CN100355418C - Magnetic nano-balls carried with cisplatin and its prepn. method - Google Patents
Magnetic nano-balls carried with cisplatin and its prepn. method Download PDFInfo
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- CN100355418C CN100355418C CNB2005101002768A CN200510100276A CN100355418C CN 100355418 C CN100355418 C CN 100355418C CN B2005101002768 A CNB2005101002768 A CN B2005101002768A CN 200510100276 A CN200510100276 A CN 200510100276A CN 100355418 C CN100355418 C CN 100355418C
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Abstract
The present invention relates to a carrying cisplatin medicine-carrying nanometer ball and a preparation method thereof. The aim of the present invention is to overcome defects existing in the prior art and provide the carrying cisplatin medicine-carrying nanometer ball with magnetic targeting performance and the preparation method thereof. The present invention uses a chemical coprecipitation method to prepare modification nanometer ferroferric oxide granules with carboxyl group polysaccharides; then, free carboxyl groups in the carboxyl group polysaccharides at the surfaces of the nanometer ferroferric oxide granules and platinum atoms form coordination to realize the connection of the cisplatin and the nanometer ferroferric oxide granules, so that carrying cisplatin nanometer balls are obtained. The carrying cisplatin medicine-carrying nanometer ball prepared by the present invention has the advantages of average diameter of less than 100 nm, strong magnetic response performance, capability of stably dispersing in blood serums, probability of being applied to a sustained-release medication system and capability of realizing the magnetic targeting chemotherapy of malignant tumor and heat treatment in magnetic liquid cells.
Description
Technical field
The present invention relates to field of nanometer technology, be specifically related to a kind of year cisplatin nano ball and preparation method thereof.
Background technology
Cisplatin (Cis-dichlorodiamine platinum) is a Cell cycle non-specific high efficiency anti-tumor medicine the most commonly used clinically, can be used for treating ovarian cancer, carcinoma of testis, bladder cancer, gastroenteric tumor, especially tumor of head and neck, thus its anticancer mechanism mainly be by between the DNA or DNA suppress duplicating of DNA with forming cross-linking agent between the protein.Yet also have a lot of problems based on the chemotherapy of cisplatin: 1. the cisplatin molecular weight is low, in blood circulation the transhipment too fast, can not well bring into play antitumaous effect; 2. intravenously administrable, systemic chemotherapy, toxic and side effects is big; 3. after the long-term chemotherapy, easily cause the body drug resistance.In order to improve drug level in the tumor tissues, to reduce the infringement of medicine to normal structure, improve therapeutic effect, carried out much researchs about pharmaceutical carrier and targeted chemotherapy.At present research is more liposome, polymer, polysaccharide etc., the release of these carrier may command medicines, but do not possess targeting.
Summary of the invention
The objective of the invention is to overcome the shortcoming that exists in the existing cisplatin medicine treatment, a kind of magnetic nano-balls carried with cisplatin is provided.
Another object of the present invention provides the preparation method of above-mentioned magnetic nano-balls carried with cisplatin.
Magnetic nano-balls carried with cisplatin of the present invention, mainly form by nano ferriferrous oxide granule, carboxylated polysaccharide and cisplatin, nano ferriferrous oxide granule surface adsorption carboxylated polysaccharide, free carboxyl group in the carboxylated polysaccharide combines with coordinate bond with cisplatin, nano ferriferrous oxide granule: carboxylated polysaccharide: the mass ratio of cisplatin=1: 3～7: 0.1～1.The average diameter of nano ferriferrous oxide granule is about 6～10 nanometers.The carboxylated polysaccharide that is adopted is a kind of in the alkali metal salt of alginic acid or alginic acid, also can be Sensor Chip CM 5.The weight average molecular weight of general carboxylated polysaccharide is between 0.5～50,000, and is best between 0.8～1.5 ten thousand.If the weight average molecular weight of carboxylated polysaccharide is too little, carboxylated polysaccharide is little in the adsorbance on nano ferriferrous oxide granule surface, and the steric hindrance of formation is less, is unfavorable for the stable of nano-particle; If the weight average molecular weight of carboxylated polysaccharide is too big, then make the modified particles coagulation by the bridging effect easily.
