CN102671220B - Radioactive anion resin microsphere and method for preparing same - Google Patents
Radioactive anion resin microsphere and method for preparing same Download PDFInfo
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- CN102671220B CN102671220B CN2011100587229A CN201110058722A CN102671220B CN 102671220 B CN102671220 B CN 102671220B CN 2011100587229 A CN2011100587229 A CN 2011100587229A CN 201110058722 A CN201110058722 A CN 201110058722A CN 102671220 B CN102671220 B CN 102671220B
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Abstract
The invention discloses a radioactive anion resin microsphere and a method for preparing the same, and belongs to the technical field of medicines. The radioactive anion resin microsphere is prepared by curing anionic radionuclide in the anion resin of which the diameter is 5 to 200 mu m and the crosslinking degree is 1 to 20 percent in a precipitation mode. The preparation method comprises the following steps of exchanging the anions of radionuclide to the anion resin, making the radionuclide in the anion resin react with a metal cation precipitator in a solution to form a precipitation in the resin, further curing the radionuclide in the resin and preparing the anion resin microsphere of P-32, I-125, I-131, Re-186 or Re-188. The novel radioactive resin microsphere using anion resin microspheres as a carrier has the characteristics of low release rate of radionuclide, high safety, simple preparation process and the like. The radioactive anion resin microsphere can be used for treating malignant tumors such as liver cancer, lung cancer, tongue cancer and the like.
Description
Technical field
The invention discloses a kind of radioactivity resin microsphere and preparation method thereof, be specifically related to a kind of resin anion (R.A.) microsphere that contains radionuclide P-32, I-125, I-131, Re-186 or Re-188 and preparation method thereof.Radioactivity resin anion (R.A.) microsphere of the present invention is mainly used in the interior Interventional radiology of the malignant tumor such as hepatocarcinoma, pulmonary carcinoma, oral cancer, cervical cancer or carcinoma of tongue.
Background technology
Malignant tumor is the No.1 killer of human health, hepatocarcinoma for example, and not only sickness rate is high, and dangerous refractory, and mortality rate is high.Malignant tumor is difficult to reach ideal effect by the single therapy means, often needs to adopt multi-disciplinary Comprehensive Treatment, as adopted the means such as surgical operation, chemotherapy, radiotherapy.Wherein radiation treatment is mainly ray and the ionizing radiation that utilizes radionuclide to send, to suppress and to destroy tumor tissues, reach therapeutic purposes.
The Radiotherapy of malignant tumor can be divided into radioactivity external radiotherapy method and radioactivity internal-radiation therapy method.The radioactivity external exposure refers to and keeps certain distance to be irradiated radioactive source and patient body, ray penetrates into certain depth in human body from patient's body surface, reach the purpose for the treatment of tumor, this when being radiated at the kill tumor cell, the damage of normal tissue is also very large; Radioactivity internal-radiation therapy method (SIRT) is to carry out radiotherapy by containing in radioisotopic infusion of medicine body or by apparatus to press close to or be inserted into target tissue, radioactive substance is transported in tumor tissues selectively, radiation dose to tumor tissues is very large, and the amount of the radioactive substance entered in surrounding tissue seldom, the infringement of normal tissue is very little.
SIRT can be divided into common radio nuclide therapy, radionuclide targeted therapy and radionuclide interventional therapy according to the method difference.Wherein the radioactivity interventional therapy comprises the interior perfusion therapy of radionuclide intracavity interventional therapy, radionuclide Implantation in Treating and arteries etc., this method almost can be for all solid tumors, the direct implantation tumour of radionuclide position, the in-plant kill tumor cell of ray, little to Normocellular infringement, be a kind of technology that clinical value is arranged very much in the radioactivity irradiation technology.According to different carriers, the radionuclide interventional therapy can be divided into radiant stand, radioactive seed source and radioactivity microsphere and other can directly be implanted to the form in tumor tissues.Wherein, the radioactivity microsphere is the microsphere that diameter that matrixes such as discharging the radionuclide that is suitable for treatment of β or low-energyγ-ray and glass, resin is made is 5 μ m～200 μ m.The nucleic that being suitable for of having found at present prepares the radioactivity microsphere has (in Table 1) such as Y-90, P-32, I-125, I-131, Ho-166, Re-188 and Sr-89.Wherein, Y-90 (T
1/2=64h, average energy 2.27MeV), for pure β emission radionuclide, owing to thering is half-life and the energy that is suitable for treatment, be clinical treatment nucleic commonly used.And P-32 (T
1/2=14.3d) compare and have advantages of long half time with Y-90, be convenient to long-distance transport, be applicable to use away from the radioactivity grown place, under Isodose, its integrated radiation dose is large, also is widely used in the treatment of malignant tumor.
Table 1 is applicable to the radionuclide for the treatment of and video picture
| Nucleic | Half-life/h | Decay mode | Mean range/mm | Purposes |
| 90Y | 64.08h | β - | 3.78 | Treatment |
| 32P | 343.2 | β - | 4.00 | Treatment |
| 125I | 1443.4 | γ、EC | ＜0.02 | Treatment |
| 131I | 192.96 | γ、β - | 0.36 | Treatment, video picture |
| 89Sr | 1214.4 | β - | 2.40 | Treatment |
| 186Re | 90.64 | γ、β | 0.98 | Treatment, video picture |
| 188Re | 16.98 | γ、β | 2.91 | Treatment, video picture |
| 177Lu | 161.04 | γ、β -、EC | 0.22 | Treatment, video picture |
| 166Ho | 26.8 | γ、β -、EC | 2.43 | Treatment, video picture |
| 153Sm | 46.27 | γ、β - | 0.50 | Treatment, video picture |
| 99mTc | 6.02 | γ、IT/EC | - | Video picture |
| 111In | 67.31 | γ、EC | ＜0.02 | Video picture |
Radioactivity microsphere especially Y-90 radioactivity microsphere, owing to having good curative effect, is widely used clinically, and P-32 also is widely used in the treatment of malignant tumor owing to being that pure β emission nucleic has advantages of long half time.Because liver has the double blood confession, blood of liver cancer 95%～99% is from Hepatic artery; And normal liver tissue blood supplies 25%～30% from Hepatic artery, 70%～75% from the portal vein blood supply.When the radioactivity microsphere by vascular perfusion to after in the liver arteries, major part will gather in tumor tissues, the radiation dose that its hetero-organization is subject to is very little, make the liver neoplasm target area be subject to high-dose irradiation and blood vessel embolism dual function and the induced tumor cell death, thereby the radioactivity microsphere have the advantage that other Therapeutic Method can not be compared aspect Hepatoma therapy.
