Magnetic nanoparticles for the application in hyperthermia, preparation thereof and use in constructs having a pharmacological application
Abstract
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16 claims: 6 independent, 10 dependent
- 1Zastrzeżenia patentowe 1. Konstrukty zawierające:magnetyczne nanometryczne cząstki funkcjonalizowane dwufunkcyjnymi związkami o ogólnym wzorze: R1-(CH2)n-R2 w którym: n oznacza liczbę całkowitą w zakresie pomiędzy 2 i 20;R1 jest wybrany spośród: CONHOH, CONHOR, PO(OH)2, PO(OH)(OR), COOH, COOR, SH, SR;R2 oznacza grupę zewnętrzną i jest wybrany spośród: OH, NH2, COOH, COOR;R oznacza grupę alkilową lub metal alkaliczny, wybrane odpowiednio spośród C1-6alkilu oraz K, Na i Li, polimer ewentualnie zawierający farmakologicznie czynną cząsteczkę i zewnętrzną warstwę ochronną środka powierzchniowego, przy czym ta farmakologicznie czynna cząsteczka jest wybrana spośród: środków przeciwnowotworowych, środków przeciwdrobnoustrojowych, środków przeciwzapalnych, immunomodulatorów, cząsteczek działających na ośrodkowy układ nerwowy lub zdolnych do znakowania komórek, tak aby umożliwić ich identyfikację zwykłymi środkami wykrywania diagnostycznego.
- 2Konstrukty według zastrzeżenia 1, w których ta farmakologicznie czynna cząsteczka, jeśli jest obecna, jest połączona z polimerem lub rozproszona w nim.
- 3Konstrukty według zastrzeżenia 1, w których te magnetyczne nanometryczne cząstki stanowią spinele lub tlenki typu M II M III 2 O 4 , gdzie M II = Fe, Co, Ni, Zn, Mn;M III = Fe, Cr) w postaci nanometrycznej.
- 4Konstrukty według zastrzeżenia 3, w których te magnetyczne nanometryczne cząstki są wybrane spośród:ferrytu kobaltowego, magnetytu i maghemitu.
- 5Konstrukty według zastrzeżenia 1, w których te dwufunkcyjne związki są wybrane spośród:tioli, kwasów karboksylowych, kwasów hydroksamowych, kwasów fosforowych, ich estrów i soli, zawierających łańcuch alifatyczny z drugą grupą funkcyjną w pozycji końcowej (oznaczonej jako (ω).
- 6Konstrukty według zastrzeżenia 5, w których grupę dwufunkcyjną stanowi 12(hydroksyamino)-12-oksododekanian etylu.
- 7Konstrukty według zastrzeżenia 6, w których ten polimer jest wybrany spośród:poliestrów, poliamidów, polibezwodników, poliortoestrów, peptydów, poliaminoamidów;albo nierozpuszczalnych cząsteczek organicznych.
- 8Konstrukty według zastrzeżenia 1, w których środki powierzchniowe są wybrane spośród:polielektrolitów, polipeptydów i białek rozpuszczalnych w wodzie;kopolimerów blokowych, modyfikowanych glikoli polietylenowych, modyfikowanych polisacharydów, fosfolipidów, poliaminoamidów, białek globularnych.
- 9Sposób wytwarzania nanocząstek o wzorze M II M III 2 O 4 w którym M II = Fe, Co, Ni, Zn, Mn;M III = Fe, Cr), w którym sól żądanego metalu dodaje się do alkoholu i roztwór ogrzewa się w trakcie mieszania w celu osiągnięcia całkowitej solubilizacji soli, ewentualnie dodaj ąc wodę w celu ułatwienia hydrolizy soli, ogrzewa się do temperatury powyżej 150°C, po czym pozostawia się do ostygnięcia, zbiera się uzyskaną zawiesinę i otrzymane w ten sposób cząstki funkcjonalizuje się.
- 10Sposób wytwarzania konstruktów według zastrzeżeń 1 - 8, w którym funkcjonalizowane nanocząstki i farmakologicznie czynną cząsteczkę wprowadza się do polimerycznej matrycy nierozpuszczalnej w wodzie i tę strukturę powleka się odpowiednimi środkami powierzchniowymi w sposób ciągły w jednym etapie.
- 11Sposób wytwarzania konstruktów według zastrzeżenia 10, w którym rozpuszczalnik organiczny mieszający się z wodą w ilości co najmniej 10% stosuje się jako rozpuszczalnik "nośnikowy" dla magnetycznych cząstek i ewentualnie leku.
- 12Sposób według zastrzeżenia 11, w którym te rozpuszczalniki są wybrane z grupy obejmuj ącej :aceton, glikol dietylenowy, acetonitryl, dimetylosulfotlenek, dimetyloformamid, keton metylowoetylowy, węglan dimetylu, metanol, etanol, propanol.
- 13Konstrukty według zastrzeżeń 1 - 8, o średniej średnicy w zakresie pomiędzy 50 i 300 nm.
- 14Konstrukty według zastrzeżenia 13, o średniej średnicy w zakresie pomiędzy 30 i 100 nm.
- 15Konstrukty według zastrzeżeń 13 - 14 , w których nanometryczną cząstkę stanowi ferryt kobaltowy.
- 16Zastosowanie konstruktów według zastrzeżeń 1 - 8 do wytwarzania kompozycji farmaceutycznych stosowanych w leczeniu hipertermicznym. Uprawniony:Colorobbia Italia S.p.a. hipertermia (°C) Wykres 1 Wydajność hipertermiczna funkcjonalizowanych cząstek i odpowiedniego gotowego konstruktu NBR1 NBR2 NBR3 NBRF1 NBRF2 NBRF3 NBRF4 NBRF5 FI funkcjonalizowany produkt H prekursor Rys.1
Independent claims16
772 paragraphs in 7 sections, as filed
[0001] The present invention relates to the field of nanometric particles, in particular metal oxides with magnetic properties, and their use in the pharmacological field.
Background Art [0002] Nanoparticles are objects with a diameter below 300 nm. In recent years, there has been a great interest in such materials in the scientific and technological environment due to their unique physicochemical properties.
[0003] In particular, the diagnostic sector using magnetic nanoparticles as a contrast agent in imaging techniques (magnetic resonance imaging), magnetic localization techniques and, mainly in a specific therapeutic field, hyperthermia mediated by magnetic fields belongs to the potential field.
[0004] The main feature of these materials essentially consists of four elements:
- the composition of the central core of the particles (which must contain materials with magnetic characteristics);
- the size of the central magnetic core (which is in the order of tens of nanometers or below)
- stability in the physiological environment
- biocompatibility.
[0005] The current usefulness of magnetic nanoparticles is, in basic analysis, related to their ability to increase the temperature of the medium in which they are enclosed when interacting with external electromagnetic fields.
[0006] Many patents relate to magnetic nanoparticles coated with biocompatible materials so as to obtain composite particles with a diameter in the range between 5 and 500 nm that can form stable suspensions in aqueous systems. See US Patent No. 5,427,767, Kresse; U.S. Patent No. 2541039, Lesniak; U.S. Patent No. 6,541,039, Lesniak.
[0007] Particular attention has been paid to methods for producing metal oxides forming the core of particles, and all of them have been directed to the preparation of iron oxides. See patent
US No. 4677027, Porath; U.S. Patent No. 5,160,725 to Pilgrim; U.S. Patent No. 4,329,241, Massart;
U.S. Patent No. 4,411,435, Hasegswa.
[0008] In all the patents mentioned, even when in some cases they are generally referred to as "metal oxides" or "iron oxides doped with other metallic elements", the examples given relate in particular only to iron oxides in their various forms and in no case the hyperthermic effect associated with other types of metal oxides was mentioned.
[0009] Generally, such nanoparticle oxides have low hyperthermic efficiency and therefore large amounts must be introduced to achieve a therapeutic effect.
[0010] In addition, there is a wide group of patents regarding methods for producing various types of coatings, stabilizers and magnetic particle protection using various methods. See US Patent No. 4,280,918, Homola; U.S. Patent No. 6,576,221, Kresse; U.S. Patent No. 4,452,773, Molday; U.S. Patent No. 4,827,945 to Groman; US Patent No. Tournier; EP
0272091, Eley.
[0011] A number of different techniques have been described for producing polymer nanoparticles containing pharmacologically active products inside; these techniques can be grouped into four classes:
a) Trapping techniques in water-insoluble and water-miscible polymers.
b) Techniques for coacervation (water-soluble) drug in water-soluble proteins or polymers, followed by the formation of nanoparticles by diluting with solvents in which the proteins or polymers are insoluble, stabilizing the structure in the form of nanoparticles with suitable binders and removing the "precipitant".
c) Techniques for introducing (water-soluble or water-insoluble) drug by emulsification in the presence of surface agents, which leads to the formation of micrometric particles, followed by removal of the solvent to reduce the particle size to nanometric levels.
d) Techniques for introducing (water-soluble or water-insoluble) drug by emulsification in the presence of proteins, which leads to the formation of micrometric particles, followed by removal of the solvent to reduce the particle size to nanometric levels.
[0012] It can be seen that the description of this large number of methods, each of which has specific variants, in fact indicates the difficulties encountered in producing a product of suitable size for use (typically in the range between 100 and 300 nm), limited size distribution and the ability to maintaining stability in a physiological environment.
[0013] Considering the techniques considered, the following problems can be identified:
- Trapping techniques for the "active substance" in polymers insoluble in water and soluble in appropriate organic solvents lead to the "simple" formation of nanoparticles, the size of which depends mainly on the concentration of the polymer and the drug, and on the dilution / water ratio. The main problem is that the nanometric particles obtained in this way are stable in water but unstable in physiological solution, and their use in the biomedical field is therefore difficult to accept.
- Coacervation techniques (water-soluble) of the drug in water-soluble proteins, followed by the formation of nanoparticles by dilution with solvents, stabilization of the structure in the form of nanoparticles with suitable binders and removal of "precipitating" solvent definitely not suitable for water-insoluble products. On the other hand, the advantage of using nanoparticulate systems is limited to products that are already soluble in an aqueous environment, since such active substances can be administered directly with effects similar to those achieved with a nanoparticle system.
- Emulsification techniques in the presence of surface agents always have the problem that emulsifying systems are rarely able to combine the ability to form sufficiently small micelles compatible with the human body at the concentration used.
- The techniques for introducing (water-soluble or water-insoluble) medicine by emulsification in the presence of proteins pose significant technical difficulties for production-type applications. Emulsification in such cases is very difficult and enforces the use of complex techniques with low efficiency in industrial conditions, which are very expensive (for example, high-pressure emulsification techniques).
[0014] In view of the above, the need for magnetic oxides in the form of nanoparticles with high hyperthermic efficiency and methods for introducing magnetic systems of pharmacologically active compounds, resulting in the production of constructs effective from a hyperthermic and pharmacological point of view, which are also stable and biologically compatible, is obvious.
Brief Description of the Drawings [0015] Fig. 1 is a graph that compares the hyperthermic performance of functionalized particles and the corresponding finished construct, expressed as ΤΤ in ° C.
Summary of the Invention [0016] The present invention relates to nanometric magnetic metal oxide particles and constructs consisting of such magnetic nanometric particles, functionalized with bifunctional compounds, a polymer optionally containing a pharmacologically active molecule and, when the polymer is insoluble in water, an outer protective layer of surface agents , and their use in hyperthermic therapies.
Detailed description of the invention [0017] The present invention overcomes the above-mentioned problems with constructs containing magnetic nanometric particles functionalized with bifunctional compounds of the general formula:
R1- (CH2) n-R2 in which:
n is an integer between 2 and 20;
R1 is selected from: CONHOH, CONHOR, PO (OH) 2, PO (OH) (OR), COOH, COOR, SH, SR;
R2 is an external group selected from: OH, NH2, COOH, COOR;
R is an alkyl or alkali metal group selected from C 1-6 alkyl and K, Na and Li, respectively, a polymer optionally containing a pharmacologically active molecule selected from: anti-cancer agents, anti-microbial agents, anti-inflammatory agents, immunomodulators, molecules acting on the central nervous system or able to label cells so as to enable their identification by ordinary diagnostic detection agents, and the outer protective layer of surface agents.
[0018] If the above-mentioned pharmacologically active molecule is present, it can be combined with the polymer or dispersed in it.
[0019] The nanometric particles according to the invention are M type spinels and oxides<sup>II</sup>M<sup>III</sup>2O4, where M<sup>II</sup> = Fe, Co, Ni, Zn, Mn; M<sup>III</sup> = Fe, Cr) in nanometric form.
[0020] It has surprisingly been found that among the above-mentioned spinels, cobalt ferrite has high hyperthermic efficiency.
