CN103861157A - MRI development embolism microballoon based on gadolinium alginate - Google Patents
MRI development embolism microballoon based on gadolinium alginate Download PDFInfo
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- CN103861157A CN103861157A CN201210547794.4A CN201210547794A CN103861157A CN 103861157 A CN103861157 A CN 103861157A CN 201210547794 A CN201210547794 A CN 201210547794A CN 103861157 A CN103861157 A CN 103861157A
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- alginic acid
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- sodium alginate
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- lanthanide metal
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Abstract
The invention discloses preparation of a magnetic resonance imaging (MRI) developpable microbead and application potential of the microbead to tumour arterial embolism treatment. Sodium alginate is taken as a raw material, the microbead is formed by employing an electrostatic drop generator, and on the basis, lanthanide metal ion such as Gd<3+> is introduced as a development group for MRI imaging, so that visualization of embolism treatment process is realized.
Description
Technical field
The present invention relates to the to develop preparation of tumor embolism microsphere, is specifically on the basis of alginic acid embolism microball, introduces the MRI composition that can develop, and realizes the visual of embolotherapy.
Background technology
1971, Folkman proposed tumor neogenetic blood vessels theory (document 1:Judah Folkman, N Engl J Med 1971; 285:1182-1186), the growth of tumor depends on new vessels.New vessels not only provides nutrition for the growth of tumor, is also the passage of primary tumo(u)r transfer and the prerequisite of metastasis hypertrophy.Artery embolization for treatment art is this feature for tumor, under the guiding of medical image means, embolism materials is optionally injected into by conduit in the supply blood vessel or lesion vessels of diseased organ, interrupts blood supply, finally reaches the object that suppresses tumor growth.Clinically, cooperatively interact with surgical removal, chemotherapy, X-ray therapy etc., for the situation of tumor, play radical-ability, Palliative and preoperative auxiliary therapy, one of oncotherapy means are absolutely necessary.
Embolization for oncotherapy has two kinds: SAE and Chemoembolization.Wherein, Chemoembolization is the blood supply target artery that embolism materials and cancer drug therapy molecular mixing is injected to tumor, has both stoped tremulous pulse blood supply, realizes embolotherapy, again can release anti-cancer medicine, realize chemical therapeutic effect.Chemoembolization is safe and reliable, especially at hepatorrhagia and liver cancer, is optimum Therapeutic Method (document 2:Zupancic et al.European Journal ofPediatric Surgery; 1995,5 (2): 88-91).
The desirable suppository of demand clinically, should meet following requirement: nontoxic, no antigen, have good biocompatibility, can be rapidly by blood vessel, the transmission of The book of Changes conduit of the inaccessible different bore different flows of demand, be easy to get, easily sterilization, can control the length of occlusion time.In the past between twenty or thirty year, scholar's research different chemoembolization materials, as gelfoam (document 3:(Matsumoto et al.1986), collagen (document 4:John R.Daniels et al.Cancer Res May 1,198848; 2446), ethyl cellulose (document 5:Ku et al.1995), poly(hydrobutyl ester) (document 6:A.Ch.Kassab et al.Journal ofBioactiveand Compatible Polyers; July 1999; 14 (4): 291-303), cyanoacrylate (document 7:Jeffrey S.Pollak, Robert I.White; Journal of Vascular andInterventional Radiology, 2001,12 (8): 907-913) etc.,
Sodium alginate is the polysaccharide polymer extracting from natural algae; sodium alginate passes through 1 by guluronic acid (G) and mannuronic acid (M); 4-glycosidic bond connect and by GG, the GM of different proportion, the copolymer that MM fragment forms (document 3:Fischer FG, HoppeSeylersZ Physiol Chem.1955; 302 (4 – 6): 186 – 203).Wherein, G unit for metal ion as Ga2+ has good gelation, two G unit and Ca2+ ions binding form eggshell structure (document 8:
o, Draget KI.Carbohydr Eur.1996; 14:6 – 12), as shown in Figure 1: alginic acid gel structure
Biocompatibility, safety and biodegradability that sodium alginate is good (document 9:Haug A, Larsen B,
o.Acta Chem Scand.1963; 17:1466 – 8), it is paid close attention to widely having obtained people aspect embolism materials research.As hysteromyoma thromboembolism (document 10:Ravina JH, et al.1995; 346 (8976): 671 – 2), primary hepatocarcinoma (document 11:J.S.KIM, B.K.KWAK, H.J.SHIM, et al.; Journal ofMicroencapsulation, August 2007; 24 (5): 408 – 419) etc.Clinically, alginate microsphere is also applied to primary hepatocarcinoma, hysteromyoma, Hypersplenism etc. as ripe technology.
