Magnetosensitive polyfunctional nanocomposites on the basis of magnetite and hydroxyapatite for their use in oncology
The results of the research directed at the development of the concept of creating the magneto-sensitive nanocomposites (NC) with multilayered hierarchic nano-architecture of a core-shell type as well as with functions of biomedical nano-robots on the basis of a single-domain magnetite (Fe3O4), whose surface is modified by hydroxyapatite (HA) have been systemized and generalized. The nanostructures of this type are characterized by bio-adaptability with a person’s organism, deficiency of mutagenicity as well as by satisfactory magnetic characteristics from the point of view of the realization of the method of address delivery of medicines and local therapy.
Fe3O4 has been synthesized according to the method of neutralizing the salts of 2- and 3-valent Ferrum. The synthesized assemblages of nanoparticles (NP) of Fe3O4 were characterized by the limits of 3-23 nm. The average size of NP of Fe3O4 depended on synthesis conditions and equaled 8-15nm, the distribution according to their size could be done using technological methods. The specific surface of the magnetite was S = 90–180 м2/g, the samples for which S= ~ 110 м2 /g were used in process. By means of IR –spectra studies of the Fe3O4 surface, were discovered some functional groups of OH, the concentration of which was calculated on the data of thermo-gravimetric analysis and equaled 2.4 mM/g.
The synthesis of HA membrane on Fe3O4 surface was performed using sol-gel method. The average crystals size of Fe3O4 and HA in the structure of NC Fe3O4/HA respectively equaled 15 and 19-21nm. By means of IR- spectra studies of Fe3O4/HA samples, groups of OH were discovered on the NC surface, their concentration was 2.2mM/g. The specific surface of NC Fe3O4 equaled Sп = 105 м2/g. Ca/P ratio was 1.6-1.7. The HA thickness on the Fe3O4 surface was estimated on Fe2p-/Fe3p-lines area to NC mass gain ratio and equaled ~4 nm.
The processes of adsorption immobilization of chemotherapeutic preparations (cisplatin (CP), doxorubicin (DR)) as well as of normal immune globulin of a man (as a model of antibody-immune-therapeutic preparation) on NC surface have been studied.
Some significant adsorption activity related to CP complexes of nano-sized Fe3O4 has been discovered. Thus, under 298K for Fe3O4 the adsorption capacity Аmax = 80,1 mg/g, the removal coefficient R = 66,2 %.
Fe3O4 modification by HA reduces the adsorption activity of NC surface related to CP: Аmax = 54 mg/g, R = 64,8%. Perhaps, it occurs due to the decrease in the concentration of hydroxyl groups on NC surface of Fe3O4/HA as compared to the surface of initial Fe3O4. The period for establishing the absorption balance for NC surface of Fe3O4 /HA is within 10 min.
The immune- globulin adsorption(Ig) was taking place in the medium of sodium chloride solution (SCS) for two hours in a dynamic regime under indoor temperature. The amount of adsorbed substance on the NC surface was determined by measuring the concentration of Ig in contact solutions before and after adsorption.
The emitting of Ig in SCS was studied on Fe3O4/HА and on Fe3O4/HА/Ag samples which contain Ig immobilized from different buffer systems (phosphate buffer, physiological solution).
The distribution coefficient (E) of immune globulin between the NC surface and the solution is 111,36 ml/g for Fe3O4/HА, and 186.67 ml/g for Fe3O4/HА/Ag. Under the adsorption from SCS for Fe3O4/HА Ε = 47, 2 ml/g, for Fe3O4/HА/Ag Е = 59,4 ml/g.
The adsorption of Ig on the surface of NC from silver NP exceeds the adsorption on the surface of Fe3O4/HA in both buffer systems. It testifies to the fact that silver nano particles on the surface of a composite serve as additional adsorption centers.
It has been determined that Ig emitting immobilized from SCS under high concentrations (A=17.38mg/g) practically does not occur.
The results of the experimental studies as to the NC effects on the cells lines MCF-7 of breast carcinoma of a man in vitro testify to the fact that the use of multifunctional magneto-sensitive NC allows to recognize specific cells, to achieve cytotoxic effect of the preparation under lower concentrations of medicines as well as to create conditions for reducing toxic and allergic effects of medical chemotherapeutic products on the organism as a whole.
By the studies of DR adsorption on the surface of NC Fe3O4/HA it has been determined that during the first two hours 60 - 70% of the substance is adsorbed, and during the period of 24 hours 93 - 97% is adsorbed. The results of the studies as to the dependence of desorption on time indicate that DR emitting decreases when its amount increases on the NC surface.
The research has submitted the data as to synthesis of new multifunctional magneto-sensitive nanostructures which are prospective for a directed delivery of medicine with chemotherapeutic mechanism of action gemcitabine (GC) into the tumors of hepatocellular carcinoma and intrahepatic cholangiocarcinoma as well as for hypothermic therapy and magnetic resonance optical tomography diagnostics by means of magnetic field with additional functions and in a regime of real time.
It has been shown that modified by HA surface of magneto-sensitive carriers of Fe3O4 is capable of adsorption mobilization of oncological medicines with different mechanisms of action as well as of their emitting into the medium of body fluid without therapeutic activity changes.
On the example of a magnetic fluid Fe3O4/HA/DR/ ol.Na/PEG+SCS, which contains a dispersion phase - sodium chloride solution (SCS), superparamagnetic carriers of Fe3O4 with a modified by HA surface and with a immobilized medicine DR, a complex stabilizer on the basis of sodium oleate and polyethylene glycol (ol.Na/PEG), the method of magnetic granulometry has been schemed out. This method can be applied to NC of super magnetic nuclear-membrane type with a complex multilayered structure.
The results of the experimental studies and of calculations, as well as their checking and comparing with literature data, testify to the fact that by using both the assemblages of magneto carriers acting as a super magnetic probe and Lanzheven’s theory of paramagnetism, we can estimate the components size of a complex shell-type nanocomposites structure. The obtained results can be useful when improving the chemical composition, structure and the qualities of new magnetic fluids and adsorbing agents on the basis of magneto-sensitive NC with a complex membrane structure.
New scientific approaches as to the introduction of magneto-sensitive polyfunctional NC of Fe3O4/HA, modified by the ions of gadolinium into neutron capture therapy have been practiced. The prospective for the creation of new types of low- toxic selective neutron- capture medicines with additional functions of magneto-sensitive direct delivery to organs or target cells and for deposition, hyperthermia and complex T1-, T2-MRT diagnostic testing in a real time regime, has been shown.
The basis for synthesis of new vector systems - magneto-sensitive drug formulations of chemotherapeutic action for cancer care on the basis of magneto fluids which contain nano-sized single-domain magnetite with a modified surface as well as cytostatic drug has been presented. It has been shown that according to the data of magnetic measurements the size parameters of vector systems can be accurately determined, it can be used for their standardization and parameters control in the productive process.
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