The present invention adopts chemical coprecipitation to prepare carboxylated polysaccharide modified Nano ferriferrous oxide particles in the presence of carboxylated polysaccharide, realize the coupling connection of cisplatin and nano magnetic particle then by the coordination of free carboxyl group in the carboxylated polysaccharide and pt atom, obtain magnetic nano-balls carried with cisplatin.The chemical equation that chemical coprecipitation prepares ferroso-ferric oxide is:
FeSO
47H
2O+2FeCl
36H
2O+8NH
4OH=Fe
3O
4+ NH
4Cl+ (NH
4)
2SO
4+ 23H
2O or FeCl
24H
2O+2FeCl
36H
2O+8NH
1OH=Fe
3O
4+ 8NH
4Cl+20H
2The chemical equation of free carboxyl group is in O cisplatin and the polysaccharide chain:
The preparation method of magnetic nano-balls carried with cisplatin of the present invention is as follows:
1. there is synthesis of nano ferriferrous oxide particles down in carboxylated polysaccharide:
With Fe
2+, Fe
3+Be 1.0～1.4 in molar ratio: 2 are mixed with mixed solution; The mixed liquor that adds ammonia and carboxylated polysaccharide then, ammonia: Fe
3+Mol ratio be 12～40: 1, carboxylated polysaccharide to the mass ratio of synthetic ferroso-ferric oxide be 2～5: 1; Under agitation reacted 40～60 minutes, mixing speed is controlled at 800～1000 rev/mins, and reaction temperature is controlled between 85～95 ℃, obtains containing unstable oarse-grained water base Fe 3 O 4 magnetic liquid.
2. unsettled bulky grain is removed in centrifugalize:
With centrifuge prepared water base Fe 3 O 4 magnetic liquid is made centrifugal treating, remove sedimentary bulky grain, collect the supernatant, be stable water-base magnetic liquid.
3. free carboxylated polysaccharide and other electrolyte in the water-base magnetic liquid are removed in ultrafiltration:
Adopt ultrafiltration apparatus that water-base magnetic liquid is carried out the cyclic washing ultrafiltration, drop to below the 1000us/cm, obtain carboxylated polysaccharide modified Nano ferriferrous oxide particles magnetic liquid up to the electrical conductivity that leaches cleaning mixture.
4. the coupling of carboxylated polysaccharide modified Nano ferriferrous oxide particles and cisplatin joins:
Cisplatin is mixed with carboxylated polysaccharide modified Nano ferriferrous oxide particles water-base magnetic liquid (carboxylated polysaccharide modified Nano ferriferrous oxide particles wherein: the mass ratio of cisplatin is 3～30: 1), under 25～45 ℃ of conditions, reacted 24～48 hours, at last reactant liquor is dialysed in distilled water and remove free cisplatin, obtain magnetic nano-balls carried with cisplatin.
The 1. described ammonia volume of step, i.e. ammonia: both mol ratios of ferric chloride should be controlled at 12～40: 1, are stabilized between 8～9.5 with the pH value that guarantees reaction system, guarantee the formation of ferroso-ferric oxide nucleus.
Above-mentioned preparation method step 4. in water-base magnetic liquid contain concentration of iron between 2～15mg/ml, the concentration of magnetic liquid is too low, is unfavorable for the carrying out of coupled reaction, if concentration is too high, nano-particle is assembled easily and is separated out or form gel.The reaction mass proportioning of carboxylated polysaccharide modified Nano ferriferrous oxide particles and cisplatin is 3～30: 1, if reaction ratio is too big, the drug loading of unit grain is with too small, if reaction ratio is too little, the medicine carrying granule stability is relatively poor.Reaction temperature is between 25～45 ℃, and reaction temperature is low, and then reaction rate is low, and the required response time is just longer, and reaction temperature is too high, and the degree of coupled reaction can reduce, and most preferred reaction temperature is 37 ℃.