The problem that clinical treatment and the technology reported now exist comprises the following aspects:
(1) distribution in vivo to suppository and effect situation do not have detection method intuitively.Clinically, thromboembolism therapy is under the guidance of medical image means, by conduit, embolism materials is optionally injected in diseased organ blood vessel.Conventionally in importing embolism materials, inject developing agent as iodized oil, iohexol etc., by the development of contrast agent, indirectly show importing and the thromboembolism situation of embolism materials.Contrast agent separates with embolism materials, make the result of the contrast agent of observing can not truly reflect the effect situation of embolism materials, and free contrast agent also has certain toxic and side effects to health.
(2) after first thromboembolism, treat clinically, easily cause state of an illness delay.After thromboembolism, the contrast agent importing goes out human body through body-internal-circulation metabolism.Embolism materials acts on after a period of time in vivo, again imports contrast agent, observes effect situation and the therapeutic effect of embolism materials, determines further therapeutic scheme according to testing result.In therapeutic process, the effect situation of embolism materials is also indefinite, and doctor can only confirm that whether this therapeutic scheme is applicable and effective according to the testing result after certain hour, and adjusts therapeutic scheme or determine next step treatment plan according to testing result.Treatment and separating of detecting, extended treatment cycle, easily makes patient miss the optimal treatment phase, delay treatment treatment.
For existing the problems referred to above in clinical, if prepare a collection of embolism materials with imaging function, collect embolotherapy and be developed in one, realize the visual of embolotherapy process, on the basis of calcium alginate plastic beads, utilize Gd to replace Ca, preparation has the alginic acid gadolinium glue pearl of imaging function, as the suppository in cancer treatment procedure
Summary of the invention
The present invention is prepared on the basis of platform at existing calcium alginate plastic beads, introduces respectively Gd
3+as the MRI group that develops, preparation has the alginic acid glue pearl of imaging function, as the visual embolism materials of a new generation with Gd-DTPA.
Technical scheme of the present invention is as follows:
Visual thromboembolism micro gel bead, taking sodium alginate as material, is introduced lanthanide metal ion Gd
3+, Eu
3+or Tb
3+, utilize Electrostatic droplet generator to prepare alginic acid gadolinium micro gel bead.
Be specially:
Under aqueous solution state, sodium alginate soln splashes into GdCl by Electrostatic droplet generator
3in solution, Gd under ionotropic change
3+by Na
+displace, with sodium alginate G fragment bonding, adjacent sodium alginate strand is changed from the rolled state naturally stretching to banded structure in good order, finally form the three-dimensional netted micro gel bead of alginic acid gadolinium.
Gadolinium is lanthanide series metal, atomic number 64, its ion has 7 unpaired electrons, it is the metal ion that a paramagnetism is very strong, can significantly shorten the relaxation time of T1, T2, especially more obvious with T1, in the scope of concentration 0~1mmol/L, relaxation time linearly declines, thereby affect the signal intensity of MRI, can be used as MRI contrast agent.
Tool of the present invention has the following advantages:
(1) sodium alginate has been widely used in clinical as embolism materials.Sodium alginate is by α-D-MANNOSE aldehydic acid (α-D-Mannuronic Acid, M unit) and β-L-guluronic acid (β-L-Gluluronic Acid, G unit) and the M sequence of mixing with G by the crosslinked electronegative straight-chain polysaccharide forming of 1-4 glycosidic bond, structural formula as shown in the figure:
Due to its good biocompatibility and biodegradability, so be widely used in the research of bio-medical material.