[0021] In addition, it has surprisingly been found that among other spinels and iron oxides, magnetite and maghemite, prepared by the methods described in the present invention, show better hyperthermic performance than similar products described in the literature.
[0022] According to the invention, the bifunctional compounds are intended to be: thiols, carboxylic acids, hydroxamic acids, phosphoric acids, their esters and salts having an aliphatic chain with a second functional group in the end position (denoted as (ω).
[0023] A preferred C1-6-alkyl is ethyl.
[0024] Particularly preferred of the above difunctional groups is ethyl 1210 (hydroxyamino) -12-oxododecanoate.
[0025] The polymers included in the construct may be water-soluble polymers or water-insoluble polymers stabilized by surface agents. [0026] According to the invention, the water-soluble polymers are, for example, polyelectrolytes, polypeptides and water-soluble proteins; water-soluble polymers selected from block copolymers, modified polyethylene glycols, modified polysaccharides, phospholipids, polyaminoamides, globular proteins are preferred. Water insoluble polymers are, for example, selected from: polyesters, polyamides, polyanhydrides, polyorthoesters, peptides, polyaminoamides; or insoluble organic molecules such as, for example, cholesterol; polyesters and cholesterol are preferred.
[0027] According to the invention, the surface agents may be: polyelectrolytes, polypeptides and water-soluble proteins; block copolymers, modified polyethylene glycols, polysaccharide glycols, phospholipids, polyaminoamides, globular proteins; human serum proteins and pluronic block copolymers are preferred.
[0028] Polymers are known or can be readily prepared by methods known in the art, for example by polyaddition of primary monoamines or secondary diamines with bisacrylamides, at room temperature for a time range from several hours to several days, as exemplified in Macromolecular Rapid Communication, 2002, 23, No. 5/6, pp. 332-355.
[0029] According to the invention, examples of polymers, both water soluble and surface agents, are:
<img file="PL2117600T3_D0001.tif" />
<img file="PL2117600T3_D0002.tif" />
h<sub>2</sub>0<sub>3</sub>p
<img file="PL2117600T3_D0003.tif" />
<img file="PL2117600T3_D0004.tif" />
<img file="PL2117600T3_D0005.tif" />
<img file="PL2117600T3_D0006.tif" />
<img file="PL2117600T3_D0007.tif" />
<img file="PL2117600T3_D0008.tif" />
<img file="PL2117600T3_D0009.tif" />
<img file="PL2117600T3_D0010.tif" />
<img file="PL2117600T3_D0011.tif" />
νη<sub>2</sub>
<img file="PL2117600T3_D0012.tif" />
<img file="PL2117600T3_D0013.tif" />
<img file="PL2117600T3_D0014.tif" />
where n is between 3 - 300, preferably between 10-100.
[0030] According to the invention, the pharmacologically active molecules are biologically active molecules usually used in various therapies, for example anti-cancer agents (such as anthracycline), antimicrobials, anti-inflammatory agents, immunomodulators, molecules acting on the central nervous system, etc. or those capable of labeling cells, so that they can be identified by common diagnostic detection means (for example, fluorescent staining agents).
[0031] The methods of making the constructs described in the present invention are extremely flexible.
[0032] Furthermore, due to the possibility of regulating their size and therefore their hyperthermic properties, the magnetic nanoparticles of the present invention are particularly suitable for the production of biocompatible nanoparticle constructs that are extremely flexible for use and active even at low magnetic nanoparticle concentrations.
[0033] This is of course an advantage in all possible biomedical applications. In the case where the constructs are based on hydrophilic polymers used as surfactants, it is known that the surfactant should be used in an amount of over 300% relative to the pharmacologically active product; by using the nanoparticles of the present invention, the amount of surfactant, which generally has low biocompatibility, can be significantly reduced. In particular with respect to cobalt ferrite, it has surprisingly been found that it has a hyperthermic efficiency of approximately an order of magnitude greater than that of iron oxides; in addition, unlike iron oxides described in the literature, the hyperthermic properties of physically immobilized cobalt ferrite nanoparticles do not change in relation to the material dispersed in the liquid matrix. This makes them more efficient in those cases where the extracellular matrix or cytoplasmic matrix is an obstacle to their rotation.
[0034] When irradiated with electromagnetic waves in the range between 10 and 1000 kHz, preferably between 50 and 500 kHz, cobalt ferrite nanoparticles exhibit much better hyperthermic properties than iron oxides with equivalent nanoparticle size (also doped with Co, Ni or impurities) other metallic elements). At the frequencies mentioned above, the magnetite and maghemite particles obtained also showed better hyperthermic efficiencies than the equivalent particles described in the literature.
[0035] The magnetic nanoparticles of the invention can be prepared by known methods, such as, for example, the polyol method widely described in the literature, which, in brief, involves the use of high boiling alcohol enabling high temperature operation, which leads to the formation of complex forming particles, which prevents their growth.
[0036] Typically, the precursors of the desired metals (preferably acetates, carbonates, sulfates, oxalates, chlorides) are added to a known volume of alcohol (e.g. diethylene glycol, DEG). The solution is then heated with stirring to completely solubilise the precursors, optionally water is added in an appropriate amount to facilitate the hydrolysis of the precursors, heated for several hours at a temperature above 150 ° C, then allowed to cool, thereby obtaining a stable suspension dispersed nanoparticles with limited size distribution.
[0037] In addition, due to the fact that the hyperthermic effect of cobalt ferrite is much more dependent on the size of nanoparticles than in the case of magnetite or maghemite, new synthesis methods have been developed, enabling repeatable regulation of the nano14 size of particles, and their hyperthermic effect, respectively. also forming part of the present invention. Size control also brought significant benefits in the synthesis of magnetite and maghemite, enabling variant products to be obtained with cobalt ferrite and more efficiently than their counterparts from the point of view of hyperthermic properties.
[0038] The following are new synthesis methods that provide the ability to control the size (and thus hyperthermic properties) of magnetic nanoparticles, which are always obtained in suspension.
Continuous process.
[0039] In this case, the procedure is carried out as described above for the polyol method, but the synthesis is carried out by adding (in an equimolar amount to the reactants) a "starter component" which is previously synthesized nanoparticles. In this way, magnetic nanoparticles larger than those introduced at the beginning of the synthesis are obtained at the end of the reaction.
[0040] In practice, the procedure for the first production is carried out by a polyol method; then the new reaction is carried out under the same conditions as the first, with all starting materials in the same amounts as previously used, and with the addition of the product obtained in the first reaction. The magnetic nanoparticles obtained in this way (which are doubled and larger in size than those introduced at the beginning of the synthesis) can be reused as the "starting component" in the next reaction. The cycle can be repeated an infinite number of times until the desired particle size is obtained.
Semi-continuous substitution process.
[0041] In practice, the first synthesis is carried out according to the polyol process, but at the end of the period of stationary heating at 180 ° C, the product is not cooled, but rather poured into a twice larger flask, in which all starting substances in the same amounts are placed as for the already reacted product. The temperature is again brought to 180 ° C, maintained for 3 hours, after which the cycle is repeated a varying number of times until the desired size is obtained.
Growth process.
[0042] In this case, the synthesis is carried out according to the polyol process described above, but the time during which the product is kept at 180 ° C is extended by a variable number of hours. In this way, a product is obtained whose dimensions depend on the time the temperature is maintained.
[0043] Magnetic nanoparticles can also be produced by a method similar to the polyol process described above, but by heating only in a microwave oven, which allows a significant reduction in reaction time and better control of size and morphology.
[0044] As a further advantage of the above-described method, it should be taken into account that with the help of these preparative techniques, the stoichiometry of nanoparticles can be modified: e.g. oxidizing environment, thus accelerating the oxidation process, which should occur naturally, but in a much longer time. In this case, the magnetic size adjustment of the nanoparticles is achieved indirectly by adjusting the size of the magnetite precursor according to one of the previously described methods.
[0045] The particle size of cobalt ferrite, magnetite and maghemite in the form of nanoparticles, obtained by the method described, was checked by DLS (Malvern Zetasizer nano-S). [0046] The size of the nanoparticles thus obtained is in the range between 4 and 200 nm, preferably between 10 and 70 nm.
[0047] The functionalization of nanoparticles was achieved by known methods or as described in patent PCT / EP2007 / 050036, e.g. by reacting difunctional derivatives dissolved in ethanol with the nanoparticles as defined above, so as to coat their surface.
[0048] The production method includes reacting the dispersion of nanoparticles in an organic solvent (e.g., ethylene glycol) with a selected binder while stirring at reduced temperature for several hours. The product is then optionally separated by extraction with a specific solvent or precipitated, e.g. with acetone, centrifuged, separated and optionally redispersed in a suitable solvent.
[0049] The above-mentioned polymeric constructs have different characteristics depending on the type of polymer used to make them.
[0050] In particular, the polymers may be insoluble or water soluble;
their use in the synthesis of the constructs of the invention is given below.
Constructs based on water-insoluble polymers [0051] They contain magnetic nanoparticles, functionalized as described above, in combination with a pharmacologically active agent contained in the water-insoluble polymer as previously described, in turn stabilized by surface agents as defined above .
[0052] According to the invention, the surface agents can be: polyelectrolytes, polypeptides and water-soluble proteins; surface agents selected from block copolymers, modified polyethylene glycols, modified polysaccharides, phospholipids, polyaminoamides, globular proteins are preferred. The method of producing such constructs according to the invention is a continuous and one-step method of introducing magnetic nanoparticles into a water-insoluble polymer matrix and coating this structure with suitable surface agents. The procedure involves the use of water (in which the surface agent has previously been dissolved) and an organic solvent miscible with it (in an amount greater than 10%), in which magnetic nanoparticles, functionalized as described above, and a previously solubilized polymer matrix. The two liquids are then mixed under appropriate conditions so as to obtain an auto combination of components previously solubilized in phases to form a controlled size construct.
[0053] The introduction of the drug into the construct takes place in the joining step by solubilization in water or an organic solvent. This can increase the number of pharmacologically active ingredients that can be incorporated into the construct.
[0054] This method allows the final product to be produced in a yield between 90 and 99%, surprisingly the hyperthermic efficiency of the construct assembled in this way is similar to that of the original inorganic particles.
[0055] The average diameter of the construct is in the range between 50 and 300 nm, and the ratio of the concentration of the drug optionally present to the concentration of the magnetic particles can easily be changed during assembly. The close combination of magnetic particles and the drug makes it possible to achieve controlled release of the drug by the thermal effect caused by the interaction of magnetic nanoparticles with the external electromagnetic field.
[0056] In this way, magnetic hyperthermia can be achieved on the one hand, and a synergistic effect on the pharmacologically active ingredients on the other.
[0057] The presence of magnetic particles in a variable percentage with respect to the drug makes it possible to enhance the hyperthermic effect, i.e. strictly pharmacological effect in the most desirable way for the particular pathology being treated.
[0058] The resulting constructs are stable in a physiological solution environment, which confirms their suitability for therapeutic use.
Constructs based on water-soluble polymers:
[0059] They consist of magnetic nanoparticles, functionalized as described above, optionally in combination with a pharmacologically active agent incorporated in a water-soluble polymer or in surface agents as defined above.
[0060] The method of the invention uses an organic solvent that is miscible with water to a degree of more than 10% as a "carrier" solvent for magnetic particles and the drug.
[0061] The procedure involves the use of water (in which the water-soluble polymer has previously been dissolved) and water miscible liquid (to a degree greater than 10%) in which functionalized magnetic nanoparticles have previously been solubilized. The two liquids are then mixed under appropriate conditions so as to obtain an auto-combination of components previously solubilized in phases to form a controlled size construct.
[0062] The introduction of the drug into the construct takes place in the joining step by solubilization in water or an organic solvent. In this way, the number of pharmacologically active ingredients that can be incorporated into the construct can be increased, and the ratio of drug concentration to magnetic particle concentration can be easily changed.
[0063] Constructs with an average diameter between 30 and 100 nm and very limited size distribution (PDI polydispersity index = 0.10 0.15) can be obtained in this way, whereas the methods described in the literature (in a more complex process whose scale it is difficult to increase), particles of about 200 nm with a broader polydispersity index (about 0.25) are obtained. This method allows the final product to be produced in a yield between 80 and 98%, surprisingly the hyperthermic efficiency of the construct thus assembled is similar to that of the original inorganic particles.
[0064] The resulting constructs are stable in a physiological solution environment, which confirms their suitability for therapeutic use.