Magnetic nano-balls carried with cisplatin not only has slow releasing function, can also realize the magnetic target administration by near the magnetic field that certain intensity is set tumor tissues; In addition, behind the tumor cell picked-up magnetic-particle, because magnetic grain radio transparent not can obviously strengthen radiotherapeutic effect; And can corresponding orientation movement take place and heat production by applying alternating magnetic field, make the magnetic nano-balls that enters in the cancerous cell, further strengthen the cytotoxic effect of cisplatin.
The present invention has following beneficial effect compared with the prior art:
1, the mole granule drug loading of the prepared magnetic nano-balls carried with cisplatin of the present invention reaches 1000 moles, and the reversible connection release of cisplatin (referring to the percentage ratio of the reversible burst size of cisplatin to cisplatin reaction total amount) reaches 65%.
2, the prepared average hydrodynamic diameter of magnetic nano-balls carried with cisplatin of the present invention is absorbed by cancerous cell easily less than 100nm;
3, the saturation magnetization of the prepared magnetic nano-balls carried with cisplatin of the present invention can reach about 3kA/m.
4, the surface potential of the prepared magnetic nano-balls carried with cisplatin of the present invention between-the 50mV, can keep stable dispersion at-30mV in serum.
5, the vitro cytotoxicity experiment shows, the prepared magnetic nano-balls carried with cisplatin of the present invention is 2.3-2.4 μ g/ml to the half kill rate (LD50) of human nasopharyngeal carcinoma CNE2 cell, half kill rate (1.44 μ g/ml) than cisplatin hangs down 1.60 times, but all＜5 μ g/ml, and when drug level reaches 9.45 μ g/ml, kill rate is nearly 80%, and drug effect is remarkable.
The assay method of above data is: the drug loading of magnetic nano-balls carried with cisplatin adopts the o-phenylenediamine colorimetry to measure with the reversible release that is connected of cisplatin, the hydrodynamics diameter adopts photon correlation spectroscopy to measure, the saturation magnetization of magnetic nano-balls carried with cisplatin adopts vibrating specimen magnetometer to measure, surface potential detection carries out on Ma Erwen 3000HSA Zetasizer instrument, and half kill rate employing thiazole basket reduction (MTT) method of human nasopharyngeal carcinoma CNE2 cell is measured.
Description of drawings
Fig. 1 is the structural representation of magnetic nano-balls carried with cisplatin of the present invention;
The transmission electron microscope photo of the magnetic nano-balls carried with cisplatin that Fig. 2 makes for the inventive method;
The transmission electron microscope photo that the cis-platinum magnetic nanosphere that Fig. 3 makes for the inventive method is absorbed by nasopharyngeal carcinoma cell.
The specific embodiment
Embodiment 1
1. get 9.6g FeCl
36H
2O is made into mass concentration and is 60% FeCl
3Solution, weighing 5g FeSO
17H
2O is made into mass concentration and is 20% FeSO
1Solution is made into iron salt mixed solution (ferrous sulfate: both mol ratios of ferric chloride=1: 2) with two kinds of solution mixing.With the 20g weight average molecular weight is that 20,000 sodium alginate is dissolved in and is made into sodium alginate ammonia mixed solution (ammonia: the mol ratio of ferric chloride is 40: 1, and sodium alginate is 5: 1 to the mass ratio of ferroso-ferric oxide) in the strong aqua ammonia that 100ml concentration is 25Wt%.Iron salt mixed solution and sodium alginate ammonia mixed solution are mixed under 800 rev/mins stirring, stir reaction down 50 minutes then, reaction temperature is stabilized in 90 ℃.2. after reaction