(2) embolism materials and radiography group are integrated, have realized the visual of thromboembolism process.By the electrostatic drop generation of mild condition, the alginic acid glue pearl that preparation collection embolism materials and radiography are detected on one, has effectively avoided embolism materials in clinical treatment to separate the problem of bringing with contrast agent, has realized directly perceived visual controlledization of therapeutic process.In the importing process of embolism materials, can intuitively see the actual thromboembolism situation of material; After thromboembolism, doctor also can detect the effect situation of embolism materials at any time, adjusts in time therapeutic scheme, makes patient obtain best treatment.
(3) traditional mode of breakthrough embolotherapy, has realized the research of suppository of new generation.
Brief description of the drawings
Fig. 1 is alginic acid gel structure;
Fig. 2 is the electron micrograph of alginic acid gadolinium gel beads;
Fig. 3 is the developing result of alginic acid gadolinium gel beads in MRI;
Fig. 4 is the variation along with alginic acid gadolinium gel beads number, corresponding MRI Strength Changes curve;
Fig. 5 is calcium alginate and the change of size block diagram of alginic acid gadolinium glue pearl in normal saline.
Detailed description of the invention
Below by embodiment, the present invention will be further described.
Contain can the develop preparation of alginic acid gadolinium gel beads of group of MRI:
1, solution preparation
1) 0.1mol/L GdCl
3solution: get 13.18g(0.05mol) GdCl
3, be dissolved in 500mL deionized water, after dissolving completely, with 0.22 μ m membrane filtration, collect filtrate for subsequent use.
2) 1.5%(w/v) sodium alginate soln: get 1.5g sodium alginate, be dissolved in 100mL deionized water, after stirring is dissolved it completely, use successively 0.8 μ m, 0.45 μ m, 0.22 μ m membrane filtration, collect filtrate and be placed in 4 ° of C refrigerators, spend the night degassed.
2, glue pearl preparation
1) 1.5%(w/v) sodium alginate soln takes out recovery room temperature from refrigerator, draws 2mL sodium alginate soln with 5mL syringe, and connection standard 5# syringe needle, is placed in Electrostatic droplet generator assigned address, and adjusting pump speed is 12.7mL/h.2) 200mL 0.1mol/L GdCl is housed
3the 250mL beaker of solution is placed under syringe needle, and syringe needle lower end and liquid level distance are 1cm.
2) open microcapsule preparing instrument, setting voltage is 50V, and frequency is 120HZ.The anodal syringe needle that connects of microcapsule preparing instrument, negative pole connects the iron coil that is placed in beaker.
3) microcapsule preparing instrument stable after, open Electrostatic droplet generator, sodium alginate soln forms droplet by syringe needle under the effect of electrostatic field, droplet enters 0.1mol/LGdCl
3solution, sodium alginate and Gd
3+gelation forms alginic acid gadolinium gel beads.
4), after having reacted, standing 30min makes the abundant gelation of alginic acid gadolinium.
5) 0.1mol/L GdCl
3solution washing gel beads 3 times, removes gel pieces, 4 ° of C Refrigerator stores.
Table 1: calcium alginate and the change of size of alginic acid gadolinium glue pearl in normal saline
Contain can the develop property representation of alginic acid gadolinium gel beads of group of MRI:
1, the pattern of alginic acid gadolinium gel beads and grain size
Fig. 1 is alginic acid gadolinium gel beads electron micrograph, and result shows to adopt alginic acid gadolinium gel beads prepared by electrostatic drop generation to be spheroidal, smooth surface, evenly, mean diameter is 351.6 μ m(n>300 to size)
2, the MRI developing performance of alginic acid gadolinium gel beads
Fig. 2 is the developing result of alginic acid gadolinium gel beads in MRI, using deionized water as blank, the glue pearl number containing is successively 1,5,20,50,100, N1(N1 >=300), N2(N2 >=500).The MRI development effect demonstration of alginic acid gadolinium glue pearl, along with increasing of glue pearl number, MRI intensity strengthens gradually, and the relative variation tendency of its intensity is as shown in Figure 3.Illustrate, alginic acid gadolinium gel beads has good MRI development effect, and its development intensity can strengthen along with containing increasing of glue pearl number, quantification according to demand in application.