[0065] The possibility of obtaining such small constructs, evenly distributed and stable in a physiological environment is a significant advantage in the event of a possible therapeutic application, because the particles can diffuse better in the areas of the body to be treated, are more difficult to detect by the immune system and thus for elimination and easier to introduce into target cells (I. Brigger, C. Dubernet, P. Couvreur, Adv. Del Rev., 2002, 54, 631. Nanoparticles in cancer thera30 py and diagnosis).
[0066] General data on synthesized nanoparticles, functionalized nanoparticles, and constructs as defined above are given in Table 1, divided as follows:
Tables 1 (a) and 1 (b): magnetic particles;
Table 1 (c): functionalized magnetic particles;
Table 1 (d): constructs with polymer coating.
[0067] Table 2 gives the particle size obtained by the methods of the invention and the corresponding hyperthermic effect is given in Table 3.
[0068] General data on functionalized nanoparticles are given in Table 4, in which the starting products, type of functionalization and hyperthermic effect (expressed as ΤΤ) of the precursor and end product are indicated under the same measurement conditions.
[0069] It is obvious from Diagram 1 that the hyperthermic effect of the construct is always similar to that of the precursor.
[0070] The crystal structure of the samples was identified by X-ray diffraction (XRD) by recording reflections in the 10-70 ° range in the 0.05 ° (2θ) scanning range for 5 s with a Philips X'pert Pro diffractometer (Cu Ka radiation). The size of the crystallites was determined on the basis of diffraction peaks using the Scherrer method.
[0071] The particles thus characterized (non-functionalized particles, functionalized particles, final construct) were subjected to hyperthermia tests, to which the samples were scattered in different media and an oscillating magnetic field generator Novastar 5 W to 5 kW supplied by Ameritherm was used. The tests were carried out in adiabatic conditions with an electromagnetic field of 170 kHz and a magnetic field strength of 21 kA / m<sup>2</sup>, using a 0.30 ml alumina crucible, completely filled with a sample dispersion in a suitable solvent. The concentration of the sample (expressed as the concentration of metal oxide) in the dispersion medium was in the range between 0.1% and 3%. [0072] The initial and final dispersion temperature was measured with a FLIR E65 thermal camera.
[0073] To better illustrate the invention, the following Examples are given.
Example 1 [0074] Preparation of nanometric cobalt ferrite by a known method (polyol process).
Product formula: NFeCo31 Reagents used:
[0075]
Fe: Co = 2: 1 ratio
9.53 g Co (Ac) 2.4H2O (23.7 wt.% Co)
Every (II) = 2.259 g = 0.038 mol
21.42 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 4.284 g = 0.077 mol
269.04 g DEG Synthesis:
[0076] The 4-necked flask is equipped with a paddle stirrer, ball cooler with a valve for possible distillation, probe and cork (additional neck). The reagents are placed in DEG in a reaction flask. The system is brought to 110 ° C in the solubilization step (time: 1 hour). Then the temperature is raised to 180 ° C and the system is refluxed for 3 hours. The process carried out while mixing leads to the formation of a black suspension.
Example 2 [0077] Preparation of nanometric magnetite by a known method (polyol process).
Product pattern: Fe74
reagents:
[0078] the ratio Fe III: Fe II = 2: 1
30.32 g Fe (Ac) 2 solution (7 wt% Fe)
Fe (II) = 2.122 g = 0.038 mol
21.42 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 4.284 g = 0.077 mol 269.04 g DEG
Synthesis:
[0079] The 4-necked flask is equipped with a paddle stirrer, ball cooler equipped with a two-way reflux system, probe and cork (additional neck). The reagents are placed with the DEG in a reaction flask. The system is brought to 120 ° C in the stabilization step and kept at this temperature for one hour. The mixture is then heated to 180 ° C maintaining the distillation step. After reaching the internal temperature of 180 ° C, the system is left under reflux for 3 hours. The process carried out while mixing leads to the formation of a brown suspension. Example 3 [0080] Preparation of manometric mixed Fe spinel<sup>III</sup>, Fe<sup>II</sup>, Ni by known method (polyol process).
Product pattern: Fe Do Ni 03 [0081]
Specification of reagents:
Fe (CH3COO) 3
Fe (CH3COO) 2
Ni (CH3COO) 2
fe
Ni
DEG
MW = 232.98 g / mol MW = 173.93 g / mol MW = 176.78 g / mol MW = 55.85 g / mol MW = 58.69 g / mol MW = 106.12 g / mol
reagents:
[0082] Fe ratio<sup>III</sup>: Fe<sup>II</sup>: Ni = 8: 3: 1 5 22.34 g Fe (Ac) 3 (Sheperda paste; c. 20% by weight Fe)
Fe (III) = 4.468 g = 80 mmol
23.94 g of Fe (Ac) 2 solution (7 wt.% Co)
Fe (II) = 1.675 g = 30 mmol
1.77 g Ni (Ac) 2
Ni = 0.588 g = 10 mmol 269.04 g DEG
Synthesis:
[0083] The 4-necked flask is equipped with a paddle stirrer, ball cooler equipped with a two-way reflux system, probe and cork (additional neck). The reagents are placed with the DEG in a reaction flask. The system is brought to 110 ° C in the stabilization step and kept at this temperature for 1 hour. The mixture is then heated to 180 ° C maintaining the distillation step. When the internal temperature reaches 180 ° C, the system is refluxed for 3 hours. The process carried out while mixing leads to the formation of a brown suspension.
Example 4
Continuous nanometer cobalt ferrite production of the present invention.
Product pattern: NFeCo36 Step 1 (Product pattern: NFeCo35) [0084]
Specification of reagents
Fe (CH3COO) 3
Co (CH3COO + 4H2O CoFe2O4 (NFeCo 31)
What
fe
DEG
MW = 232.98 g / mol MW = 248.93 g / mol MW = 234.62 g / mol MW = 58.93 g / mol MW = 55.85 g / mol MW = 106.12 g / mol
reagents:
[0085]
Fe: Co = 2: 1 ratio
9.53 g Co (Ac) 2 ^ 4 H2O (23.7 wt.% Co)
Every (II) = 2.259 g = 0.038 mol
21.42 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 4.284 g = 0.077 mol 269.04 g DEG
287 g NFeCo 31
Synthesis:
[0086] The 4-necked flask is equipped with a paddle stirrer, ball condenser with distillation valve, probe and plug (additional neck). The reagents are placed with the DEG in a reaction flask. The system is brought to a temperature of 110 ° C in the solubilisation step (time: 1 hour). Then the temperature is raised to 180 ° C and the system is refluxed for 3 hours. The process carried out while mixing leads to the formation of a black suspension. 570 g of product are obtained.
Stage 2 (Product formula: NFeCo36)
Specification of reagents: as above
reagents:
[0087]
Fe: Co = 2: 1 ratio
19.06 g Co (Ac) 2 ^ 4H2O (23.7 wt.% Co)
Every (II) = 4.518 g = 0.076 mole
42.84 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 8.568 g = 0.154 mole
538 g DEG 570 g NFeCo_35
Synthesis:
[0088] The 4-necked flask is equipped with a paddle stirrer, ball condenser with distillation valve, probe and plug (additional neck). The reagents are placed with the DEG in a reaction flask. The system is brought to 110 ° C in the solubilization step (time: 1 hour). Then the temperature is raised to 180 ° C and the system is refluxed for 3 hours. The process carried out while mixing leads to the formation of a black suspension. 1105 g of product are obtained.
Example 5 [0089] Preparation of nanometric magnetite with product formula Fe76 by the continuous method of the present invention.
Stage 1 (Product formula Fe75) [0090]
<td colspan="2">Specification of reagents:</td>
<td>Fe (CH3COO) 3</td><td>MW = 232.98 g / mol</td>
<td>Fe (CH3COO) 2</td><td>MW = 248.93 g / mol</td>
<td>Fe3O4 (Fe74)</td><td>MW = 231.53 g / mol</td>
<td>fe</td><td>MW = 55.85 g / mol</td>
<td>DEG</td><td>MW = 106.12 g / mol</td>
reagents:
[0091] Fe ratio<sup>III</sup> : Fe<sup>II</sup> = 2 : 1
30.32 g Fe (Ac) 2 solution (7 wt% Fe)
Fe (II) = 2.122 g = 0.038 mol
21.42 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 4.284 g = 0.077 mol
269.04 g DEG 279 g Fe74
Synthesis:
[0092] The 4-necked flask is equipped with a paddle stirrer, ball cooler equipped with a two-way reflux system, probe and cork (additional neck). The reagents are placed with the DEG in a reaction flask. The system is brought to 120 ° C in the stabilization step and kept for 1 hour at this temperature. The mixture is then heated to 180 ° C maintaining the distillation step. When the internal temperature reaches 180 ° C, the system is refluxed for 3 hours.
The process carried out while mixing leads to the formation of a brown suspension.
Total quantity received: 552 g.
Stage 2 (Product design: Fe76)
Reagent specification: as above Reagents:
[0093] the ratio Fe III: Fe II = 2: 1
60.64 g Fe (Ac) 2 solution (7 wt% Fe)
Fe (II) = 4.244 g = 0.076 mol
42.84 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 8.568 g = 0.154 mole
538.08 g DEG
552 g Fe75
Synthesis:
[0094] The 4-necked flask is equipped with a paddle stirrer, ball cooler equipped with a two-way reflux system, probe and cork (additional neck). The reagents are placed with the DEG in a reaction flask. The system is brought to 120 ° C in the stabilization step and kept for 1 hour at this temperature. The mixture is then heated to 180 ° C maintaining the distillation step. When the internal temperature reaches 180 ° C, the system is refluxed for 3 hours. The process carried out while mixing leads to the formation of a brown suspension.
Total quantity received: 1113 g.
Example 6 [0095] A method for producing cobalt ferrite by the semi-continuous substitution method of the present invention. Product pattern: NFeCoCONT-03B3 Step 1 (Product pattern: NFeCoCONT-03B1) [0096]
Specification of reagents:
Fe (CH3COO) 3
Co (CH3COO) 2 ^ 4H2O
CoFe2O4 (NFeCo 31)
What
fe
DEG
MW = 232.98 g / mol MW = 248.93 g / mol MW = 234.62 g / mol MW = 58.93 g / mol MW = 55.85 g / mol
MW = 106.12 g / mol
reagents:
[0097]
Fe: Co = 2: 1 ratio
9.53 g Co (AcMH2O (23.7 wt.% Co))
Every (II) = 2.259 g = 0.038 mol
21.42 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 4.284 g = 0.077 mol 269.04 g DEG
285 g NFeCo_31
Synthesis:
[0098] The 1-liter 4-necked flask is equipped with a paddle stirrer, ball condenser with distillation valve, probe and plug (additional neck). Cobalt acetate and iron acetate are placed together with DEG in the reaction flask and warm NFeCo31 from the previous reaction is still added. The temperature is brought to 180 ° C and the system is refluxed for 3 hours. 575 g of product are obtained. Stage 2 (Product formula: NFeCoCONT-03B2)
Specification of reagents: as above
reagents:
[0099]
Fe: Co = 2: 1 ratio
19.06 g Co (ACMH2O (23.7% w / w Co)
Every (II) = 4.518 g = 0.076 mole
42.84 g Fe (CH3COO) 3 (Sheperda paste; c. 20% by weight Fe) Fe (III) = 8.568 g = 0.154 mole
538 g DEG
575 g NFeCoCONT-03B1 Synthesis:
[0100] A 2-liter 4-necked flask is equipped with a paddle stirrer, ball condenser with valve for possible distillation, probe and plug (additional neck). Cobalt acetate and iron acetate are placed with the DEG in the reaction flask and warm Nfe-CoCont_31B1 from the previous reaction is further added. The temperature is brought to 180 ° C and the system is refluxed for 3 hours. 1105 g of product are obtained.
Stage 3 (Product formula: NFeCoCONT-03B3)
Specification of reagents: as above
reagents:
[0101]
Fe: Co = 2: 1 ratio
38.12 g Co (Ac) 2-4H<sub>2</sub>O (23.7% by weight Co)
Every (II) = 9.036 g = 0.152 mole
85.68 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 17.136 g = 0.308 mol
1076 g DEG
1105 g NFeCoCONT-03B2
Synthesis:
[0102] A 5 liter 4-necked flask is equipped with a paddle stirrer, ball condenser with valve for possible distillation, probe and plug (additional neck). Cobalt acetate and iron acetate are placed with the DEG in the reaction flask and warm NfeCoCont_31B12 from the previous reaction is further added. The temperature is brought to 180 ° C and the system is refluxed for 3 hours. 2210 g product was obtained.
Example 7 [0103] Preparation of nanometric cobalt ferrite in the growth process of the present invention.