Gray etc. have carried out the embolotherapy of Y-90 resin microsphere first to 10 patients' metastatic hepatic neoplasm (MCRC), find that it is to the patient's successful over 80%, wherein carcinoembryonic antigen level (CEA) level more than 50% has had obvious reduction.1994, Andrews etc. reported 17 routine MCRC patients have been carried out to the treatment of the SIRT of the various dose from 50Gy to 150Gy.Find wherein through the CT imaging that 60% patient tumors is stable and even dwindle to only have 17% patient the side reaction of gastrointestinal ulceration to occur.At Gray in 2000 etc., 71 routine MCRC patients have been carried out the SIRT treatment of Y-90 resin, found that optimum reaction has in various degree appearred in 85% patient wherein.2002, Wong etc. reported the Y-90 glass microsphere treatment that 8 routine MCRC patients are carried out, and found that 75% patient's CEA level all decreases.2002, Herba and Thirlwell shifted liver tumor to 37 examples and are studied, and wherein 33 routine MCRC patients have been carried out the treatment of the Y-90 glass microsphere of SIRT method.The absorbed dose of full liver are from 50Gy to 150Gy.Finding by follow-up CT imaging that 15 examples (41%) patient tumors has had significantly dwindles.2004, Carr etc. reported that liver cancer patient that 65 examples can not excision carries out the therapeutic outcome of Y-90 glass microsphere thromboembolism.Use the PCTF means patient to be injected to the dosage of average 134Gy.Wherein 25 (38.4%) patients are partial rcsponse through CT observation display effect.Mean survival time (MST) is 649d, than historical control, is that 244d has had obvious prolongation.Lau etc. calendar year 2001 further perfect their research, research comprises 82 routine cases, has found that at low AFP level and higher T/N, than in situation, can significantly extend the life cycle of case, even large tumor and postoperative recurrence, this treatment is also effective.
The radioactivity microsphere not only has curative effect preferably to hepatocarcinoma, can the radioactivity microsphere be imported to tumor locus by perfusion for other euangiotic tumor and be used for treating.Lewandowski etc. have reported 11 routine neuroendocrine tumor patients' Y-90 glass microsphere treatment, and have obtained good effect.2006, Kennedy etc. were studied the treatment situation of the SIRT method of neuroendocrine tumor patient Y-90 resin microsphere, wherein 89% patient's remission.A nearest research report SIRT method of Y-90 glass microsphere to 27 routine metastatic breast cancer patients' treatment situation, find to surpass 90% patient's symptom and all obviously improve, and obvious toxic and side effects do not occur.The people such as Coldwell have carried out the embolotherapy of microsphere to 44 routine patient with breast cancers, after 3 months, 17% patient tumors disappears fully, 58% patient tumors partial rcsponse, and 47 maintenance is stable existing.Coldwell etc. have reported the SIRT treatment to 23 routine carcinoma of gallbladder cases, and average injected dose is 1.5GBq, and the average absorbed dose of tumor is 150Gy.Mean survival time (MST), reached 14 months.Tian etc. report use
32p-GMS directly injects in cerebroma for 267 times totally, and obvious side effect and complication do not occur, and following up a case by regular visits to of 6m～48m shows, 104 people (74.3%) remission, and CT scan discovery tumor is dwindled.The large Zhang Caiyong of king injects in mouth neoplasm
32p-GMS treatment oral cancer has been obtained certain progress.The people such as Yang Pei adopt and inject in uterine artery
32p-GMS treats cervical cancer, and effect is remarkable.The people such as Chen Zhangqin have reported that employing is to BAI radioactivity microsphere treatment advanced lung cancer, and its effective percentage has reached 83.3%.
Therefore, up to now, prior art is the verified effectiveness of radioactivity microsphere aspect the treatment entity tumor.When the radioactivity microsphere is used for the treatment of tumor, be suitable for the radionuclide for the treatment of and make the radioactivity microsphere as long as select, the radioactivity microsphere (amount of radionuclide is determined by the volume of tumor and the factors such as half-life of nucleic thereof) that will contain a certain amount of radionuclide arrives tumor locus by the mode of pouring into, just can launch β or low-energyγ-ray by radionuclide is killed and wounded to tumor the purpose that reaches treatment and (is generally used for the treatment of hepatocarcinoma, its radioactivity consumption is 5Gy～25Gy, the highlyest can not surpass 30Gy).Yet, the radioactivity microsphere must guarantee that radionuclide can stably be retained in microsphere inside when the treatment tumor, can or very little from inner release of microsphere, not enter blood, if too much radionuclide comes off and enters blood of human body in the radioactivity microsphere, may produce harm to human body.Therefore, (release rate refers to that the radioactivity microsphere is injected in human body or after the solution soaking of the environment of simulation blood of human body to control the release rate of radionuclide, enter into the ratio of amount and the original radionuclide amount of radioactivity microsphere of the radionuclide microsphere from inner disengaging of radioactivity microsphere), to reach effectively the killing and wounding of tumor tissues, and avoid normal structure is affected as far as possible.Therefore, the selection of radionuclide carrier is to be also one of the key technology of the internal radiotherapy agent research and development of tumor.Up to now, glass microsphere, biodegradable radioactivity polymer microballoon and resin microsphere are still the main carriers of preparation radioactivity microsphere.
