇ 170 s ' VmMFe of the dextran coated superparamagnetic iron oxides particles.
• Viability of cells in a medium under a presence of the hybrid nanoparticles (0.11 HIM MI D achieves approximately 95 %.
• the particles thus can be used also for the cells marking and due to their higher relaxivity better results can be achieved for substantially lower concentrations than for standardly used contrast agent Endorem based on iron oxides .
• the relaxation ratio of the cell suspension 2.1 s "1 (related to 10 6 cells/ml) at concentration of 1.1 mMF e in media (Endorem contrast agent) is achieved marking of the cells by hybride La 1-x Sr x MnO 3 nanoparticles gives the value of the relaxation ratio 2.9 s "1 (related to 10 6 cells/ml) at concentration ten times lower, of 0.11 mMi*,.
• Nanoparticles of the ferromagnetic phase of the composition Lao, 75 Sro. ;25 Mn0 3 were synthesized by a two stage procedure, preparation of the precursor by a sol - gel citrate method and subsequent thermal treatment.
• the starting compounds La 2 O 3, SrCO 3 and MnCO 3 of the contents of the cationic components determined by the chemical analysis were separately dissolved in 1:1 diluted nitric acid and mixed with citric acid in the ratio of (0,75 [La 3+ ]+0,25[Sr 2+ ]+[Mn 2+ ])/l, 5 [citric acid] /2,25[ethylenglycol] and pH was adjusted to 9 by an addition Of NH 4 OH.
• Precursor of an amorphous character confirmed by the X-ray diffraction powder analysis was prepared by the evaporation of water at 80 0 C - 90 0 C and drying at 160 0 C.
• the precursor was calcinated for 6 hours at 400 0 C in air and then heated in air for 3 hours at temperature of 700 0 C.
• Single phase product of the mean size of the grains 30 nm was obtained.
• the synthesized material was subjected to a combined mechanical treatment by rolling and milling. Vertical arrangement of the rollers of the diameter 54 mm from the hardened steel was applied for the rolling. Rotation speed of the rollers was 9 rev/min, process was three times repeated and the distance betwen the rollers was gradually decreased on less than 0.03 mm.
• Vibrational mill with milling can of the volume 25 ml and one grinding ball of the diameter 20 mm, both from the stainless steel were employed for the subsequent milling. Milling parameters: weight of the sample 0.5 g, volume of the liquid (ethanol) 10 ml, milling time 60 min, vibration frequency 30 vib/sec.
• Stability of the agglomerates is disrupted by rolling when the bridges connecting the grains, arising as a consequence of a tendency to sintering during the thermal treatment, are broken.
• the grains are then dispersed by vibrating milling in the liquid media.
• nanoparticles (130 mg) were treated by 1 M ice-cold nitric acid (20 ml) in an ultrasound bath. After the removal of the nitric acid by centrifugation the nanoparticles were redispersed in the ice-cold 0.1 M citric acid (20 ml) using ultrasound homogenization for 15 min. Then the particles were separated by centrifugation from the solution of citric acid and a redundant amount of the citric acid was eliminated in one cycle by washing (20 ml of water) and centrifugation.
• the particles were redispersed in water alkalized by a small amount of ammonia (5 drops) in order to transfer the residual citric acid, fixed on the surface of the nanoparticles, to ammonium citrate, stabilizing nanoparticles in the water suspension.
• the suspension was exposed to ultrasound irradiation and dispersed for 30 min. Then the suspension was added drop wise under ultrasound and mechanical stirring into a flask located in an ultrasound thermostatic bath warmed on 40 °C, containing a mixture of ethanol (96 % azeotropic mixture), water (70 ml) and ammonia (25% water solution) in the ratio 15 : 4 :1 (400 ml).
• Amount of tetraethoxysilan corresponding to the required thickness of the envelope layer (2670 ⁇ l for 25 ran) was added and the mixture was left in the thermostatic ultrasound bath for 24 hours under mechanical stirring.
• the required fraction was isolated from the reaction mixture.
• This procedure included collection of the supernatant by centrifugation in angular rotor at 3000 rev./min for 15 min, separation of the nanoparticles from the supernatant by the centrifugation at 8000 rev./min for 40 min.
• the separated nanoparticles were than purified by two washing cycles in ethaiiol and four cycles in water (always 60 ml of the wash liquid). After the last cycle the sediment of nanoparticles was filled up to 20 ml and redispersed by ultrasonification.
• the suspension was warmed in a vacuum dryer at temperature of 35 °C and pressure of ⁇ 1 Pa for 1 hour.
• Measurement of the hydrodynamic size of the coated particles evidenced a narrow distribution function described by the values 134 ⁇ 18 nm at the 80% probability level.
• Transmission electron microscopy confirmed presence of the envelope layer of the approximate thickness of 25 nm. Its chemical character was confirmed by the infrared spectroscopy.
• Measurement of the zeta potential in the range of pH 1 - 13 affirmed stability of the suspensions of the coated nanoparticles in the water media in the range of pH needed for medical applications.
• Nanoparticles of the ferromagnetic perovskite phase of the composition Lao ;75 Sro .;25 Mn0 3 and mean size of the grains 30 nm were prepared according to the procedure described in the example 1. Charge of the nanoparticles (200 mg) was treated by 1 M ice- cold nitric acid (20 ml) in an ultrasound bath for 15 min. Removing of the residual nitric acid was carried out in three washing cycles (always 25 ml of water). Then the nanoparticles were dispersed by ultrasound probe in water (50 ml) for 1 hour.
• composition of the mixture entering into the reaction was selected as follows: 400 ml suspension with the concentration of the perovskite phase 0.5 mg/ml, containing total amount 3.67 g of PVP, corresponding to the ratio of 15 molecules of the PVP polymer per 1 nm 2 of the surface of the nanoparticles with the diameter of 30 nm.
• the suspension was homogenized in the thermostatic ultrasound bath at 25 °C for 24 hours. During ultrasonification the adsorption equilibrium of PVP on the surface of nanoparticles was established. Stabilized nanoparticles were separated by centrifugation and the redundant PVP was eliminated by one washing cycle in ethanol (20 ml). The solid residue was transferred into a flask (500 ml) and filled up by ethanol (400 ml). The suspension was dispersed in a thermostatic bath at 25 0 C for 5 min under simultaneous acting of ultrasound and mechanical stirring. Subsequent mixing of the mixture was carried out only by mechanical stirring.
• tetraethoxysilan in the amount which according to the mentioned spheric approximation, corresponds to the formation of an envelope layer of the thickness of 4 nm (236 ⁇ l), presently aminopropyltriethoxysilan in an amount four times lower (59 ⁇ l) and finally after a short mixing 64 ml of ammonia (25 % water solution) which catalyses basic hydrolysis of alkoxysilanes were added into the flask. The mixture was left in the thermostatic ultrasound bath for 24 hours.
• Hybride nanoparticles of the multicomponent complex metallic oxides are utilizable in medicine, e.g. as contrast agents for diagnostic magnetic resonance imaging and for therapy by magnetic fluid hyperthermia and for combine therapy mediated by molecules fixed on amino groups on the surface of complex silica layers.

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