finishes, with centrifuge prepared water base Fe 3 O 4 magnetic liquid is made centrifugal treating, remove sedimentary bulky grain, guarantee that the even also stable dispersion of nano ferriferrous oxide granule size is in water, collect the supernatant, obtain stable water base Fe 3 O 4 magnetic liquid.3. adopt ultrafiltration apparatus that water-base magnetic liquid is carried out the cyclic washing ultrafiltration, drop to below the 1000us/cm up to the electrical conductivity that leaches cleaning mixture, obtain sodium alginate-modified nano ferriferrous oxide granule magnetic liquid (sodium alginate is about 5: 1 to the mass ratio of nano ferriferrous oxide granule).4. the sodium alginate-modified nanometer Fe 3 O 4 magnetic liquid (the sodium alginate-modified nano ferriferrous oxide granule that contains 60mg approximately) of getting the 2ml iron-holder and be 5mg/ml reacted 24 hours under 37 ℃ of conditions with the 10mg cisplatin, then reactant liquor is dialysed in distilled water and remove free cisplatin, obtain the magnetic nano-balls carried with cisplatin of stable dispersion in water, the reversible connection burst size of cisplatin is about 6.5mg, nano ferriferrous oxide granule wherein: carboxylated polysaccharide: the mass ratio of cisplatin=1: 5: 0.65, mole granule drug loading reaches about 850 moles, the structure of magnetic nano-balls carried with cisplatin as shown in Figure 1, transmission electron microscope photo is as shown in Figure 2.The average hydrodynamic diameter of magnetic nano-balls carried with cisplatin is less than 100nm, and easily by the picked-up of cancerous cell picked-up nasopharyngeal carcinoma cell, its transmission electron microscope photo that is absorbed by nasopharyngeal carcinoma cell as shown in Figure 3.The saturation magnetization of magnetic nano-balls carried with cisplatin reaches 3kA/m.The magnetic nano-balls carried with cisplatin surface potential is about-42mV, can keep stable dispersion in serum.The vitro cytotoxicity experiment shows that prepared magnetic nano-balls carried with cisplatin is 2.37 μ g/ml to the half kill rate (LD50) of human nasopharyngeal carcinoma CNE2 cell.
Embodiment 2
1. get 9.6g FeCl
36H
2O is made into mass concentration and is 30% FeCl
3Solution, weighing 6g FeSO
47H
2O is made into mass concentration and is 15% FeSO
4Solution is made into iron salt mixed solution (ferrous sulfate: both mol ratios of ferric chloride=1.2: 2) with two kinds of solution mixing.With the 16g weight average molecular weight is that 20,000 potassium alginate is dissolved in and is made into potassium alginate ammonia mixed solution (ammonia: the mol ratio of ferric chloride is 32: 1, and potassium alginate is 4: 1 to the mass ratio of ferroso-ferric oxide) in the strong aqua ammonia that 80ml concentration is 25Wt%.Iron salt mixed solution and potassium alginate ammonia mixed solution are mixed under 800 rev/mins stirring, stir reaction down 50 minutes then, reaction temperature is stabilized in 90 ℃.Step 2. with step 3. with embodiment 1, obtain potassium alginate modified Nano ferriferrous oxide particles (potassium alginate is 5: 1 to the mass ratio of nano ferriferrous oxide granule).4. the potassium alginate modified Nano Fe 3 O 4 magnetic liquid (the potassium alginate modified Nano ferriferrous oxide particles that contains 30mg approximately) of getting the 2ml iron-holder and be 2.5mg/ml reacted 24 hours under 37 ℃ of conditions with the 10mg cisplatin, obtain the magnetic nano-balls carried with cisplatin of part stable dispersion in water, the reversible connection burst size of cisplatin is about 4.5mg, nano ferriferrous oxide granule wherein: carboxylated polysaccharide: the mass ratio of cisplatin=1: 5: 0.9, a mole granule drug loading reaches about 1000 moles.