Chinese patent CN 1080266A in 1994 disclose the preparation method of P-32 glass microsphere, the powder that will contain P-31 and other frit mixes, the purity of each component in its Raw is higher than 99.9%, then these raw materials are made to powder mixture or wet mixture 1,500 ℃～1, be placed in platinum crucible under the high temperature of 600 ℃ and be fused into the nature of glass, then quenching bursts.The powder obtained by the screening of milling is fired into spherical on flame, and then microsphere particle is placed in to reactor, and after neutron irradiation, the Y-31 in frit changes Y-32 into.Because the chemical property of glass microsphere is more stable, but the higher (2.0cm of its density
3/ g～2.7cm
3/ g), can only be directed into tumor locus with glycerol, may affect the effect for the treatment of.Because the purity requirement to preparing frit is higher, cause the impurity such as Na that may contain in frit after neutron irradiation, produce and discharge gamma-ray nucleic, and make the patient suffer unnecessary radiation injury.In addition, radioactive glass microsphere must carry out irradiation with reactor, so the production of product must be subject to the constraint of reactor.Canada NORDION company produces
the Y-90 glass microsphere becomes one of radioactivity microsphere of two kinds of listings, but, because radioactive glass microsphere need to be used reactor irradiation, causes its market application to be limited to, and can only use in North America; In addition, because the glass microsphere raw materials quality is unstable, after irradiation, may produce gamma-rays, Some Areas of USA has been forbidden the Y-90 glass microsphere.
The degradable radioactive microsphere is that the form that radionuclide is closed by physical absorption or valence bond is combined in the surperficial or inner of microsphere by radionuclide.The material that can be used in the preparation of biodegradable radioactivity polymer microballoon comprises some straight chain polymer polymer, gelatin, albumen etc.The radioembolization that degradable microsphere forms in vivo can be absorbed by the body over time, therefore, if this microsphere can be applied to the embolotherapy of malignant tumor, can look the state of an illness and repeatedly treat.But, because the anti-irradiation ability of the polymer such as albumen is poor, causing its poor stability, the release rate of radionuclide is higher.This type of microsphere only rests on the laboratory research stage at present, there is no the value of clinical practice.
The radioactivity resin microsphere is to utilize resin for carrier, radionuclide is solidified by ion exchange, precipitant or the method for resin surface overlay film, radionuclide is fixed on to the inside of resin.The advantage of this microsphere is the less (0.5cm of density
3/ g～1.5cm
3/ g), therefore can import treatment with normal saline, the radioactivity microsphere can more effectively arrive tumor locus.In addition, the radioactivity resin microsphere does not need reactor irradiation, can be prepared in the place away from reactor, is conducive to transportation and the application of product, so the radioactivity resin microsphere is the main development direction of radioactivity microsphere technology of preparing.
It is that carrier prepares the Y-90 resin microsphere that the disclosed patent of U.S. Pat 0253898 in 2007 adopts the cationic resin microsphere, and Australian SIRTEX company adopts this technology to produce commercialization
resin microsphere.This resin microsphere is that the employing cationic resin is adsorbing material, after Y-90 is exchanged to cationic resin inside, then adds precipitant that the Y-90 in resin is formed to precipitation, thereby reaches the curing purpose of Y-90.But the release rate of resin microsphere Y-90 prepared by this method higher (5%), may bring radiation damage to human body, at present
the side effect of resin microsphere clinical report comprises that radiation hepatitis may be relevant therewith.
It is material that Zhao Ming waits by force the people to adopt resin anion (R.A.), will
125i exchanges to resin inside, then with coated method attempt by
125i is solidificated in resin inside (preparation research of radioactivity resin microsphere, China Atomic Energy Science Research Institute's annual report, 2006).This method can't make resin microsphere be coated with equably and cause the high requirement that can't meet treatment of its release rate.And adopt chemical connection method, will
125the method that I is connected with resin anion (R.A.), the release rate of its radionuclide is up to 10%～30%.
As mentioned above, glass microsphere and resin microsphere are still the main path of preparation radioactivity microsphere.But because glass microsphere density is high, material purity require high, preparation technology is more complicated and the shortcoming such as dependent reaction heap, the application of radioactive glass microsphere is restricted.And that resin microsphere has density is low, the advantage such as preparation technology is simple, but microsphere release rate prepared by existing method is higher, therefore needs to adopt new preparation technology to reduce the radionuclide release rate of radioactivity resin microsphere.
Summary of the invention
The object of the invention is to overcome above-mentioned deficiency of the prior art, a kind of radioactivity resin anion (R.A.) microsphere and preparation method thereof is provided.Radioactivity resin anion (R.A.) microsphere prepared by the present invention has lower radionuclide release rate, applicable to the internal radiotherapy of the malignant tumor such as hepatocarcinoma, pulmonary carcinoma, carcinoma of tongue.
To achieve these goals, the invention provides following technical scheme:
A kind of radioactivity resin anion (R.A.) microsphere, comprise that diameter is the resin anion (R.A.) that 5 μ m～200 μ m, the degree of cross linking are 1%～20%, and solidify in the radionuclide of described resin anion (R.A.) inside with precipitation form;
Described solidifying in the radionuclide of resin anion (R.A.) inside with precipitation form is to be formed by the anion of anion radionuclide P-32, I-125, I-131, Re-186 or Re-188 and the cationoid reaction of on-radiation calcium metal, barium, copper, silver, ferrum, magnesium, strontium, zinc, yttrium, aluminum or indium.
In above-mentioned radioactivity resin anion (R.A.) microsphere, it is the resin anion (R.A.) that 10 μ m～100 μ m, the degree of cross linking are 4%～10% that described resin anion (R.A.) is preferably diameter.
In above-mentioned radioactivity resin anion (R.A.) microsphere, described resin anion (R.A.) can be strongly basic anionic resin or weak anion resin.
In above-mentioned radioactivity resin anion (R.A.) microsphere, the anion of described anion radionuclide P-32, I-125, I-131, Re-186 or Re-188 can be
32pO
4 3-, H
32pO
4 2-, H
2 32pO
4 -,
131i
-,
125i
-,
131iO
3 -,
125iO
3 -,
186reO
4 -or
188reO
4 -.