Product pattern: NAMA06 602 [0104]
Specification of reagents
Fe (CH3COO) 3
Co (CHsCOO) 2 ^ 4 H2O Co
fe
DEG
MW = 232.98 g / mol MW = 248.93 g / mol MW = 58.93 g / mol MW = 55.85 g / mol MW = 106.12 g / mol
reagents:
[0105]
Fe: Co = 2: 1 ratio
9.53 g Co (AcMH2O (23.7 wt.% Co))
Every (II) = 2.259 g = 0.038 mol
21.42 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 4.284 g = 0.077 mol 269.04 g DEG
Synthesis:
[0106] The 4-necked flask is equipped with a paddle stirrer, ball condenser with valve for possible distillation, probe and plug (additional neck). The reagents are placed with the DEG in a reaction flask. The system is brought to 110 ° C in the solubilization step (time: 1 hour). Then the temperature is raised to 180 ° C and the system is refluxed for 5 hours. The process carried out under stirring leads to a black suspension.
Total quantity received: g 282.
Example 8 [0107] Preparation of nanometric cobalt ferrite in the growth process of the present invention.
Product pattern: NAMA06 601 [0108]
Specification of reagents
Fe (CH3COO) 3
Co (CHsCOO) 2 ^ 4H2O
What
MW = 232.98 g / mol MW = 248.93 g / mol MW = 58.93 g / mol
Specification of reagents:
Fe MW = 55.85 g / mol
DEG MW = 106.12 g / mol
reagents:
[0109]
Fe: Co = 2: 1 ratio
9.53 g Co (Ac)<sub>2</sub>^ 4H<sub>2</sub>O (23.7% by weight Co)
Every (II) = 2.259 g = 0.038 mol
21.42 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 4.284 g = 0.077 mol 269.04 g DEG
Synthesis:
[0110] The 4-necked flask is equipped with a paddle stirrer, ball condenser with valve for possible distillation, probe and plug (additional neck). The reagents are placed with the DEG in a reaction flask. The system is brought to 110 ° C in the solubilization step (time: 1 hour). Then the temperature is raised to 180 ° C and the system is refluxed for 9 hours. The process carried out under stirring leads to a black suspension.
Total quantity received: 280 g.
Example 9 [0111] Preparation of nanometric cobalt ferrite in a growth process according to the present invention.
Product pattern: NfeCo66 [0112]
Specification of reagents:
Fe (CH3COO) 3
Co (CHsCOO) 2 ^ 4H2O
What
fe
DEG
MW = 232.98 g / mol MW = 248.93 g / mol MW = 58.93 g / mol MW = 55.85 g / mol
MW = 106.12 g / mol
reagents:
[0113]
Fe: Co = 2: 1 ratio
9.53 g Co (AcMH2O (23.7 wt.% Co))
Every (II) = 2.259 g = 0.038 mol
21.42 g Fe (CH3COO) 3 (Sheperda paste; c. 20% w / w Fe)
Fe (III) = 4.284 g = 0.077 mol 269.04 g DEG
Synthesis:
[0114] The 4-necked flask is equipped with a paddle stirrer, ball cooler with valve for eventual distillation, probe and plug (additional neck). The reagents are placed with the DEG in a reaction flask. The system is brought to 110 ° C in the solubilization step (time: 1 hour). Then the temperature is raised to 180 ° C and the system is refluxed for 24 hours. The process carried out while mixing leads to the formation of a black suspension.
Total quantity received: 280 g.
Example 10 [0115] A method for producing cobalt ferrite with microwave heating according to the present invention.
Product pattern: NFeCoMW01 [0116]
Specification of reagents
Fe (CH3COO) 3
Co (CHsCOO) 2 ^ 4H2O
What
fe
DEG
MW = 232.98 g / mol MW = 248.93 g / mol MW = 58.93 g / mol MW = 55.85 g / mol MW = 106.12 g / mol
Reagents [0117]
Fe: Co = 2: 1 ratio
11.10 g Co (AcMH2O (23.7 wt.% Co))
Every (II) = 2.632 g = 0.0447 mol
19.23 g Fe (CH3COO) 3 (Sheperd powder; c. 26 wt% Fe)
Fe (III) = 4.998 g = 0.0895 mol
319.67 g DEG Synthesis:
[0118] All reagents are placed in a 500-ml 1-neck flask. It is equipped with a 5 ball cooler. The flask is placed in a microwave chamber keeping the ball cooler out of it. The power is brought on for 7 minutes under reflux.
Example 11 [0119] A method for producing cobalt ferrite with microwave heating according to the present invention.
Product pattern: NFeCoMW03 [0120]
Specification of reagents
Fe (CH3COO) 3
Co (CII<sub>5</sub>COO)<sub>2</sub>4II<sub>2</sub>ABOUT
What
fe
DEG
MW = 232.98 g / mol MW = 248.93 g / mol MW = 58.93 g / mol MW = 55.85 g / mol
reagents:
[0121]
Fe: Co = 2: 1 ratio
11.10 g Co (Ac)<sub>2</sub>4I<sub>2</sub>O (23.7% by weight Co)
Every (II) = 2.632 g = 0.0447 mol
19.23 g Fe (CH<sub>3</sub>COO)<sub>3</sub> (Sheperd powder; c. 26 wt. Fe)
Fe (III) = 4.998 g = 0.0895 mol
319.67 g DEG
Synthesis:
[0122] All reagents are placed in a 500-ml 1-neck flask. It is equipped with a ball cooler. The flask is placed in a microwave chamber keeping the ball cooler out of it. The power is brought on for 30 minutes, maintaining the reflux.
Example 12 [0123] A method for producing maghemite by acetic acid oxidation according to the present invention
Product pattern: Fe59.1.1.1 [0124]
Specification of reagents:
CH3COOH MW = 60.05 g / mol
Fe3O4 (Fe74) MW = 231.53 g / mol
NaHCO3 MW = 84.00 g / mol
reagents:
[0125] g solution of Fe3O4 (Fe74) DEG, 0.5 wt. Fe3O4 Fe3O4 200 mg 0.864 mmol
1.00 g CH3COOH 6.7 mmol
1.2 g NaHCO3 14.3 mmol
Synthesis:
[0126] The magnetite solution in DEG and acetic acid are placed in a stirred flask with a bubble capillary and ball cooler. The whole is heated to 80 ° and kept at this temperature for 2.5 hours.
[0127] At the end of the reaction, the mixture is cooled to room temperature and sodium bicarbonate is added. Stirring is maintained for 1 hour, after which the remaining solid product is filtered off. The clear dark brown solution is characterized by spectrometry
Mossbauer to check the full creation of the maghemite. The solution is then evaporated in a rotary vacuum evaporator to the desired concentration.
TABLE 1 (a) Synthesis of non-functionalized magnetic nanoparticles
<td>Pattern</td><td colspan="7">Reagents (moths)</td><td colspan="3">SYNTHESIS</td><td></td>
<td></td><td>Fe III acetate</td><td>Fe II acetate.</td><td>Co-acetate II.</td><td>Ni II acetate</td><td>Zn II acetate</td><td>Mn II acetate</td><td>Cr III acetate</td><td>Synthesis Type</td><td>cycles</td><td>Time*</td><td>Described example</td>
<td>Fe Do Co 01</td><td> 0,04</td><td> 0,019</td><td> 0,001</td><td></td><td></td><td></td><td></td><td>BR</td><td> -</td><td> -</td><td></td>
<td>Fa Do Cr 01</td><td> 0,039</td><td> 0,02</td><td></td><td></td><td></td><td></td><td> 0,001</td><td>BR</td><td> -</td><td> -</td><td></td>
<td>Fe Do Mn 01</td><td> 0,04</td><td> 0,019</td><td></td><td></td><td></td><td> 0,001</td><td></td><td>BR</td><td> -</td><td> -</td><td></td>
<td>Fe Do Ni 01</td><td> 0,04</td><td> 0,019</td><td></td><td> 0,001</td><td></td><td></td><td></td><td>BR</td><td> -</td><td> -</td><td></td>
<td>Fe Do Ni 03</td><td> 0,04</td><td> 0,015</td><td></td><td> 0,005</td><td></td><td></td><td></td><td>BR</td><td> -</td><td> -</td><td> 3</td>
<td>Fe Do Zn 01</td><td> 0,04</td><td> 0,019</td><td></td><td></td><td> 0,001</td><td></td><td></td><td>BR</td><td> -</td><td> -</td><td></td>
<td>Fe74</td><td> 0,04</td><td> 0,02</td><td></td><td></td><td></td><td></td><td></td><td>BR</td><td> -</td><td> -</td><td> 2</td>
<td>NFeCo31</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>BR</td><td> -</td><td> -</td><td> 1</td>
<td>NFeNI03</td><td> 0,04</td><td></td><td></td><td></td><td></td><td></td><td> 0,02</td><td>BR</td><td> -</td><td> -</td><td></td>
<td>NFeCoCONT-04B9</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>WHAT</td><td> 9</td><td> -</td><td></td>
<td>NFeCoCONT-03B1</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>WHAT</td><td> 1</td><td> -</td><td> 6</td>
<td>NFeCoCONT-03B2</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>WHAT</td><td> 2</td><td> -</td><td> 6</td>
<td>NFeCoCONT-03B3</td><td> 0,04</td><td> 0,02</td><td> 0,02</td><td> 0,02</td><td></td><td></td><td></td><td>WHAT</td><td> 3</td><td> -</td><td> 6</td>
<td>NFeCoMW01</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>MO</td><td> -</td><td> 7</td><td> 10</td>
<td>Pattern</td><td colspan="7">Reagents (moths)</td><td colspan="3">SYNTHESIS</td><td></td>
<td></td><td>Fe III acetate</td><td>Fe II acetate.</td><td>Co-acetate II.</td><td>Ni II acetate</td><td>Zn II acetate</td><td>Mn II acetate</td><td>Cr III acetate</td><td>Synthesis Type</td><td>cycles</td><td>Time*</td><td>Described example</td>
<td>NFeCoMW02</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>MO</td><td> -</td><td> 10</td><td></td>
<td>NFeCoMW03</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>MO</td><td> -</td><td> 30</td><td> 11</td>
<td>NFeCoMW04</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>MO</td><td> -</td><td> 6</td><td></td>
<td>NFeCoMW05</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>MO</td><td> -</td><td> 8</td><td></td>
<td>NFeCoMW06</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>MO</td><td></td><td> 38</td><td></td>
<td>Fe Do Co 02</td><td> 0,04</td><td> 0,018</td><td> 0,002</td><td></td><td></td><td></td><td></td><td>RI</td><td> 1</td><td> -</td><td></td>
<td>Fe Do Co 03</td><td> 0,04</td><td> 0,015</td><td> 0,005</td><td></td><td></td><td></td><td></td><td>RI</td><td> 2</td><td> -</td><td></td>
<td>Fe Do Cr 02</td><td> 0,038</td><td> 0,02</td><td></td><td></td><td></td><td></td><td> 0,002</td><td>RI</td><td> 1</td><td> -</td><td></td>
<td>Fe Do Cr 03</td><td> 0,035</td><td> 0,02</td><td></td><td></td><td></td><td></td><td> 0,005</td><td>RI</td><td> 2</td><td> -</td><td></td>
<td>Fe Do Mn 02</td><td> 0,04</td><td> 0,018</td><td></td><td></td><td></td><td> 0,002</td><td></td><td>RI</td><td> 1</td><td> -</td><td></td>
<td>Fe Do Mn 03</td><td> 0,04</td><td> 0,015</td><td></td><td></td><td></td><td> 0,005</td><td></td><td>RI</td><td> 2</td><td> -</td><td></td>
<td>Fe Do Ni 02</td><td> 0,04</td><td> 0,018</td><td></td><td> 0,002</td><td></td><td></td><td></td><td>RI</td><td> 1</td><td> -</td><td></td>
<td>Fe Do Zn 02</td><td> 0,04</td><td> 0,018</td><td></td><td></td><td> 0,002</td><td></td><td></td><td>RI</td><td> 1</td><td> -</td><td></td>
<td>Fe Do Zn 03</td><td> 0,04</td><td> 0,015</td><td></td><td></td><td> 0,005</td><td></td><td></td><td>RI</td><td> 2</td><td> -</td><td></td>
<td>Pattern</td><td colspan="7">Reagents (moths)</td><td colspan="3">SYNTHESIS</td><td></td>
<td></td><td>Fe III acetate</td><td>Fe II acetate.</td><td>Co-acetate II.</td><td>Ni II acetate</td><td>Zn II acetate</td><td>Mn II acetate</td><td>Cr III acetate</td><td>Synthesis Type</td><td>cycles</td><td>Time*</td><td>Described example</td>
<td>Fe70</td><td> 0,04</td><td> 0,02</td><td></td><td></td><td></td><td></td><td></td><td>RI</td><td> 5</td><td> -</td><td></td>
<td>Fe75</td><td> 0,04</td><td> 0,02</td><td></td><td></td><td></td><td></td><td></td><td>RI</td><td> 1</td><td> -</td><td> 5</td>
<td>Fe76</td><td> 0,04</td><td> 0,02</td><td></td><td></td><td></td><td></td><td></td><td>RI</td><td> 2</td><td> -</td><td> 5</td>
<td>Fe77</td><td> 0,04</td><td> 0,02</td><td></td><td></td><td></td><td></td><td></td><td>RI</td><td> 3</td><td> -</td><td></td>
<td>Fe78</td><td> 0,04</td><td> 0,02</td><td></td><td></td><td></td><td></td><td></td><td>RI</td><td> 4</td><td> -</td><td></td>
<td>NFeCo35</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>RI</td><td> 1</td><td> -</td><td> 4</td>
<td>NFeCo38</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>RI</td><td> 2</td><td> -</td><td> 4</td>
<td>NFeCo38</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>RI</td><td> 3</td><td> -</td><td></td>
<td>NFeCo42</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>RI</td><td> 4</td><td> -</td><td></td>
<td>NFeCo44</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>RI</td><td> 5</td><td> -</td><td></td>
<td>NAMA06</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>ST</td><td> -</td><td> 4</td><td></td>
<td>NAMA06 602</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>ST</td><td> -</td><td> 5</td><td> 7</td>
<td>NAMA06 601</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>ST</td><td> -</td><td> 9</td><td> 8</td>
<td>NFeCo66</td><td> 0,04</td><td></td><td> 0,02</td><td></td><td></td><td></td><td></td><td>ST</td><td> -</td><td> 24</td><td> 9</td>
PTTIT 7001: BR semi-continuous CO substitution method
Microwave method: MO continuous process: RI growth method: ST * time in minutes (MO) or hours (ST)
TABLE 1 (b) Indirect synthesis of magnetic nanoparticles
<td>Pattern</td><td>Solvent</td><td>oxidizer</td><td>Time reaction</td><td>precursor</td><td></td><td>Described example</td>
<td>Fa59.1.1.1</td><td>CH3COOH</td><td> 02</td><td>2.5 hours</td><td>Fe74</td><td rowspan="5"></td><td> 12</td>
<td>Fe59.1.1.2</td><td>CH3COOH</td><td> 02</td><td>2.5 hours</td><td>Fe75</td><td></td>
<td>Fe59.1.1.4</td><td>CH3COOH</td><td> 02</td><td>2.5 hours</td><td>Fe76</td><td></td>
<td>Fe59.1.1.5</td><td>CH3COOH</td><td> 02</td><td>2.5 hours</td><td>Fe77</td><td></td>
<td>Fe59.1.1.3</td><td>CH3COOH</td><td> 02</td><td>2.5 hours</td><td>Fe78</td><td></td>
Example 13 (comparative) [0128] Functionalization of cobalt ferrite nanoparticles with palmitic acid according to the present invention.