Embodiment 3
1. get 9.6g FeCl
36H
2O is made into mass concentration and is 45% FeCl
3Solution, weighing 7g FeSO
47H
2O is made into mass concentration and is 20% FeSO
4Solution is made into iron salt mixed solution (ferrous sulfate: both mol ratios of ferric chloride=1.4: 2) with two kinds of solution mixing.With the 16g weight average molecular weight is that 20,000 alginic acid is dissolved in and is made into alginic acid ammonia mixed solution (ammonia: the mol ratio of ferric chloride is 40: 1, and alginic acid is 4: 1 to the mass ratio of ferroso-ferric oxide) in the strong aqua ammonia that 100ml concentration is 25Wt%.Iron salt mixed solution and alginic acid ammonia mixed solution are mixed under 800 rev/mins stirring, stir reaction down 50 minutes then, reaction temperature is stabilized in 90 ℃.Step 2. with step 3. with embodiment 1, obtain alginic acid modified Nano ferriferrous oxide particles (alginic acid is about 5: 1 to the mass ratio of nano ferriferrous oxide granule).4. the alginic acid modified Nano Fe 3 O 4 magnetic liquid (the alginic acid modified Nano ferriferrous oxide particles that contains 180mg approximately) of getting the 3ml iron-holder and be 10mg/ml reacted 24 hours under 37 ℃ of conditions with the 10mg cisplatin, obtain the magnetic nano-balls carried with cisplatin of stable dispersion in water, the reversible connection burst size of cisplatin is about 6.8mg, nano ferriferrous oxide granule wherein: carboxylated polysaccharide: the mass ratio of cisplatin=1: 5: 0.23, a mole granule drug loading reaches about 300 moles.
Embodiment 4
1. get 9.6g FeCl
36H
2O is made into mass concentration and is 60% FeCl
3Solution, weighing 6g FeSO
47H
2O is made into mass concentration and is 20% FeSO
4Solution is made into iron salt mixed solution (ferrous sulfate: both mol ratios of ferric chloride=1.2: 2) with two kinds of solution mixing.With the 16g weight average molecular weight is that 0.8 ten thousand alginic acid is dissolved in and is made into alginic acid ammonia mixed solution (ammonia: the mol ratio of ferric chloride is 40: 1, and alginic acid is 4: 1 to the mass ratio of ferroso-ferric oxide) in the strong aqua ammonia that 100ml concentration is 25Wt%.Iron salt mixed solution and alginic acid ammonia mixed solution are mixed under 800 rev/mins stirring, stir reaction down 50 minutes then, reaction temperature is stabilized in 90 ℃.Step 2. with step 3. with embodiment 1, obtain alginic acid modified Nano ferriferrous oxide particles (alginic acid is about 3: 1 to the mass ratio of nano ferriferrous oxide granule).4. the alginic acid modified Nano Fe 3 O 4 magnetic liquid (the alginic acid modified Nano ferriferrous oxide particles that contains 120mg approximately) of getting the 3ml iron-holder and be 10mg/ml reacted 24 hours under 37 ℃ of conditions with the 10mg cisplatin, obtain the magnetic nano-balls carried with cisplatin of stable dispersion in water, the reversible connection burst size of cisplatin is about 6.8mg, nano ferriferrous oxide granule wherein: carboxylated polysaccharide: the mass ratio of cisplatin=1: 3: 0.23, a mole granule drug loading reaches about 300 moles.
Embodiment 5
1. get 9.6g FeCl
36H
2O is made into mass concentration and is 60% FeCl
3Solution, weighing 6g FeSO
47H
2O is made into mass concentration and is 20% FeSO
4Solution is made into iron salt mixed solution (ferrous sulfate: both mol ratios of ferric chloride=1.2: 2) with two kinds of solution mixing.