In above-mentioned radioactivity resin anion (R.A.) microsphere, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, the mol ratio of on-radiation metal cation and radionuclide anion is at least 10: 1, and the mol ratio of on-radiation metal cation and radionuclide anion can reach 10
6: 1, the mol ratio of on-radiation metal cation and radionuclide anion can be 10～10
6: 1.
In above-mentioned radioactivity resin anion (R.A.) microsphere, described anion radionuclide is P-32, and its anion can be
32pO
4 3-, H
32pO
4 2-or H
2 32pO
4 -, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, the mol ratio of on-radiation metal cation and radionuclide anion is preferably 15～10
6: 1.
In above-mentioned radioactivity resin anion (R.A.) microsphere, described anion radionuclide is I-125 or I-131, and its anion can be
131i
-,
125i
-,
131iO
3 -or
125iO
3 -, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～14GBq, the mol ratio of on-radiation metal cation and radionuclide anion is preferably 10～10
6: 1.
In above-mentioned radioactivity resin anion (R.A.) microsphere, described anion radionuclide is Re-186 or Re-188, and its anion can be
186reO
4 -or
188reO
4 -, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, the mol ratio of on-radiation metal cation and radionuclide anion is preferably 10～10
6: 1.
A kind of preparation method of above-mentioned radioactivity resin anion (R.A.) microsphere comprises the following steps:
(1) resin anion (R.A.) is made the transition as OH or Cl type resin anion (R.A.);
(2) step (1) gained resin anion (R.A.) is reacted to 10min～4h in the solution that contains the anion radionuclide, reaction temperature is 25 ℃～60 ℃, by the anion exchange of radionuclide to resin anion (R.A.) inside;
(3) step (2) gained resin anion (R.A.) is joined in the solution that contains on-radiation metal cation precipitant, react 10min～6h at 25 ℃～60 ℃ temperature, make the radionuclide anionic reactive of on-radiation metal cation in solution and resin anion (R.A.) inside form precipitation, radionuclide is formed to precipitation and be solidificated in resin inside;
(4) step (3) gained radioactivity resin anion (R.A.) microsphere is re-used after water cleans to the 0.1mol/L～5.0mol/L NaOH solution soaking 30min～24h of 25 ℃～60 ℃, be prepared into the resin anion (R.A.) microsphere;
Described on-radiation metal cation precipitant be can with the soluble-salt of calcium metal, barium, copper, silver, ferrum, magnesium, strontium, zinc, yttrium, aluminum or the indium of the anion generation precipitation of radionuclide P-32, I-125, I-131, Re-186 or Re-188 in any one.
In above-mentioned radioactivity resin anion (R.A.) method for preparing microsphere, described in step (1), resin anion (R.A.) is strongly basic anionic resin, be OH type strongly basic anionic resin transition, and the pH value that contains on-radiation metal cation precipitant solution described in step (3) is 2～12.
In the preparation method of above-mentioned radioactivity resin anion (R.A.) microsphere, described in step (1), resin anion (R.A.) is weak anion resin, be Cl type weak anion resin transition, and the pH value that contains on-radiation metal cation precipitant solution described in step (3) is less than 4.
In above-mentioned radioactivity resin anion (R.A.) method for preparing microsphere, described anion radionuclide is P-32, and its anion can be
32pO
4 3-, H
32pO
4 2-or H
2 32pO
4 -described on-radiation metal cation precipitant is preferably any one in the metal cation soluble-salt of calcium, barium, copper, silver, ferrum, ferrous iron, magnesium, strontium, zinc, yttrium, indium or aluminum, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 15～10
6: 1.
In above-mentioned radioactivity resin anion (R.A.) microsphere, described anion radionuclide is I-125, and its anion is
125i
-described on-radiation metal cation precipitant is preferably the soluble-salt of copper or silver, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～14GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
In above-mentioned radioactivity resin anion (R.A.) microsphere, described anion radionuclide is I-131, and its anion can be
131i
-described on-radiation metal cation precipitant is preferably the soluble-salt of copper or silver, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
In above-mentioned radioactivity resin anion (R.A.) microsphere, described anion radionuclide is I-125, and its anion can be
125iO
3 -described on-radiation metal cation precipitant is preferably any one in the soluble-salt of calcium, barium, copper, silver, strontium, zinc or indium, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～14GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
In above-mentioned radioactivity resin anion (R.A.) microsphere, described anion radionuclide is I-131, and its anion can be
131iO
3 -described on-radiation metal cation precipitant is preferably any one in the soluble-salt of calcium, barium, copper, silver, strontium, zinc or indium, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
In above-mentioned radioactivity resin anion (R.A.) microsphere, described anion radionuclide is Re-186 or Re-188, and its anion can be
186reO
4 -or
188reO
4 -described on-radiation metal cation precipitant is preferably any one in the soluble-salt of calcium, barium, strontium or aluminum, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
The advantages such as it is low that resin microsphere has density, and preparation technology is simple, prior art up to now is the verified effectiveness of radioactivity resin microsphere aspect the treatment entity tumor.Yet microsphere release rate prepared by existing method is higher, may produce harm to human body.The inventor is through long term test, at the temperature of 25 ℃～60 ℃, by the anion exchange of radionuclide to resin anion (R.A.) inside; Described resin anion (R.A.) can be strongly basic anionic resin, it can be also weak anion resin, when preparation radioactivity resin anion (R.A.), before being used, strongly basic anionic resin soaks with NaOH the OH type that is converted to, before being used, weak anion resin soaks with NaCl or HCl the Cl type that is converted to.