Product pattern CoFe14 [0129]
Specification of reagents:
Palmitic acid MW = 256.42 g / mol
Et-OH MW = 4607 g / mol n - hexane MW = 86.17 g / mol
CoFe2O4 (: NFeCoCONT-03B3) MW = 234.62 g / mol
reagents:
[0130]
twenty g of a NAMA06 solution in DEG (3 wt.% Co Fe2O4
2.56 mmol
0.45 g palmitic acid 1.76 mmol g Et-OH
40 gn - hexane
Synthesis:
[0131] Ethanol and palmitic acid are placed in an Erlenmeyer flask with a magnetic stirrer. The flask is carefully heated with stirring on a hot plate to 45-50 ° C.
Stirring is continued until the palmitic acid is completely dissolved. A cobalt ferrite solution in the form of nanoparticles is added. The temperature is set to about 40 ° C.
The whole is stirred for 1 hour.
[0132] The contents are poured from an Erlenmeyer flask into a separating funnel and extraction with hexane is carried out. The non-polar phase is then washed twice with 40 ml dilute aqueous sodium bicarbonate solution (0.6 g in 100 ml water) and then with 40 ml water. The resulting organic phase is concentrated in vacuo to the desired volume.
Example 14 [0133] Functionalization of ethyl 12- (hydroxyamino) -12-oxododecanoate cobalt ferrite nanoparticles according to the present invention.
Product formula of CoFe38H [0134]
Specification of reagents:
Ethyl 12- (hydroxyamino) -12-oxododecanoate MW = 273.37 g / mol CoFe2O4 (: NFeCoCONT-03B3) MW = 234.62 g / mol
Butanol MW = 74.12
Water
reagents:
[0135] 60 g: a solution of NFeCoCONT-03B3 in DEG (3 wt% CoFe2O4) 7.67 mmol 0.90 g ethyl 12- (hydroxyamino) -12-oxododecanoate 3.29 mmol 120 g butanol
Synthesis:
[0136] 120 g of butanol and 0.60 g of ethyl 12- (hydroxyamino) -12-oxododecanoate are placed in a 500-ml flask (complete dissolution within a few minutes). 60 g of cobalt ferrite nanoparticle dispersion in glycol are added to this solution and mixed for 2 hours.
[0137] The sample was washed with 200 g water ( butanol / water-glycol biphasic system formed ) and the aqueous phase separated in a separatory funnel . The solid product was obtained by removing butanol in vacuo and then redisperse in acetone.
TABLE 1 (c) Functionalization of magnetic nanoparticles
<td>Pattern</td><td>Precursor</td><td>functionalization</td><td>SYNTHESIS</td><td>described example</td>
<td>Fe70.AK11</td><td>FE70</td><td>C16 phosphate</td><td>See application PCT PCT / EP2007 / 050036</td><td></td>
<td>Pattern</td><td>Precursor</td><td>functionalization</td><td>SYNTHESIS</td><td>described example</td>
<td>CoFe14</td><td>NFeCoCONT03B3</td><td>Palmitic acid</td><td>See application PCT PCT / EP2007 / 050036</td><td> 13</td>
<td>CoFe17</td><td>NAMA06</td><td>C16 phosphate</td><td>See application PCT PCT / EP2007 / 050036</td><td></td>
<td>CoFe170L</td><td>NAMA06</td><td>Oleic acid</td><td>See application PCT PCT / EP2007 / 050036</td><td></td>
<td>CoFe25</td><td>NAMA06</td><td>C12 Hydroksam.OH</td><td>See application PCT PCT / EP2007 / 050036</td><td></td>
<td>CoFe31</td><td>NAMA06</td><td>NHOHCOC12NH2</td><td>See application PCT PCT / EP2007 / 050036</td><td></td>
<td>CoFe38</td><td>NFeCoCONT03B1</td><td>NHOHCOC12COOR</td><td>See application PCT PCT / EP2007 / 050036</td><td></td>
<td>CoFe38H</td><td>NFeCoCONT03B3</td><td>NHOHCOC12COOR</td><td>See application PCT PCT / EP2007 / 050036</td><td> 14</td>
<td>CoFe8H</td><td>NFeKokos04B9</td><td>C16-hydroxyethyl.</td><td>See application PCT PCT / EP2007 / 050036</td><td></td>
<td>CoFe42ANF</td><td>NFeCo42</td><td>C16 phosphate</td><td>See application PCT PCT / EP2007 / 050036</td><td></td>
Example 15 [0138] Preparation of a construct consisting of: nanometric cobalt ferrite, PLGA and albumin according to the present invention.
<td>Product pattern:</td><td colspan="3">NBR1</td>
<td>reagents:</td><td>Quantity</td><td colspan="2">Molecular weight</td>
<td>Ultra-clean water</td><td>1000 ml</td><td> 18</td><td>d = 1.00 g / cm<sup>3</sup></td>
<td>Acetone</td><td>25 ml</td><td> 58,08</td><td>d = 0.79 g / cm<sup>3</sup></td>
<td>PLGA 75/25</td><td>0.05 g</td><td></td><td></td>
<td>Cofek</td><td>0.02 g</td><td></td><td></td>
<td>BSA Fraction V</td><td>1 g</td><td></td><td></td>
Synthesis:
[0139] A PLGA solution in acetone (0.05 gram in 25 ml acetone), a solution of BSA in ultra pure water (1 gram BSA in 1000 ml water) is pre-prepared. 0.4 ml of a 5% (w / v) CoFe38H suspension in acetone is added to the PLGA solution.
[0140] A double peristaltic pump is used to continuously add an acetone solution (containing PLGA and CoFe38H) in a BSA containing water stream (acetone / water ratio = 1/40). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions.
[0141] The pumping ratio of the two peristaltic pumps is set to 1/40, so that the two solutions are consumed at the same time. The final mixing product is collected in a graduated cylinder. The pumping speed is adjusted so that the mixing of solutions takes place within 10 minutes.
[0142] The resulting final solution is subjected to a vacuum treatment, so as to completely remove acetone. The resulting final solution is concentrated under high vacuum at T <45 ° C or by ultrafiltration until the desired concentration is reached.
Characterization of quantities using DLS:
[0143]
<td>A sample</td><td>Solvent</td><td>PDI</td><td>Average diameter</td><td>dilution</td>
<td>NBR1</td><td>Water solution</td><td> 0,16</td><td> 190</td><td> 7-380</td>
Example 16 [0144] Preparation of a construct comprising: nanometric cobalt ferrite, paclitaxel, PLGA and albumin according to the present invention.
Product pattern: NBR1 F1 [0145]
<td>reagents:</td><td>Quantity</td><td>Weight c</td><td>ząsteczkowa</td>
<td>Ultra-pure water</td><td>956 ml</td><td> 18</td><td>d = 1.00 g / cm<sup>3</sup></td>
<td>Acetone</td><td>104 ml</td><td> 58,08</td><td>d = 0.79 g / cm<sup>3</sup></td>
<td>PLGA 75/25</td><td>0.5 g</td><td></td><td></td>
<td>CoFe38H</td><td>0.2 g</td><td></td><td></td>
<td>BSA, Faction V</td><td>1 g</td><td></td><td></td>
<td>paclitaxel</td><td>10 mg</td><td> 853,91</td><td></td>
Synthesis:
[0146] A PLGA solution in acetone (0.5 gram in 100 ml acetone) and a solution of BSA in ultra pure water (1 gram BSA in 800 ml water) are pre-prepared. 10 mg of paclitaxel and 4 ml of a 5% (w / v) CoFe38H suspension in acetone are added to the PLGA solution in acetone.
[0147] A double peristaltic pump is used to continuously add an acetone solution (containing PLGA, CoFe38H and paclitaxel) in a water stream containing BSA (volume ratio acetone / water = 1/8). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions. The pumping ratio of the two peristaltic pumps is set to 1/8, so that the two solutions are consumed at the same time. The final mixing product is collected in a graduated cylinder. The pumping speed is adjusted so that the mixing of solutions takes place within
10 minutes.
[0148] The resulting final solution is subjected to a vacuum treatment so as to completely remove acetone.
[0149] The resulting final solution is concentrated under high vacuum at T <45 ° C or by ultrafiltration until the desired concentration is reached.
Example 17 [0150] Preparation of a construct comprising: nanometric cobalt ferrite, 9-nitrocamptothecin, PLGA and albumin, according to the present invention.
Product pattern: NBR1 F2 [0151]
<td>reagents:</td><td>Quantity</td><td>Molecular weight</td>
<td>Ultra pure water</td><td>1356 ml</td><td>18 d = 1.00 g / cm</td>
<td>Acetone</td><td>104 ml</td><td>58.08 d = 0.79 g / cm</td>
<td>PLGA 75/25</td><td>0.5 g</td><td></td>
<td>CoFe38H</td><td>0.2 g</td><td></td>
<td>BSA, Faction V</td><td>1 g</td><td></td>
<td>NaCl</td><td>14.4 g</td><td> 58,44</td>
<td>9-nitrocamptothecin</td><td>25 mg</td><td></td>
<td>Glutaraldehyde</td><td>1.56 mg</td><td> 100,1</td>
Synthesis:
[0152] A PLGA solution in acetone (0.5 gram in 100 ml acetone) and a solution of BSA in ultra pure water (1 gram BSA in 800 ml water) are pre-prepared. 25 mg of 9-nitrocamptothecin and 4 ml of a 5% (w / v) CoFe38H suspension in acetone are added to the PLGA solution in acetone.