With the 16g mean molecule quantity is that 40,000 sodium alginate is dissolved in and is made into sodium alginate ammonia mixed solution (ammonia: the mol ratio of ferric chloride is 40: 1, and sodium alginate is 4: 1 to the mass ratio of ferroso-ferric oxide) in the strong aqua ammonia that 100ml concentration is 25Wt%.Iron salt mixed solution and sodium alginate ammonia mixed solution are mixed under 800 rev/mins stirring, stir reaction down 50 minutes then, reaction temperature is stabilized in 90 ℃.Step 2. with step 3. with embodiment 1, obtain sodium alginate-modified nano ferriferrous oxide granule (sodium alginate is about 7: 1 to the mass ratio of nano ferriferrous oxide granule).4. the alginic acid modified Nano Fe 3 O 4 magnetic liquid (the alginic acid modified Nano ferriferrous oxide particles that contains 240mg approximately) of getting the 3ml iron-holder and be 10mg/ml reacted 24 hours under 37 ℃ of conditions with the 10mg cisplatin, obtain the magnetic nano-balls carried with cisplatin of stable dispersion in water, the reversible connection burst size of cisplatin is about 6.8mg, nano ferriferrous oxide granule wherein: carboxylated polysaccharide: the mass ratio of cisplatin=1: 7: 0.23, a mole granule drug loading reaches about 300 moles.
Embodiment 6
1. get 9.6g FeCl
36H
2O is made into mass concentration and is 60% FeCl
3Solution, weighing 4.6g FeCl
24H
2O is made into mass concentration and is 20% FeCl
24H
2O solution is made into iron salt mixed solution (ferrous chloride: both mol ratios of ferric chloride=1.2: 2) with two kinds of solution mixing.With the 8g mean molecule quantity is that 20,000 Sensor Chip CM 5 is dissolved in and is made into Sensor Chip CM 5 ammonia mixed solution (ammonia: the mol ratio of ferric chloride is 24: 1, and Sensor Chip CM 5 is 4: 1 to the mass ratio of ferroso-ferric oxide) in the strong aqua ammonia that 60ml concentration is 25Wt%.Iron salt mixed solution and Sensor Chip CM 5 ammonia mixed solution are mixed under 800 rev/mins stirring, stir reaction down 40 minutes then, reaction temperature is stabilized in 90 ℃; Step 2. with step 3. with embodiment 1, obtain Sensor Chip CM 5 modified Nano ferriferrous oxide particles (Sensor Chip CM 5 is about 3: 1 to the mass ratio of nano ferriferrous oxide granule).4. the Sensor Chip CM 5 modified Nano Fe 3 O 4 magnetic liquid (containing 80mg Sensor Chip CM 5 modified Nano ferriferrous oxide particles approximately) of getting the 2ml iron-holder and be 10mg/ml reacted 24 hours under 37 ℃ of conditions with the 10mg cisplatin, obtain the magnetic nano-balls carried with cisplatin of stable dispersion in water, the reversible connection burst size of cisplatin is about 6.9mg, wherein nano ferriferrous oxide granule: carboxylated polysaccharide: the mass ratio of cisplatin=1: 3: 0.34.
Embodiment 7
1. get 9.6g FeCl
36H
2O is made into mass concentration and is 60% FeCl
3Solution, weighing 4.6g FeCl
24H
2O is made into mass concentration and is 20% FeCl
24H
2O solution is made into iron salt mixed solution (ferrous chloride: both mol ratios of ferric chloride=1.2: 2) with two kinds of solution mixing.With the 16g mean molecule quantity is that 20,000 Sensor Chip CM 5 is dissolved in and is made into Sensor Chip CM 5 ammonia mixed solution (ammonia: the mol ratio of ferric chloride is 32: 1, and Sensor Chip CM 5 is 4: 1 to the mass ratio of ferroso-ferric oxide) in the strong aqua ammonia that 80ml concentration is 25Wt%.Iron salt mixed solution and Sensor Chip CM 5 ammonia mixed solution are mixed under 800 rev/mins stirring, stir reaction down 40 minutes then, reaction temperature is stabilized in 90 ℃.Step obtains Sensor Chip CM 5 modified Nano ferriferrous oxide particles (Sensor Chip CM 5 is about 3: 1 to the mass ratio of nano ferriferrous oxide granule) 2. with 3. with embodiment 1.4. the Sensor Chip CM 5 modified Nano Fe 3 O 4 magnetic liquid (containing 120mg Sensor Chip CM 5 modified Nano ferriferrous oxide particles approximately) of getting the 3ml iron-holder and be 10mg/ml reacted 24 hours under 45 ℃ of conditions with the 10mg cisplatin, obtain the magnetic nano-balls carried with cisplatin of stable dispersion in water, the reversible connection burst size of cisplatin is about 6.6mg, wherein nano ferriferrous oxide granule: carboxylated polysaccharide: the mass ratio of cisplatin=1: 3: 0.22.