The resin anion (R.A.) that will contain the anion radionuclide joins in the solution that contains on-radiation metal cation precipitant, react 10min～6h at 25 ℃～60 ℃ temperature, make the on-radiation metal cation in solution react the formation precipitation with the anion radionuclide of resin inside, radionuclide is formed to precipitation and be solidificated in resin inside, prepare and a kind ofly comprise that take precipitation form is present in the radionuclide of anion inside and the radioactivity resin anion (R.A.) microsphere that diameter is 1%～20% as 5 μ m～200 μ m, the degree of cross linking.The present invention first by the anion exchange of radionuclide to resin anion (R.A.), make again radionuclide react with on-radiation metal cation precipitant and form precipitation, further radionuclide is solidificated in to resin inside, thereby make radioactivity resin microsphere of the present invention with precipitation form, radioactivity anion nucleic be solidified in resin anion (R.A.) inside, make the release rate of radionuclide lower.
By strongly basic anionic resin and weak anion resin at PO
4 3-, I
-, IO
3 -or ReO
4 -different pH value in soak, use spectrophotometer (TU-1201 after soaking, Beijing is general analyse general) measure the concentration of P in solution or I, or with inductively coupled plasma emission spectra (IRRS-H2-DVO, U.S.'s thermoelectricity) measure the concentration of Re in solution, with formula (1), calculate anion static allocation COEFFICIENT K d (in Table 2) on resin anion (R.A.) in different pH value.Ion static allocation coefficient refers to that resin is for the exchange adsorption of certain ion or element in specific solution.In general, the static allocation coefficient of certain ion is higher, means that resin is more intense to the selectivity exchange of this ion, and higher exchange capacity is also arranged; Otherwise exchange capacity is poor.
In formula, Kd is the static allocation coefficient, mL/g; C is concentration of element in solution after soaking, μ g/mL; V is liquor capacity, mL; C
0for soaking concentration of element in front solution, μ g/mL; W is resin anion (R.A.) weight, g.
From table 2 data, in the scope that strongly basic anionic resin is 2～12 at pH value to PO
4 3-, I
-and IO
3 -exchange capacity better, ReO
4 -the static allocation coefficient relatively low, but reasonable commutativity still arranged.Weak anion resin in the scope of pH≤2 to PO
4 3-, I
-and IO
3 -commutativity better, also there is a certain amount of exchange pH value 2～4 o'clock, and substantially do not exchange afterwards in pH>4; PH>4 are rear to ReO
4-exchange poor, but in pH≤2 o'clock, certain exchange capacity is arranged, can meet every gram resins exchange 370GBq's
186re or
188the requirement of Re.
Table 2 resin anion (R.A.) in the solution of different pH value to PO
4 3-, I
-, IO
3 -and ReO
4 -partition coefficient
Take strongly basic anionic resin as material, is 8～12 interior first by a certain amount of PO at pH value
4 3-, I
-, IO
3 -or ReO
4 -(amount of the P contained, I or Re is 500 μ g) exchanges to strongly basic anionic resin, after water cleans, more respectively the resin that adsorbs P, I or Re added to the Ca that contains that pH is 1～8
2+, Ag
+, Sr
2+or Y
3+the precipitated cationic agent solution in, precipitant forms precipitation with P, the I of exchange in resin and Re, further P, I and Re is solidificated in to resin inside, after water cleans again by resin immersion treatment 1h in the normal saline of 40 ℃.The 10g resin for preparing is soaked to 10d in 25mL, the normal saline solution of 37 ℃, measure the content of P, I in soak or Re, calculate the release rate (result of the test is in Table 3) of P, I or Re.
From the data of table 3, the ion of resins exchange is PO
4 3-the time, Ca
2+, Y
3+and Sr
2+with PO
4 3-mol ratio be greater than 15: 1 after, the release rate of P is less than 1 ‰; Work as Ag
+with PO
4 3-mol ratio be greater than 20: 1 after, the release rate of P is less than 1 ‰.The ion of resins exchange is I
-the time, Ag
+with I
-mol ratio be greater than 10: 1 after, the release rate of P is less than 1 ‰.The ion of resins exchange is IO
3 -the time, Ag
+, Ca
2+and Sr
2+with I
-mol ratio be greater than 10: 1 after, the release rate of P is less than 1 ‰.The ion of resins exchange is ReO
4 -the time, Ca
2+and Sr
2+mol ratio be greater than 15: 1 after, the release rate of P is less than 1 ‰.Above-mentioned result of the test shows, with Ca
2+, Ag
+, Sr
2+or Y
3+for precipitant, under certain ratio, can be with exchange at the PO of resin inside
4 3-, I
-, IO
3 -or ReO
4 -form precipitation, P, I or Re further are solidificated in to the inside of resin, to reduce the release rate of nucleic.
The impact of table 3 precipitated cationic agent on preparation P, I and Re resin anion (R.A.) microsphere
Take strongly basic anionic resin as material, is a certain amount of PO in 8～12 interior first exchanges at pH value
4 3-, I
-, IO
3 -or ReO
4 -(P, the I that every grams value contains or the amount of Re are 500 μ g), after the resin water cleans, then add respectively the Ca that contains that pH is 1～8
2+, Ag
+or Sr
2+the precipitated cationic agent solution, P, the I of exchange on resin and Re, in the inner precipitation that forms of resin, further P, I or Re are solidificated in to resin inside, and water are cleaned to resin.Again resin is divided into to several parts, a copy of it is directly used, in addition several parts of NaOH solution washings of at room temperature using respectively variable concentrations.The microsphere that to process by these methods soaks 7d with 37 ℃ of normal saline, the concentration of P, I or Re in the mensuration soak, the release rate (release rate of P, I or Re the results are shown in Table 4) of calculating P, I or Re.
Data from table 4, exchange is the anion of resin inside is reacted the formation precipitation with precipitant after, anionic part does not fully form precipitation and is present in resin inside with adsorption form with precipitant, when using NaOH to be soaked, the anion that does not form precipitation will discharge and be eliminated, and can further reduce the release rate of resin microsphere.Therefore, when preparation radioactivity microsphere, absorption has the resin of anion radionuclide to react with the precipitant added, resin is after water cleans, resin can be soaked in 0.1mol/L～4mol/LNaOH solution, unsettled radionuclide is leached, further to avoid the radioactivity microsphere, inject the risk discharged again after human body, the safety that improves the radioactivity microsphere.