[0153] A double peristaltic pump is used to continuously add acetone solution (containing PLGA, CoFe38H and 9-nitrocamptothecin) in a stream of water containing BSA (volume ratio acetone / water = 1/8). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions. The pumping ratio of the two peristaltic pumps is set to 1/8, so that the two solutions are consumed at the same time. The final mixing product is collected in a graduated cylinder, which already contains 400 ml of water containing 3.6% NaCl. The pumping speed is adjusted so that the solutions are mixed within 10 minutes.
[0154] The resulting final solution is subjected to a vacuum treatment so as to completely remove acetone.
[0155] Then 156 ml of an aqueous glutaraldehyde solution (10 mg / L glutaraldehyde concentration) are added and allowed to rest for 10 h.
[0156] The resulting final solution is concentrated under high vacuum at T <45 ° C or by ultrafiltration until the desired concentration is reached.
Example 18 (comparative) [0157] Preparation of a construct comprising nanometric cobalt ferrite and block polymer according to the present invention.
Product pattern: NBR2 [0158]
<td>reagents:</td><td>Quantity</td><td>Mass</td><td>Molecular</td>
<td>Ultra-clean water</td><td>400 ml</td><td> 18</td><td>d = 1.00 g / cm<sup>3</sup></td>
<td>Acetone</td><td>200 g</td><td> 58,08</td><td>d = 0.79 g / cm<sup>3</sup></td>
<td>CoFe38H</td><td>1 g</td><td></td><td></td>
<td>Pluronics F-68</td><td>5.6 g</td><td></td><td></td>
Synthesis:
[0159] A solution of CoFe38H in acetone (1 gram in 200 ml acetone) is pre-prepared. [0160] A double peristaltic pump is used to continuously add an acetone solution (containing CoFe38H) in a stream of water containing Pluronics F-68 (volume ratio acetone / water 1/2). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions. The pumping ratio of the two peristaltic pumps is adjusted to 1/2, so that the two solutions are consumed at the same time. The pumping speed is adjusted so that the solutions mix within 10 minutes.
[0161] The resulting final solution is subjected to a vacuum treatment so as to completely remove the acetone.
Characterization of quantities using DLS ::
[0162]
<td>A sample</td><td>Solvent</td><td>PDI</td><td>Average diameter</td><td>dilution</td>
<td>NBR2</td><td>Physiological solution</td><td> 0,15</td><td> 66</td><td> 7-240</td>
[0163] DLS confirms the stability of nanoparticles in aqueous solution and physiological solution.
[0164] Analysis of the raw image clearly shows dark cores of about 17-45 nm in the case of STEM, and separation layers with an average size of about 5-15 nm (surfactant layer) are clearly visible.
Example 19 [0165] Preparation of a construct comprising: nanometric cobalt ferrite, cis-diaminoplatin (II) dichloride, PLGA and albumin according to the present invention.
Product pattern: Product pattern: NBR1F3 [0166]
<td>reagents:</td><td>Quantity</td><td>Molecular weight</td>
<td>Ultra-clean water</td><td>1356 ml</td><td>18 d = 1.00 g / cm<sup>3</sup></td>
<td>Acetone</td><td>104 ml</td><td>58.08 d = 0.79 g / cm<sup>3</sup></td>
<td>PLGA 75/25</td><td>0.5 g</td><td></td>
<td>CoFe38H</td><td>0.2 g</td><td></td>
<td>BSA, fraction V</td><td>1 g</td><td></td>
<td>NaCl</td><td>14.4 g</td><td> 58,44</td>
<td>cis-diaminoplatin (II) dichloride</td><td>100 mg</td><td> 300,1</td>
Synthesis:
[0167]
Pre-prepared
PLGA solution in acetone (0.5 grams in 100 ml acetone);
BSA solution in ultra-pure water (1 gram BSA in 800 ml water);
A solution of NaCl in ultra-pure water (14.4 g of NaCl in 400 ml water) diaminoplatin (II) is dissolved in aqueous albumin.
[0169] A double peristaltic pump is used to continuously add an acetone solution (containing PLGA and CoFe38H) in a BSA containing water stream (acetone / water volume ratio = 1/8). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions.
[0170] The pumping ratio of the two peristaltic pumps is set to 1/8, so that the two solutions are consumed at the same time. The final mixing product is collected in a graduated cylinder, which already contains 400 ml of water containing 3.6% NaCl. The pumping speed is adjusted so that the solutions mix within 10 minutes.
[0171] The resulting final solution is concentrated under high vacuum at T <45 ° C or by ultrafiltration until the desired concentration is reached.
Example 20 [0172] Preparation of a construct containing nanometric cobalt ferrite, paclitaxel and block polymer.
Product pattern: NBR2F1 [0173]
<td>reagents:</td><td>Quantity</td><td>Mass</td><td>Molecular</td>
<td>Water</td><td>80 ml</td><td> 18</td><td>d = 1.00 g / cm<sup>3</sup></td>
<td>Acetone</td><td>40 g</td><td> 58,08</td><td>d = 0.79 g / cm<sup>3</sup></td>
<td>CoFe38H</td><td>0.2 g</td><td></td><td></td>
<td>Pluronics F-68</td><td>1.12 g</td><td></td><td></td>
<td>paclitaxel</td><td>10 mg</td><td> 853,9</td><td></td>
Synthesis:
[0174] A solution of CoFe38H in acetone (0.2 gram in 40 ml acetone) is pre-prepared and 25 mg of paclitaxel are dissolved in the mixture.
[0175] A double peristaltic pump is used to continuously add an acetone solution (containing CoFe38H and a drug) in a water stream containing Pluronics F43 (volume ratio acetone / water = 1/2). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions. The pumping ratio of the two peristaltic pumps is set to 1/2 so that the two solutions are consumed at the same time. The pumping speed is adjusted so that the solutions are mixed within 6 minutes.
[0176] The resulting final solution is subjected to a vacuum treatment so as to completely remove acetone.
Characterization of quantities using DLS:
[0177]
<td>A sample</td><td>Solvent</td><td>PDI</td><td>Average diameter</td><td>dilution</td>
<td>NBR2F1</td><td>Physiological solution</td><td> 0,12</td><td> 52</td><td> 7-310</td>
[0178] DLS confirms the stability of nanoparticles in aqueous solution and physiological solution.
Example 21 (comparative) [0179] Preparation of a construct comprising nanometric magnetite and water-soluble polyaminoamide polymer (BAC-EDDA) of formula (A) according to the present invention.
Product pattern: NBR4 [0180]
<td>reagents:</td><td>Quantity</td><td colspan="2">Molecular weight</td>
<td>Water</td><td>200 ml</td><td> 18</td><td>d = 1.00 g / cm<sup>3</sup></td>
<td>Diethylene glycol</td><td>40 g</td><td> 106,1</td><td>d = 1.12 g / cm<sup>3</sup></td>
<td>Fe77</td><td>0.2 g</td><td></td><td></td>
<td>BAC-EDDA polymer</td><td>1.12 g</td><td></td><td></td>
water-soluble "stealth" (shielding) polymer based on ethylenediamine diacetic acid Synthesis:
[0181]
A solution of magnetite in diethylene glycol (0.2 gram in 40 ml of solvent) is prepared;
solution of BAC-EDDA polymer in water (1.12 grams in 200 ml of solvent) [0182] A double peristaltic pump is used to continuously add an organic solution (containing magnetite) in a water stream containing the BACEDDA polymer (diethylene glycol / water volume ratio = 1/5). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions.
The pumping ratio of two peristaltic pumps is set to 1/5, so that two solutions are consumed at the same time. The pumping speed is adjusted so that the solutions mix within 12 minutes.
[0183] The resulting final solution is dialyzed against ultra pure water to remove most of the organic solvent to obtain a solution containing at most 0.1% of diethylene glycol.
Characterization of quantities using DLS:
[0184]
<td>A sample</td><td>Solvent</td><td>PDI</td><td>Average diameter</td><td>dilution</td>
<td>NBR4</td><td>Physiological solution</td><td> 0,19</td><td> 41</td><td> 7-340</td>
[0185] DLS confirms the stability of nanoparticles in aqueous solution and physiological solution.
Example 22 (comparative) [0186] Preparation of a construct comprising nanometric magnetite, water soluble polymer (BAC-EDDA) and cis-diaminoplatin (II) dichloride, according to the present invention.
Product pattern: NBR4F1 [0187]
<td>reagents:</td><td>Quantity</td><td>Mass</td><td>Molecular</td>
<td>Water</td><td>200 ml</td><td> 18</td><td>d = 1.00 g / cm<sup>3</sup></td>
<td>Diethylene glycol</td><td>40 g</td><td> 106,1</td><td>d = 1.12 g / cm<sup>3</sup></td>
<td>Fe77</td><td>0.2 g</td><td></td><td></td>
<td>BAC-EDDA polymer</td><td>1.12 g</td><td></td><td></td>
<td>Cis-diaminoplatin (II) dichloride</td><td>100 mg</td><td></td><td> 300,1</td>
• Water-soluble "stealth" polymer based on ethylenediamine diacetic acid
Synthesis:
[0188]
A solution of magnetite in diethylene glycol (0.2 gram in 40 ml of solvent) was prepared;
solution of BAC-EDDA polymer in water (1.12 grams in 200 ml of solvent) with
100 mg cis-diaminoplatin (II) dichloride [0189] A double peristaltic pump is used to continuously add an organic solution (containing magnetite) in a water stream containing the BACEDDA polymer and cis-diaminoplatin (II) dichloride (diethylene glycol / water volume ratio = 1 / 5). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions. The pumping ratio of two na10 peristaltic pumps is set to 1/5, so that two solutions are consumed at the same time. The pumping speed is adjusted so that the solutions mix within 8 minutes.
[0190] The resulting final solution is dialyzed against ultra pure water to remove most of the organic solvent to obtain a solution containing at most 0.1% of diethylene glycol.
Characterization of quantities using DLS:
[0191]
<td>A sample</td><td>Solvent</td><td>PDI</td><td>Average diameter</td><td>dilution</td>
<td>NBR3F1</td><td>Physiological solution</td><td> 0,14</td><td> 52</td><td> 7-320</td>
[0192] DLS confirms the stability of nanoparticles in aqueous solution and physiological solution.
Example 23 (comparative) [0193] Preparation of a construct comprising nanometric cobalt ferrite, PLGA and block polymer according to the present invention.
Product pattern: NBR32 [0194]
<td>reagents:</td><td>Quantity</td><td colspan="2">Molecular weight</td>
<td>Ultra-clean water</td><td>800 ml</td><td> 18</td><td>d = 1.00 g / cm<sup>3</sup></td>
<td>Acetone</td><td>20 g</td><td> 58,08</td><td>d = 0.79 g / cm<sup>3</sup></td>
<td>CoFe38H</td><td>0.02 g</td><td></td><td></td>
<td>PLGA</td><td>0.05 g</td><td></td><td></td>
<td>Pluronics F-68</td><td>0.8 g</td><td></td><td></td>
Synthesis:
[0195] A PLGA solution in acetone (0.05 gram in 20 ml acetone) is pre-prepared, a solution of Pluronic F-68 in ultra pure water (0.8 gram PLURONIC F-68 in 800 ml water).
0.4 ml of a 5% (w / v) CoFe38H suspension in acetone is added to the PLGA solution.
[0196] A double peristaltic pump is used to continuously add an acetone solution (containing PLGA and CoFe38H) in a stream of water containing PLURONIC F-68 (volume ratio acetone / water = 1/40). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions.
[0197] The pumping ratio of the two peristaltic pumps is set to 1/40 so that the two solutions are consumed at the same time. The final mixing product is collected in a graduated cylinder. The pumping speed is adjusted so that the solutions mix within 10 minutes.
[0198] The resulting final solution is subjected to a vacuum treatment so as to completely remove the acetone. The resulting final solution is concentrated under high vacuum at T <45 ° C or by ultrafiltration until the desired concentration is reached.
EXAMPLE 24 (comparative) [0199] Preparation of a construct comprising nanometric cobalt ferrite, PLGA and block polymer according to the present invention.
Product pattern: NBR5 [0200]
<td>reagents:</td><td>Quantity</td><td>Molecular weight</td>
<td>Ultra-clean water</td><td>800 ml</td><td>18 d = 1.00 g / cm<sup>3</sup></td>
<td>Ethanol</td><td>20 g</td><td></td>
<td>CoFe38H</td><td>0.02 g</td><td></td>
<td>cholesterol</td><td>0.05 g</td><td></td>
<td>Pluronics F-68</td><td>0.8 g</td><td></td>
Synthesis:
[0201] A solution of cholesterol in ethanol (0.05 grams in 20 ml of acetone), a solution of Pluronic F-68 in ultrapure water (0.8 grams of PLURONIC F-68 in 800 ml of water) is pre-prepared. 0.4 ml of a 5% (w / v) CoFe38H suspension in acetone is added to the cholesterol solution.