Embodiment 8
Step obtains alginic acid modified Nano ferriferrous oxide particles (alginic acid is about 5: 1 to the mass ratio of nano ferriferrous oxide granule) 1. 2. 3. with embodiment 3.4. the alginic acid modified Nano Fe 3 O 4 magnetic liquid (the alginic acid modified Nano ferriferrous oxide particles that contains 120mg approximately) of getting the 2ml iron-holder and be 10mg/ml reacted 48 hours under 25 ℃ of conditions with the 10mg cisplatin, obtain the magnetic nano-balls carried with cisplatin of stable dispersion in water, the reversible connection burst size of cisplatin is about 5.6mg, wherein nano ferriferrous oxide granule: carboxylated polysaccharide: the mass ratio of cisplatin=1: 3: 0.28.
Claims (3)
1. a magnetic nano-balls carried with cisplatin is made of nano ferriferrous oxide granule: carboxylated polysaccharide: the mass ratio of cisplatin=1: 3～7: 0.1～1 nano ferriferrous oxide granule, carboxylated polysaccharide and cisplatin; Described carboxylated polysaccharide is the alkali metal salt or the Sensor Chip CM 5 of alginic acid or alginic acid, and the weight average molecular weight of carboxylated polysaccharide is between 0.5 ten thousand～50,000;
Preparation method may further comprise the steps:
1. there is synthesis of nano ferriferrous oxide particles down in carboxylated polysaccharide:
With Fe
2+, Fe
3+Be 1.0～1.4 in molar ratio: 2 are mixed with mixed solution; The mixed liquor that adds ammonia and carboxylated polysaccharide then, ammonia: Fe
3+Mol ratio be 12～40: 1, carboxylated polysaccharide to the mass ratio of synthetic ferroso-ferric oxide be 2～5: 1; Under agitation reacted 40～60 minutes, mixing speed is controlled at 800～1000 rev/mins, and reaction temperature is controlled between 85～95 ℃, obtains containing unstable oarse-grained water base Fe 3 O 4 magnetic liquid;
2. unsettled bulky grain is removed in centrifugalize:
With centrifuge prepared water base Fe 3 O 4 magnetic liquid is made centrifugal treating, remove sedimentary bulky grain, collect the supernatant, be stable water-base magnetic liquid;
3. free carboxylated polysaccharide and other electrolyte in the water-base magnetic liquid are removed in ultrafiltration:
Adopt ultrafiltration apparatus that water-base magnetic liquid is carried out the cyclic washing ultrafiltration, drop to below the 1000us/cm, obtain carboxylated polysaccharide modified Nano ferriferrous oxide particles magnetic liquid up to the electrical conductivity that leaches cleaning mixture;
4. the coupling of carboxylated polysaccharide modified Nano ferriferrous oxide particles and cisplatin joins:
Cisplatin is mixed with carboxylated polysaccharide modified Nano ferriferrous oxide particles water-base magnetic liquid, carboxylated polysaccharide modified Nano ferriferrous oxide particles: the mass ratio of cisplatin is 3～30: 1, under 25～45 ℃ of conditions, reacted 24～48 hours, at last reactant liquor is dialysed in distilled water and remove free cisplatin, obtain magnetic nano-balls carried with cisplatin.
2. magnetic nano-balls carried with cisplatin according to claim 1, the weight average molecular weight that it is characterized in that described carboxylated polysaccharide is between 0.8 ten thousand～1.5 ten thousand.
3. magnetic nano-balls carried with cisplatin according to claim 1, what it is characterized in that described water-base magnetic liquid contains concentration of iron between 2～15mg/ml.
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