The impact of table 4 variable concentrations NaOH process resin on the radionuclide release rate
Compared with prior art, beneficial effect of the present invention.The present invention uses resin anion (R.A.) for material, and anion radionuclide P-32, I-125, I-131, Re-186 or Re-188 are deposited in to resin anion (R.A.) inside, is prepared into radioactivity resin anion (R.A.) microsphere.Its preparation method be by the anion exchange of radionuclide to resin anion (R.A.), the radionuclide that makes again resin anion (R.A.) inside and GOLD FROM PLATING SOLUTION belong to the precipitated cationic agent and react and form precipitation, further radionuclide is solidificated in to resin inside, is prepared into the resin anion (R.A.) microsphere of P-32, I-125, I-131, Re-186 or Re-188.A class provided by the invention is used the Novel radioactive resin microsphere that the resin anion (R.A.) microsphere is carrier, has the characteristics such as the radionuclide release rate is low, safe, preparation technology is simple.
Radioactivity resin anion (R.A.) microsphere of the present invention can be used for the treatment of the malignant tumor such as hepatocarcinoma, pulmonary carcinoma, carcinoma of tongue.When radioactivity microsphere of the present invention is used for the treatment of malignant tumor, determine that by the volume of tumor and the factors such as half-life of nucleic thereof the consumption of radioactivity resin anion (R.A.) microsphere (is generally used for the treatment of hepatocarcinoma, its dosage is 5Gy～25Gy, the highlyest can not surpass 30Gy), mode by perfusion arrives tumor locus, just can launch β or low-energyγ-ray is killed and wounded the purpose that reaches treatment to tumor by radionuclide.
The specific embodiment
Below in conjunction with the specific embodiment, technical solution of the present invention is described further.
Embodiment 1:
32p resin anion (R.A.) microsphere
(1) styrene that by the 2g degree of cross linking be 4%, diameter is 10 μ m～100 μ m-divinylbenzene anion exchange resin (201 * 7 resin) transition is OH type strongly basic anionic resin;
(2) under room temperature condition, by step (1) gained strongly basic anionic resin, at 20mL, pH value, being 10 contains 8GBq
32the Na of P
3pO
4react 1h in solution, by radionuclide anion exchange to resin anion (R.A.) inside;
Extract reaction solution with the low background α of BH1216 type, β measuring instrument (Beijing Nuclear Instrument Factory's production) is measured in solution remaining
32p activity, calculate
32the utilization rate of P, then water cleans resin to the pH value of cleanout fluid and is less than 8;
(3) 1g exchange is wherein had
32the resin of P joins the YCl that contains 200 μ gY that 20mL, pH value are 5
3in solution, in room temperature reaction 4h, make the Y in solution
3+with resin inside
32pO
4 3-reaction forms precipitation, and P-32 further is fixed on to resin inside;
(4) precipitation has
32the pH value that the resin anion (R.A.) of P is washed with distilled water to cleaning mixture is 6, then resin is soaked to 4h in 1mol/L NaOH solution, filters, and obtains
32p resin anion (R.A.) microsphere.
P-32 resin anion (R.A.) microsphere that will be curing through precipitant is got respectively 0.5g and soak 20d in the normal saline of 37 ℃ and people's whole blood, the activity of P-32 calculate the release rate (table 5) of P-32 in every day sampling and measuring soak.Having the resin microsphere of P-32 not add precipitant other 1g exchange is cured, with washed with de-ionized water to pH value, be directly 6 and get respectively 0.5g and soak 20d in the normal saline of 37 ℃ and people's whole blood, the activity of P-32 calculate the release rate (table 5) of P-32 in every day sampling and measuring soak.
The data of table 5 show, do not add the curing P-32 microsphere prepared of precipitant and P-32 can not be fixed on to microsphere inside; And using the curing P-32 microsphere of precipitant, its release rate is lower.And use 40 ℃ of normal saline that the P-32 microsphere prepared is first soaked, and the unsettled P-32 of part can be removed, can further reduce the radioactivity microsphere and enter the high risk of release rate after human body.
Table 5 solidifies and the P-32 microsphere performance comparison curing without precipitant through precipitant
Embodiment 2:I-131 resin anion (R.A.) microsphere
To in the NaI solution that contains 5.2GBq I-131 that OH type strong-basicity styrene-divinylbenzene anion exchange resin (201 * 7 resin) is 10 at 20mL, pH value under room temperature condition that the 2g degree of cross linking is 4%, diameter is 10 μ m～100 μ m, soak 1h, by radionuclide anion exchange to resin anion (R.A.) inside;
Get above-mentioned reaction gained reactant liquor, with F-613 type radioactive counter (Beijing Nuclear Instrument Factory), measure remaining I-131 activity in solution, calculate the utilization rate of I-131, then water cleaning resin to the pH value of cleanout fluid is less than 8;
There is the resin of I-131 to join the AgNO that contains 1mg Ag that 20mL, pH value are 3 1g exchange
3in solution, room temperature reaction 3h, the pH value that is washed with distilled water to cleaning mixture is 6, then in 1mol/L NaOH solution, soaks 4h, filters, and obtains the I-131 resin anion (R.A.) microsphere curing through precipitant.
Get respectively the 0.5g microsphere and soak 15d in the normal saline of 37 ℃ and people's whole blood, the activity of I-131 calculate the release rate (table 6) of I-131 in every day sampling and measuring soak.
Having the resin microsphere of I-131 not add precipitant other 1g exchange is cured, after cleaning and be 6 to the cleanout fluid pH value with distilled water, get respectively the 0.5g resin and soak 15d in the normal saline of 37 ℃ and people's whole blood, the activity of I-131 calculate the release rate (table 6) of I-131 in every day sampling and measuring soak.