[0202] A double peristaltic pump is used to continuously add an acetone solution (containing cholesterol and CoFe38H) in a stream of water containing
PLURONIC F-68 (volume ratio acetone / water = 1/40). Appropriate submerged tubes allow direct suction of the solution from tanks containing two solutions.
[0203] The pumping ratio of the two peristaltic pumps is set to 1/40 so that the two solutions are consumed at the same time. The final mixing product is collected in a graduated cylinder. The pumping speed is adjusted so that the solutions mix within 10 minutes.
[0204] The resulting final solution is subjected to a vacuum treatment so as to completely remove the acetone. The resulting final solution is concentrated under high vacuum at T <45 ° C or by ultrafiltration until the desired concentration is reached. In addition, for completeness, the following are examples of making certain polymers useful in the context of the invention as stated above.
<td colspan="8">TABLE 1 (d) CONSTRUCTIONS</td>
<td>Pattern</td><td>Precursor</td><td>Metal oxide coating</td><td>Polymer</td><td>Surface measure</td><td>Bow</td><td>described example</td><td></td>
<td>NBR1</td><td>CoFe38H</td><td>NHOHCOC12COOR</td><td>PLGA</td><td>BSA</td><td>lack</td><td> 15</td><td></td>
<td>NBR2</td><td>CoFe38H</td><td>NHOHCOC12COOR</td><td>Pluronic</td><td>lack</td><td>lack</td><td> 18</td><td><sub>*</sub></td>
<td>NBR3</td><td>Fe77</td><td>lack</td><td>Polymer BACEDDA</td><td>lack</td><td>lack</td><td> 21</td><td><sub>*</sub></td>
<td>NBRF1</td><td>CoFe38H</td><td>NHOHCOC12COOR</td><td>PLGA</td><td>BSA</td><td>paclitaxel</td><td> 16</td><td></td>
<td>NBRF2</td><td>CoFe38N</td><td>NHOHCOC12COOR</td><td>PLGA</td><td>BSA</td><td>9-nitrocamptothecin</td><td> 17</td><td></td>
<td>NBRF3</td><td>CoFe38H</td><td>NHOHCOC12COOR</td><td>PLGA</td><td>BSA</td><td>Cis-diaminoplatin (II) dichloride</td><td> 19</td><td></td>
<td>NBRF4</td><td>CoFe38H</td><td>NHOHCOC12COOR</td><td>Pluronic</td><td>lack</td><td>paclitaxel</td><td> 20</td><td><sub>*</sub></td>
<td>NBRF5</td><td>Fe77</td><td>lack</td><td>Polymer BACEDDA</td><td>lack</td><td>Cis-diaminoplatin (II) dichloride</td><td> 22</td><td><sub>*</sub></td>
<td colspan="8">TABLE 1 (d) CONSTRUCTIONS</td>
<td>Pattern</td><td>Precursor</td><td>Metal oxide coating</td><td>Polymer</td><td>Surface measure</td><td>Bow</td><td>described example</td><td></td>
<td colspan="8">* comparative examples</td>
Table 2 (Particle Size)
<td>Pattern</td><td>Oxide</td><td>Synthesis</td><td>Particle size (nm)</td><td>PDI</td>
<td>Fe59.1.1.1</td><td>Maghemit</td><td>OX</td><td> 5,73</td><td> 0,25</td>
<td>Fe59.1.1.2</td><td>Maghemit</td><td>OX</td><td> 7,53</td><td> 0,13</td>
<td>Fe59.1.1.3</td><td>Maghemit</td><td>OX</td><td> 19,2</td><td> 0,18</td>
<td>Fe59.1.1.4</td><td>Maghemit</td><td>OX</td><td> 9,72</td><td> 0,21</td>
<td>Fe59.1.1.5</td><td>Maghemit</td><td>OX</td><td> 14,1</td><td> 0,19</td>
<td>Fe Do Co 01</td><td>Magnetite (doped with Co)</td><td>BR</td><td> 38,6</td><td> 0,21</td>
<td>Fe Do Cr 01</td><td>Magnetite (Cr doped)</td><td>BR</td><td> 40</td><td> 0,19</td>
<td>Fe Do Mn 01</td><td>Magnetite (doped with Mn)</td><td>BR</td><td> 39,8</td><td> 0,14</td>
<td>Fe Do Ni 01</td><td>Magnetite (doped with Ni)</td><td>BR</td><td> 36,9</td><td> 0,22</td>
<td>Fe Do Ni 03</td><td>Magnetite (doped with Ni)</td><td>BR</td><td> 40</td><td> 0,18</td>
<td>Fe Do Zn 01</td><td>Magnetite (doped with Zn)</td><td>BR</td><td> 43,2</td><td> 0,18.</td>
<td>Fe74</td><td>Magnetite</td><td>BR</td><td> 40,3</td><td> 0,22</td>
<td>NFeCo31</td><td>Cobalt ferrite</td><td>BR</td><td> 7,46</td><td> 0,18</td>
<td>NFeNiO3</td><td>Nickel ferrite</td><td>BR</td><td> 9,7</td><td> 0,25</td>
<td>NFeCoCONT-03B1</td><td>Cobalt ferrite</td><td>WHAT</td><td> 9,2</td><td> 0,18</td>
<td>NFeCoCONT-03B2</td><td>Cobalt ferrite</td><td>WHAT</td><td> 11,5</td><td> 0,16</td>
<td>NFeCoCONT-03B3</td><td>Cobalt ferrite</td><td>WHAT</td><td> 14,63</td><td> 0,13</td>
<td>NfeCocont-04B9</td><td>Cobalt ferrite</td><td>WHAT</td><td> 36</td><td> 0,14</td>
<td>NFeCoMW01</td><td>Cobalt ferrite</td><td>MO</td><td> 90</td><td> 0,21</td>
<td>NFeCoMW02</td><td>Cobalt ferrite</td><td>MO</td><td> 100</td><td> 0,18</td>
<td>NFeCoMW03</td><td>Cobalt ferrite</td><td>MO</td><td> 28</td><td> 0,43</td>
<td>Pattern</td><td>Oxide</td><td>Synthesis</td><td>Particle size (nm)</td><td>PDI</td>
<td>NFeCoMW04</td><td>Cobalt ferrite</td><td>MO</td><td> 87</td><td> 0,22</td>
<td>NFeCoMW05</td><td>Cobalt ferrite</td><td>MO</td><td> 101</td><td> 0,27</td>
<td>NFeCoMW06</td><td>Cobalt ferrite</td><td>MO</td><td> 80</td><td> 0,19</td>
<td>Fe Do Co 02</td><td>Magnetite (doped with Co)</td><td>RI</td><td> 41,2</td><td> 0,18</td>
<td>Fe Do Co 03</td><td>Magnetite (doped with Co)</td><td>RI</td><td> 40,6</td><td> 0,23</td>
<td>Fe Do Cr 02</td><td>Magnetite (Cr doped)</td><td>RI</td><td> 40,9</td><td> 0,26</td>
<td>Fe Do Cr 03</td><td>Magnetite (Cr doped)</td><td>RI</td><td> 41,2</td><td> 0,19</td>
<td>Fe Do Mn 02</td><td>Magnetite (doped with Mn)</td><td>RI</td><td> 42,6</td><td> 0,16</td>
<td>Fe Do Mn 03</td><td>Magnetite (doped with Mn)</td><td>RI</td><td> 41,1</td><td> 0,16</td>
<td>Fe Do Ni 02</td><td>Magnetite (doped with Ni)</td><td>RI</td><td> 39,6</td><td> 0,19</td>
<td>Fe Do Zn 02</td><td>Magnetite (doped with Zn)</td><td>RI</td><td> 42,6</td><td> 0,23</td>
<td>Fe Do Zn 03</td><td>Magnetite (doped with Zn)</td><td>RI</td><td> 43,2</td><td> 0,2</td>
<td>Fe70</td><td>Magnetite</td><td>RI</td><td> 68,8</td><td> 0,13</td>
<td>Fe75</td><td>Magnetite</td><td>RI</td><td> 32,7</td><td> 0,2</td>
<td>Fe76</td><td>Magnetite</td><td>RI</td><td> 37,8</td><td> 0,19</td>
<td>Fe77</td><td>Magnetite</td><td>RI</td><td> 43,8</td><td> 0,16</td>
<td>Fe78</td><td>Magnetite</td><td>RI</td><td> 57,8</td><td> 0,23</td>
<td>NFeCo35</td><td>Cobalt ferrite</td><td>RI</td><td> 9,09</td><td> 0,13</td>
<td>NFeCo36</td><td>Cobalt ferrite</td><td>RI</td><td> 11,2</td><td> 0,2</td>
<td>NFeCo38</td><td>Cobalt ferrite</td><td>RI</td><td> 13,36</td><td> 0,09</td>
<td>NFeCo42</td><td>Cobalt ferrite</td><td>RI</td><td> 16</td><td> 0,11</td>
<td>NFeCo44</td><td>Cobalt ferrite</td><td>RI</td><td> 22</td><td> 0,06</td>
<td>NAMA06</td><td>Cobalt ferrite</td><td>ST</td><td> 16</td><td> 0,19</td>
<td>NAMA06 602</td><td>Cobalt ferrite</td><td>ST</td><td> 18,94</td><td> 0,13</td>
<td>NAMA06 601</td><td>Cobalt ferrite</td><td>ST</td><td> 33</td><td> 0,16</td>
<td>NFeCo66</td><td>Cobalt ferrite</td><td>ST</td><td> 137,87</td><td> 0,18</td>
Table 3 (hyperthermic effect of non-functionalized nanoparticles)
<td>Pattern</td><td>Oxide</td><td>Synthesis</td><td>Particle size (nm)</td><td>Hyperthermic effect (° C)</td>
<td>Fe59.1.1.1</td><td>Maghemit</td><td>OX</td><td> 5,73</td><td> 0,3</td>
<td>Fe59.1.1.2</td><td>Maghemit</td><td>OX</td><td> 7,53</td><td> 3,6</td>
<td>Fe59.1.1.3</td><td>Maghemit</td><td>OX</td><td> 19,2</td><td> 5,8</td>
<td>Fe59.1.1.4</td><td>Maghemit</td><td>OX</td><td> 9,72</td><td> 3,7</td>
<td>Fe59.1.1.5</td><td>Maghemit</td><td>OX</td><td> 14,1</td><td> 4,6</td>
<td>Fe Do Co 01</td><td>Magnetite (doped with Co)</td><td>BR</td><td> 38,6</td><td> 1,8</td>
<td>Fe Do Cr 01</td><td>Magnetite (Cr doped)</td><td>BR</td><td> 40</td><td> 2</td>
<td>Fe Do Mn 01</td><td>Magnetite (doped with Mn)</td><td>BR</td><td> 39,8</td><td> 1,3</td>
<td>Fe Do Ni 01</td><td>Magnetite (doped with Ni)</td><td>BR</td><td> 36,9</td><td> 1,6</td>
<td>Fe Do Ni 03</td><td>Magnetite (doped with Ni)</td><td>BR</td><td> 40</td><td> 0,9</td>
<td>Fe Do Zn 01</td><td>Magnetite (doped with Zn)</td><td>BR</td><td> 43,2</td><td> 1,4</td>
<td>Fe74</td><td>Magnetite</td><td>BR</td><td> 40,3</td><td> 7</td>
<td>NFeCo31</td><td>Cobalt ferrite</td><td>BR</td><td> 7,46</td><td> 2,2</td>
<td>NFeNi03</td><td>Nickel ferrite</td><td>BR</td><td> 9,7</td><td> 0,2</td>
<td>NFeCoCONT03B1</td><td>Cobalt ferrite</td><td>WHAT</td><td> 9,2</td><td> 5,3</td>
<td>NFeCoCONT03B2</td><td>Cobalt ferrite</td><td>WHAT</td><td> 11,5</td><td> 13,1</td>
<td>NFeCoCONT03B3</td><td>Cobalt ferrite</td><td>WHAT</td><td> 14,63</td><td> 30,2</td>
<td>NfeCocont-04B9</td><td>Cobalt ferrite</td><td>WHAT</td><td> 36</td><td> 41,4</td>
<td>NFeCoMW01</td><td>Cobalt ferrite</td><td>MO</td><td> 90</td><td> 7,7</td>
<td>Pattern</td><td>Oxide</td><td>Synthesis</td><td>Particle size (nm)</td><td>Hyperthermic effect (° C)</td>
<td>NFeCoMW02</td><td>Cobalt ferrite</td><td>MO</td><td> 100</td><td> 8,1</td>
<td>NFeCoMW03</td><td>Cobalt ferrite</td><td>MO</td><td> 28</td><td> 1,2</td>
<td>NFeCoMW04</td><td>Cobalt ferrite</td><td>MO</td><td> 87</td><td> 3,9</td>
<td>NFeCoMW05</td><td>Cobalt ferrite</td><td>MO</td><td> 101</td><td> 7,9</td>
<td>NFeCoMW06</td><td>Cobalt ferrite</td><td>MO</td><td> 80</td><td> 3,7</td>
<td>Fe Do Co 02</td><td>Magnetite (doped with Co)</td><td>RI</td><td> 41,2</td><td> 1,6</td>