3, alginic acid gadolinium gel beads is at 0.9%(w/v) stability in NaCl solution
With calcium alginate gel beads in contrast, calcium alginate and alginic acid gadolinium gel beads are placed in to 0.9%(w/v) NaCl solution, a shooting electron micrograph of fixing time, pattern and the change of size of observing glue pearl.Along with the prolongation of time, calcium alginate plastic beads is swelling gradually, is still smooth spheroidal, but particle diameter increases gradually, and significant change does not occur alginic acid gadolinium gel beads.Calcium alginate plastic beads and the change of size of alginic acid gadolinium glue pearl in normal saline are as shown in table 1, and its relative size change of particles trend as shown in Figure 4.As can be seen from Figure, in normal saline, along with the continuity of time, the particle diameter of calcium alginate plastic beads increases gradually, increase to original 1.8 times, and significant change does not occur the particle diameter of alginic acid friction pearl when 48h.Explanation thus, compared with calcium alginate gel beads, in normal saline, alginic acid gadolinium gel beads is very stable.
Claims (6)
1. the embolism microball that can develop of the MRI based on alginic acid, is characterized in that: taking sodium alginate as material, introduce lanthanide metal ion on alginic acid, form alginic acid lanthanide series metal gel beads by electrostatic drop generation, as the visual suppository of MRI.
2. according to the alginic acid embolism microball that can develop of the MRI described in claim, it is characterized in that: wherein lanthanide metal ion is the visual group of MRI, and under ionotropic change, lanthanide metal ion is by Na
+displace, with sodium alginate G fragment bonding, adjacent sodium alginate strand is changed from the rolled state naturally stretching to banded structure in good order, finally form the three-dimensional netted micro gel bead of alginic acid lanthanide series metal.
3. the MRI according to claim 1 and 2 MRI development group in alginic acid embolism microball that can develop, is characterized in that: the lanthanide metal ion described in it is Gd
3+, Eu
3+or Tb
3+.
4. the MRI of claim 1 based on the alginic acid preparation method for embolism microball of can developing, is characterized in that:
Rare earth lanthanide metal ion is replaced to the Na in sodium alginate
+, form more stable alginic acid lanthanide complex; Detailed process, by sodium alginate soln, forms droplet by Electrostatic droplet generator, and droplet enters in the chloride solution of rare earth lanthanide metal ion, and under ionotropic change, rare earth lanthanide metal ion is by the Na in sodium alginate
+displace, form the alginic acid gel beads of lanthanide series metal, thereby prepare the alginic acid embolism microball with MRI developing function.
5. can the develop preparation method of embolism microball of the MRI based on alginic acid according to claim 4, is characterized in that:
The chloride mol ratio of described sodium alginate and lanthanide metal ion is less than 3, and sodium alginate soln mass volume ratio scope is 0.01-50%(w/v), rare earth lanthanide metal ion molar concentration scope is 1 × 10
-6-100mol/L.The sodium alginate monomer that example is concrete adopted herein and the chloride mol ratio of lanthanide metal ion are 0.0075, and sodium alginate soln concentration is 1.5%(w/v), the chloride solution molar concentration of rare earth lanthanide metal ion is 0.1mol/L.
6. the MRI of claim 1 based on the alginic acid application for embolism microball of can developing, is characterized in that: the embolism microball that can develop of the MRI based on alginic acid can be used for the visual development of MRI of thromboembolism process.
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Cited By (2)
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CN106552284A (en) * | 2016-12-06 | 2017-04-05 | 华中科技大学 | A kind of development embolism materials and preparation method thereof |
CN106620829A (en) * | 2017-03-13 | 2017-05-10 | 安疗生命科学(武汉)有限公司 | Developing embolism material and preparation method thereof |
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Cited By (3)
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CN106552284A (en) * | 2016-12-06 | 2017-04-05 | 华中科技大学 | A kind of development embolism materials and preparation method thereof |
CN106552284B (en) * | 2016-12-06 | 2020-07-03 | 华中科技大学 | Developing embolism material and preparation method thereof |
CN106620829A (en) * | 2017-03-13 | 2017-05-10 | 安疗生命科学(武汉)有限公司 | Developing embolism material and preparation method thereof |
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Application publication date: 20140618 |