The data of table 6 show, do not add the curing I-131 microsphere prepared of precipitant and I-131 can not be fixed on to microsphere inside, and I-131 substantially can not be in the inner reservation of resin; And using the curing I-131 microsphere of precipitant, its release rate is lower.Use 40 ℃ of normal saline that the I-131 microsphere prepared is first soaked, the unsettled I-131 of part can be removed, after immersion treatment, the release rate of I-131 can be reduced to below 1 ‰, reduces the radioactivity microsphere and enters the high risk of release rate after human body.
Table 6 solidifies and the I-131 microsphere performance comparison curing without precipitant through precipitant
Test example
32p-RMS and
125the inhibitory action of I-RMS to tumor
According to the preparation method in embodiment 1, prepare
32p-RMS (
32p resin anion (R.A.) microsphere); By radionuclide by
131i replaces to
125i, prepare according to the preparation method in embodiment 2
125i-RMS (
125i resin anion (R.A.) microsphere).
The average diameter of all microspheres is 25 μ m ± 10 μ m, and wherein diameter is less than 5% (w/w) lower than the microsphere of 15 μ m, and the microsphere that is greater than 35 μ m is less than 10% (w/w);
32the P-RMS specific radioactivity is about 15mCi/g-80mCi/g (555MBq/g-2960MBq/g);
125the I-RMS specific radioactivity is about 50mCi/g (1850MBq/g);
32p-RMS and
125the radionuclide purity of I-RMS all is greater than 95%; Density is 1.2-1.3g/mL;
32p-RMS and
125the release rate of I-RMS 20d in 37 ℃ of normal saline is less than 0.1%; RMS can inject after being suspended with normal saline before use.
Nude mice is provided by Sichuan Institute of Tradition Chinese Medicine in experiment.The liver tumor tissue culture procedures of experiment mice is as follows: by the human liver cancer cell (H-CS of built strain, Sichuan Institute of Tradition Chinese Medicine provides) be inoculated into nude mice (the weight average body weight 21.3g in 100 5 week ages, be male) subcutaneous tissue of back, every is injected volume is 0.2mL (approximately 10
7individual oncocyte), then be placed in aseptic raising on ultra-clean biological platform, after the incubation period of 10d, all mices all grow tumor.
From tumor-bearing mice, random choose goes out 80 and grouping, 10 every group, is divided into totally 8 groups of A, B, C, D, E, F, G and H.Wherein B, C, D, E, F organize conduct
32the P-RMS treatment group, inject
32the activity of P-RMS is followed successively by: B organizes 30MBq, and C organizes 65MBq, and D organizes 120MBq, and E organizes 180MBq, and F organizes 240MBq; G group and the conduct of H group
125the I-RMS treatment group, inject respectively
125the activity of I-RMS is 33MBq and 120MBq; A organizes as a control group, the resin microsphere of the "dead" nucleic of injection and other radioactivity resin microsphere treatment group equals in quality.
All mices all putting to death in 14 days after administration, separate complete tumor tissues and take the weight of tumor tissues, then according to tumor weight, calculate suppression ratio (suppression ratio=(in matched group tumor weight-treatment group tumor)/matched group tumor weight * 100%).Result of the test is in Table 7.
Experimental result (table 7) shows,
32p-RMS and
125i-RMS all has the effect of obvious inhibition tumor growth.Compare with matched group, wherein, use
32in the tumor-bearing mice that P-RMS is treated, after local injection radioactivity resin anion (R.A.) microsphere, tumor growth obtained effectively controlling; After 2 weeks, the suppression ratio of tumor reaches 22.5%-47.2%, and the relation of the suppression ratio of tumor and dosage is comparatively obvious, uses below 120MBq
32during P-RMS, the suppression ratio of tumor is proportional with the activity of the microsphere be injected into; When the microsphere activity of injecting is 120-240MBq, the inhibitory action of tumor is apparent in view, and all more than 40%, and the activity of injection microsphere is little on the impact of suppression ratio, explanation after higher than certain activity, continues to strengthen the use amount of microsphere to the not too many impact of the raising of tumour inhibiting rate.
Use
125the volume of the tumor-bearing mice that I-RMS is treated tumor in 2 weeks also has certain variation, uses activity for 33MBq's
125the group that I-RMS is treated, tumour inhibiting rate is 16.9%, and uses activity for 120MBq's
125the group that I-RMS is treated, tumour inhibiting rate is 20.4%, explanation
125i-RMS can play inhibitory action to tumor propagation under certain activity.
Contrast is with under activity
32p-RMS and
125the tumor suppression effect of I-RMS treatment group can find, uses with activity
32the tumour inhibiting rate of P-RMS treatment group will higher than
125the I-RMS treatment group, illustrate under same time,
32p give tumor tissues effective dose will higher than
125i, thus cause
32the P treatment group has higher tumour inhibiting rate.
Table 7
32p-RMS and
125the suppression ratio of I-RMS to the tumor-bearing mice in-vivo tumour
Claims (15)
1. a radioactivity resin anion (R.A.) microsphere, it is characterized in that: it comprises that diameter is the resin anion (R.A.) that 5 μ m～200 μ m, the degree of cross linking are 1%～20%, and solidifies in the radionuclide of described resin anion (R.A.) inside with precipitation form;
Described solidifying in the radionuclide of resin anion (R.A.) inside with precipitation form is to be formed by the anion of anion radionuclide P-32, I-125, I-131, Re-186 or Re-188 and the cationoid reaction of on-radiation calcium metal, barium, copper, silver, ferrum, magnesium, strontium, zinc, yttrium, aluminum or indium;
Described radioactivity resin anion (R.A.) microsphere is to resin anion (R.A.) inside by the anion exchange of radionuclide; The resin anion (R.A.) that then will contain the anion radionuclide joins in the solution that contains on-radiation metal cation precipitant, the radioactivity resin anion (R.A.) microsphere prepared;
Described resin anion (R.A.) is strongly basic anionic resin or weak anion resin, and resin is converted to OH or Cl type resin anion (R.A.) before using;
In every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, and the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
2. radioactivity resin anion (R.A.) microsphere according to claim 1, it is characterized in that: the anion of described anion radionuclide P-32, I-125, I-131, Re-186 or Re-188 is
32pO
4 3-, H
32pO
4 2-, H
2 32pO
4 -,
131i
-,
125i
-,
131iO
3 -,
125iO
3 -,
186reO
4 -or
188reO
4 -.