<td>Fe Do Co 03</td><td>Magnetite (doped with Co)</td><td>RI</td><td> 40,6</td><td> 1,9</td>
<td>Fe Do Cr 02</td><td>Magnetite (Cr doped)</td><td>RI</td><td> 40,9</td><td> 1,8</td>
<td>Fe Do Cr 03</td><td>Magnetite (Cr doped)</td><td>RI</td><td> 41,2</td><td> 2,3</td>
<td>Fe Do Mn 02</td><td>Magnetite (doped with Mn)</td><td>RI</td><td> 42,6</td><td> 0,9</td>
<td>Fe Do Mn 03</td><td>Magnetite (doped with Mn)</td><td>RI</td><td> 41,1</td><td> 1,1</td>
<td>Fe Do Ni 02</td><td>Magnetite (doped with Ni)</td><td>RI</td><td> 39,6</td><td> 2,1</td>
<td>Fe Do Zn 02</td><td>Magnetite (doped with Zn)</td><td>RI</td><td> 42,6</td><td> 2,1</td>
<td>Fe Do Zn 03</td><td>Magnetite (doped with Zn)</td><td>RI</td><td> 43,2</td><td> 2</td>
<td>Fe70</td><td>Magnetite</td><td>RI</td><td> 68,8</td><td> 3,1</td>
<td>Fe75</td><td>Magnetite</td><td>RI</td><td> 32,7</td><td> 4,5</td>
<td>Fe76</td><td>Magnetite</td><td>RI</td><td> 37,8</td><td> 12,2</td>
<td>Fe77</td><td>Magnetite</td><td>RI</td><td> 43,8</td><td> 10,1</td>
<td>Fe78</td><td>Magnetite</td><td>RI</td><td> 57,8</td><td> 14,5</td>
<td>NFeCo35</td><td>Cobalt ferrite</td><td>RI</td><td> 9,09</td><td> 4,3</td>
<td>Pattern</td><td>Oxide</td><td>Synthesis</td><td>Particle size (nm)</td><td>Hyperthermic effect (° C)</td>
<td>NFeCo36</td><td>Cobalt ferrite</td><td>RI</td><td> 11,2</td><td> 11,2</td>
<td>NFeCo38</td><td>Cobalt ferrite</td><td>RI</td><td> 13,36</td><td> 21,8</td>
<td>NFeCo42</td><td>Cobalt ferrite</td><td>RI</td><td> 16</td><td> 49,6</td>
<td>NFeCo44.</td><td>Cobalt ferrite</td><td>RI</td><td> 22</td><td> 64,1</td>
<td>NAMA06</td><td>Cobalt ferrite</td><td>ST</td><td> 16</td><td> 9,3</td>
<td>NAMA06 602</td><td>Cobalt ferrite</td><td>ST</td><td> 18,94</td><td> 13,3</td>
<td>NAMA06 601</td><td>Cobalt ferrite</td><td>ST</td><td> 33</td><td> 20</td>
<td>NFeCo66</td><td>Cobalt ferrite</td><td>ST</td><td> 137,87</td><td> 1</td>
Table 4 (hyperthermic effect of functionalized particles and constructs)
<td>Product pattern</td><td>Precursor</td><td>Oxide</td><td>Functionalization of particles</td><td>Polymer</td><td>Surface measure</td><td>Bow</td><td>Center dispersant</td><td>Conc. in oxide metal (%)</td><td>Precursor hyperthermia (normalized to 1%)</td><td>Product hyperthermia (normalized to 1%)</td><td></td>
<td>CoFe14</td><td>NFeCoCONT03B3</td><td>Ferrite cobaltic</td><td>Palmitic acid</td><td>lack</td><td>lack</td><td>lack</td><td>hexane</td><td> 0,5</td><td> 10,07</td><td> 12,80</td><td rowspan="6"></td>
<td>CoFe17</td><td>NAMA06</td><td>Ferrite cobaltic</td><td>C16 phosphate</td><td>lack</td><td>lack</td><td>lack</td><td>hexane</td><td> 1,5</td><td> 3,10</td><td> 4,93</td>
<td>CoFe17</td><td>NAMA06</td><td>Ferrite cobaltic</td><td>C16 phosphate</td><td>lack</td><td>lack</td><td>lack</td><td>paraffin</td><td> 1,5</td><td> 3,10</td><td> 3,47</td>
<td>CoFe17OL</td><td>NAMA06</td><td>Ferrite cobaltic</td><td>Oleic acid</td><td>lack</td><td>lack</td><td>lack</td><td>hexane</td><td> 0,5</td><td> 3,10</td><td> 4,60</td>
<td>CoFe25</td><td>NAMA06</td><td>Ferrite cobaltic</td><td>C12Hydroksyam.OH</td><td>lack</td><td>lack</td><td>lack</td><td>paraffin</td><td> 1,5</td><td> 3,10</td><td> 3,13</td>
<td>CoFe31</td><td>NAMA06</td><td>Ferrite</td><td>NHOHCOC1</td><td>lack</td><td>lack</td><td>lack</td><td>Water</td><td> 0,5</td><td> 3,10</td><td> 1,00</td>
<td>Product pattern</td><td>Precursor</td><td>Oxide</td><td>Functionalization of particles</td><td>Polymer</td><td>Surface measure</td><td>Bow</td><td>Center dispersant</td><td>Conc. in oxide metal (%)</td><td>Precursor hyperthermia (normalized to 1%)</td><td>Product hyperthermia (normalized to 1%)</td><td rowspan="3"></td>
<td></td><td></td><td>cobaltic</td><td>2-NH2</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>CoFe31</td><td>NAMA06</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-NH2</td><td>lack</td><td>lack</td><td>lack</td><td>DEG</td><td> 1,5</td><td> 3,10</td><td> 2,80</td>
<td>CoFe38</td><td>NFeCoCONT03B1</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-COOR</td><td>lack</td><td>lack</td><td>lack</td><td>butanol</td><td> 1,5</td><td> 1,77</td><td> 1,33</td><td rowspan="5"></td>
<td>CoFe38H</td><td>NFeCoCONT03B3</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-COOR</td><td>lack</td><td>lack</td><td>lack</td><td>acetone</td><td> 3</td><td> 10,07</td><td> 11,07</td>
<td>CoFe38H</td><td>NFeCoCONT03B3</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-COOR</td><td>lack</td><td>lack</td><td>lack</td><td>DEG</td><td> 3</td><td> 10,07</td><td> 10,47</td>
<td>CoFe42ANF</td><td>NFeCo42</td><td>Ferrite cobaltic</td><td>C16 phosphate</td><td>lack</td><td>lack</td><td>lack</td><td>hexane</td><td> 1</td><td> 16,53</td><td> 35,20</td>
<td>CoFe42ANF</td><td>NFeCo42</td><td>Ferrite cobalt</td><td>C16 phosphate</td><td>lack</td><td>lack</td><td>lack</td><td>paraffin</td><td> 1</td><td> 16,53</td><td> 21,80</td>
<td>Product pattern</td><td>Precursor</td><td>Oxide</td><td>Functionalization of particles</td><td>Polymer</td><td>Surface measure</td><td>Bow</td><td>Center dispersant</td><td>Conc. in oxide metal (%)</td><td>Precursor hyperthermia (normalized to 1%)</td><td>Product hyperthermia (normalized to 1%)</td><td rowspan="5"></td>
<td></td><td></td><td>thats you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>CoFe8H</td><td>NFe-kokos04B9</td><td>Ferrite cobaltic</td><td>C16hydroksyam.</td><td>lack</td><td>lack</td><td>lack</td><td>CHCl3</td><td> 0,5</td><td> 13,80</td><td> 25,20</td>
<td>Fe70.AK1 1</td><td>FE70</td><td>Magnetite</td><td>C16 phosphate</td><td>lack</td><td>lack</td><td>lack</td><td>hexane</td><td> 1,5</td><td> 1,03</td><td> 2,07</td>
<td>Fe70.AK.1</td><td>FE70</td><td>Magnetite</td><td>C16 phosphate</td><td>lack</td><td>lack</td><td>lack</td><td>paraffin</td><td> 1,5</td><td> 1,03</td><td> 0,20</td>
<td>NBR1</td><td>CoFe38H</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-COOR</td><td>PLGA</td><td>BSA</td><td>lack</td><td>Water</td><td> 0,20</td><td> 10,47</td><td> 10,00</td><td></td>
<td>NBR2</td><td>CoFe38H</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-COOR</td><td>Pluronic</td><td>lack</td><td>lack</td><td>Water</td><td> 0,35</td><td> 10,47</td><td> 10,00</td><td><sub>*</sub></td>
<td>NOR3</td><td>Fe77</td><td>Magnetite</td><td>lack</td><td>Polymer BACEDDA</td><td>lack</td><td>lack</td><td>Water</td><td> 0,51</td><td> 5,05</td><td> 4,51</td><td><sub>*</sub></td>
<td>Product pattern</td><td>Precursor</td><td>Oxide</td><td>Functionalization of particles</td><td>Polymer</td><td>Surface measure</td><td>Bow</td><td>Center dispersant</td><td>Conc. in oxide metal (%)</td><td>Precursor hyperthermia (normalized to 1%)</td><td>Product hyperthermia (normalized to 1%)</td><td></td>
<td>NBRF1</td><td>CoFe38H</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-COOR</td><td>PLGA</td><td>BSA</td><td>paclitaxel</td><td>Water</td><td> 0,20</td><td> 10,47</td><td> 9,50</td><td></td>
<td>NBRF2</td><td>CoFe38H</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-COOR</td><td>PLGA</td><td>BSA</td><td>9-nitrocamptothecin</td><td>Water</td><td> 0,26</td><td> 10,47</td><td> 9,23</td><td></td>
<td>NBRF3</td><td>CoFe38H</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-COOR</td><td>PLGA</td><td>BSA</td><td>Cisdiaminoplatin (II) dichloride</td><td>Water</td><td> 0,52</td><td> 10,47</td><td> 10,00</td><td></td>
<td>NBRF4</td><td>CoFe38H</td><td>Ferrite cobaltic</td><td>NHOHCOC1 2-COOR</td><td>Pluronic</td><td>lack</td><td>paclitaxel</td><td>Water</td><td> 0,31</td><td> 10,47</td><td> 10,00</td><td><sub>*</sub></td>
<td>NBRF5</td><td>Fe77</td><td>Magnetite</td><td>lack</td><td>Polymer BACEDDA</td><td>lack</td><td>Cisdiaminoplatin (II) dichloride</td><td>Water</td><td> 0,36</td><td> 5,05</td><td> 3,89</td><td><sub>*</sub></td>
<td colspan="12">* comparative examples</td>
[0205] All measurements were made at irradiation at 170 KHz at a magnetic field strength of 21 KA / m<sup>2</sup> for 30 seconds
Contents7
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Titles2
- English
- MAGNETIC NANOPARTICLES FOR THE APPLICATION IN HYPERTHERMIA, PREPARATION THEREOF AND USE IN CONSTRUCTS HAVING A PHARMACOLOGICAL APPLICATION
- Polish
- Magnetyczne nanocząsteczki do stosowania w hipertermii, ich wytwarzanie i zastosowanie w konstruktach o zastosowaniu farmakologicznym
Classification
- CPC, 27
- A61K41/0052
- A61K47/50
- A61K9/1647
- A61K9/5094
- A61K9/5153
- A61K9/5169
- A61K47/59
- A61K47/6923
- A61K47/6929
- A61K47/6951
- B82Y5/00
- B82Y25/00
- B82Y30/00
- C01G49/0018
- C01G49/0063
- C01G49/0072
- C01P2002/32
- C01P2004/64
- C01P2006/42
- C09C1/24
- H01F1/0054
- H01F1/344
- C01G53/82
- C01G51/82
- A61K9/16
- A61K49/00
- A61K51/06
- IPC, 10
- A61K47 48
- A61K9 00
- A61K9 127
- A61K41 00
- A61K49 00
- A61K51 06
- C01G49 00
- C01G49 08
- C01G51 00
- C09C1 24