3. radioactivity resin anion (R.A.) microsphere according to claim 1, is characterized in that described resin anion (R.A.) is that diameter is the resin anion (R.A.) that 10 μ m～100 μ m, the degree of cross linking are 4%～10%.
4. radioactivity resin anion (R.A.) microsphere according to claim 1, it is characterized in that: described anion radionuclide is P-32, and its anion is
32pO
4 3-, H
32pO
4 2-or H
2 32pO
4 -, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, the mol ratio of on-radiation metal cation and radionuclide anion is 15～10
6: 1.
5. radioactivity resin anion (R.A.) microsphere according to claim 1, it is characterized in that: described anion radionuclide is I-125 or I-131, and its anion is
131i
-,
125i
-,
131iO
3 -or
125iO
3 -, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～14GBq, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
6. radioactivity resin anion (R.A.) microsphere according to claim 1, it is characterized in that: described anion radionuclide is Re-186 or Re-188, and its anion is
186reO
4 -or
188reO
4 -, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
7. the preparation method of the described radioactivity resin anion (R.A.) of a claim 1-3 any one microsphere is characterized in that comprising the following steps:
(1) resin anion (R.A.) is made the transition as OH
-or Cl
-the type resin anion (R.A.);
(2) step (1) gained resin anion (R.A.) is reacted to 10min～4h in the solution that contains the anion radionuclide, reaction temperature is 25 ℃～60 ℃, by the anion exchange of radionuclide to resin anion (R.A.) inside;
(3) step (2) gained resin anion (R.A.) is joined in the solution that contains on-radiation metal cation precipitant, react 10min～6h at 25 ℃～60 ℃ temperature, make the radionuclide anionic reactive of on-radiation metal cation in solution and resin anion (R.A.) inside form precipitation, radionuclide is formed to precipitation and further be solidificated in resin inside;
Described on-radiation metal cation precipitant be can with the soluble-salt of calcium metal, barium, copper, silver, ferrum, magnesium, strontium, zinc, yttrium, aluminum or the indium of the anion generation precipitation of radionuclide P-32, I-125, I-131, Re-186 or Re-188 in any one;
(4) step (3) gained radioactivity resin anion (R.A.) microsphere is re-used after water cleans to the 0.1mol/L～4.0mol/L NaOH solution soaking 30min～24h of 25 ℃～60 ℃, be prepared into the resin anion (R.A.) microsphere.
8. radioactivity resin anion (R.A.) method for preparing microsphere according to claim 7, it is characterized in that: described in step (1), resin anion (R.A.) is strongly basic anionic resin, makes the transition as OH
-the type strongly basic anionic resin, the pH value that contains on-radiation metal cation precipitant solution described in step (3) is 2～12.
9. radioactivity resin anion (R.A.) method for preparing microsphere according to claim 7, it is characterized in that: described in step (1), resin anion (R.A.) is weak anion resin, makes the transition as Cl
-the type weak anion resin, the pH value that contains on-radiation metal cation precipitant solution described in step (3) is less than 4.
10. radioactivity resin anion (R.A.) method for preparing microsphere according to claim 7, it is characterized in that: described anion radionuclide is P-32, and its anion is
32pO
4 3-, H
32pO
4 2-or H
2 32pO
4 -any one in the metal cation soluble-salt that described on-radiation metal cation precipitant is calcium, barium, copper, silver, ferrum, ferrous iron, magnesium, strontium, zinc, yttrium, indium or aluminum, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 15～10
6: 1.
11. radioactivity resin anion (R.A.) method for preparing microsphere according to claim 7 is characterized in that:
Described anion radionuclide is I-125, and its anion is
125i-, the soluble-salt that described on-radiation metal cation precipitant is copper or silver, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～14GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
12. radioactivity resin anion (R.A.) method for preparing microsphere according to claim 7 is characterized in that: described anion radionuclide is I-131, and its anion is
131i
-the soluble-salt that described on-radiation metal cation precipitant is copper or silver, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
13. radioactivity resin anion (R.A.) method for preparing microsphere according to claim 7 is characterized in that: described anion radionuclide is I-125, its anion can be
125iO
3 -the soluble-salt that described on-radiation metal cation precipitant is calcium, barium, copper, silver, strontium, zinc or indium, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～14GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
14. radioactivity resin anion (R.A.) method for preparing microsphere according to claim 7 is characterized in that: described anion radionuclide is I-131, its anion can be
131iO
3 -the soluble-salt that described on-radiation metal cation precipitant is calcium, barium, copper, silver, strontium, zinc or indium, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
15. radioactivity resin anion (R.A.) method for preparing microsphere according to claim 7 is characterized in that: described anion radionuclide is Re-186 or Re-188, and its anion is
186reO
4 -or
188reO
4 -the soluble-salt that described on-radiation metal cation precipitant is calcium, barium, strontium or aluminum, in every gram resin anion (R.A.), the radioactivity of the anion radionuclide of load is 370MBq～37GBq, and in solution, the mol ratio of on-radiation metal cation and radionuclide anion is 10～10
6: 1.
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| CN106178006B (en) * | 2016-08-11 | 2019-09-03 | 成都纽瑞特医疗科技有限公司 | Medical iodine -131 carbosphere and preparation method thereof |
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| CN111939276B (en) * | 2020-08-26 | 2023-09-26 | 成都纽瑞特医疗科技股份有限公司 | Carbon microsphere loaded with metal nuclide as well as preparation method and application thereof |
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| CN1798580A (en) * | 2003-04-04 | 2006-07-05 | 生物领域医疗公司 | Microspheres comprising therapeutic and diagnostic radioactive isotopes |
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| US5011677A (en) * | 1984-11-19 | 1991-04-30 | The Curators Of The University Of Missouri | Radioactive glass microspheres |
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