CN100502957C - Temperature sensing nano gel system for blood vessel embolism material - Google Patents
Temperature sensing nano gel system for blood vessel embolism material Download PDFInfo
- Publication number
- CN100502957C CN100502957C CNB2006101245393A CN200610124539A CN100502957C CN 100502957 C CN100502957 C CN 100502957C CN B2006101245393 A CNB2006101245393 A CN B2006101245393A CN 200610124539 A CN200610124539 A CN 200610124539A CN 100502957 C CN100502957 C CN 100502957C
- Authority
- CN
- China
- Prior art keywords
- temperature
- gel
- temperature sensing
- gel system
- nanogel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Abstract
The invention relates to a vessel plug material used in intervene treatment. Wherein, said material is temperature-sensitive nanometer gel system based on polymer N-isopropyl acrylamide (PNIPAAm), which comprises polymer N-isopropyl acrylamide nanometer gel and dispersed medium, while the gel mass percentages is 3-20% and the particle diameter of temperature-sensitive nanometer gel is 50-1000nm. The inventive temperature-sensitive nanometer gel system also can contain developer, soluble antineoplastic. The invention can control the polymer monomer kinds and ratios, the crosslinker amount and the density of temperature-sensitive nanometer gel, to control the sol-gel transformation temperature of said system, and the inventive product has better external flow property and high sol-gel transformation speed, to be used to treat vessel plug, etc.
Description
Technical field
The present invention relates to biomedical engineering field, be specially a kind of novel interventional therapy vascular suppository material-temperature sensing nano gel system.
Background technology
Embolotherapy is meant that causing suppository by the selective catheterizaiton importing makes corresponding vascular occlusion reach therapeutic purposes.Now existing multiple intervention vascular suppository material.Mainly be divided into graininess embolism materials such as gelatin, albumin, the Pseudobulbus Bletillae (Rhizoma Bletillae) and polyvinyl alcohol etc.; Liquid embolism materials such as dehydrated alcohol, iodized oil etc.; Large-scale embolism materials such as bung flange, can take off sacculus etc.; (Sheng Xizhong etc., Medical Imaging magazine .2004,14 (10): 852 such as magnetic embolism materials such as glucosan magnetic composite microsphere and radioactivity embolism materials; Li Shipu etc., biological orthopaedics material and clinical research .2005,12 (2): 46).Above-mentioned embolism materials respectively has its pluses and minuses and the scope of application.At present clinical what be used for malignant tumor arteries thromboembolism mainly is biodegradable peripheral vessel embolism materials, as iodized oil and gelatin etc.The time that they keep thromboembolism in vivo is generally for 2 weeks～February, needs repeatedly thromboembolism; The viscosity of iodized oil and gelatin is bigger in addition, is difficult for injecting and medicine carrying (Jiang Xiaoliang etc., modern tumor medical science .2006,14 (1): 112).
The temperature sensitive type poly compound can sense ambient temperature variation, in very narrow temperature range, take place to change mutually, be widely used in field (Li SK, et al.JControl Release.2001, the 75:55 such as immobilization, organizational project of pharmaceutical carrier, enzyme; Shimizu T, et al.Tissue Eng.2001,7:141; Ding Z, et al.Nature.2001,411:59).Poly-N-isopropyl acrylamide (PNIPAAm) base polymer owing to its phase transition temperature near human body temperature become one research focus (Schild H G.Prog Polym Sci, 1992,17:163).The aqueous solution that Bae etc. have reported LINEAR N-N-isopropylacrylamide (NIPAAm) and acrylic acid (AA) copolymer has reversible gelation behavior (Han CK, et al.Polym.1998,39 (13): 2809) at 32 ℃ on critical concentration the time.Hu etc. have prepared the interpenetrating polymer networks nanoparticle of polyacrylic acid and poly-N-isopropyl acrylamide, the aqueous dispersion of this nanoparticle at room temperature is flowable, more than 33 ℃ because of physical crosslinking become solid (Hu ZB, et al.Adv Mater.2004,16:305-309).1233), (Li X, et al.Biomaterials.2005,26:7002 such as Liu contain recently (Sheng Xizhong etc., practical radiology magazine .2005,21 (12): such as uncommon loyalty; Liu Wen is wide etc., CN 1679620A, CN1546057A) and (Bae HL such as Bae, et al.Biomacromolecules.2006,7:2059.) done of the research of PNIPAAm class linear polymer solution respectively as the liquid embolic material, point out that this type of suppository has non-adhesive, zoopery has obtained better effects.And as vascular suppository material,, avoided the use of organic solvent and cross-linking agent with the temperature sensitive type material owing to only with the regulation and control factor of temperature as colloidal sol-gel conversion, safer.
Compare with temperature sensitive type linear polymer solution, its rheology of temperature sensitive type nanogel dispersion of higher concentration has stronger temperature sensitivity and lower viscosity (Stieger M, et al.Langmuir.2004,20:7283; Macromolecules.2003,36:8811).At present, the poly-N-isopropyl acrylamide class nanogel vascular suppository material that is used for interventional therapy yet there are no report.
Summary of the invention
The purpose of this invention is to provide a kind of temperature sensing nano gel system that is used for vascular suppository material, this temperature sensing nano gel system has external good fluidity, the fireballing characteristic of colloidal sol-gel conversion.
A kind of temperature sensing nano gel system that is used for vascular suppository material provided by the invention, it is characterized in that, this temperature sensing nano gel system has three-dimensional net structure, it comprises poly-N-isopropyl acrylamide base polymer nanogel and disperse medium, wherein, the mass percent concentration of poly-N-isopropyl acrylamide base polymer nanogel is 3～20%, surplus is a disperse medium, the chemical constitution skeleton symbol of poly-N-isopropyl acrylamide base polymer nanogel is: poly (A-co-B), wherein, A is the N-N-isopropylacrylamide, and B is a comonomer, is the acrylic acid or derivatives thereof, A, the molar percentage of B is 80～99:1～20, cross-linking agent is the bisacrylamide compounds that N-replaces, and dosage of crosslinking agent is 0.2～10mol% of A and B consumption sum, and the particle diameter of nanogel is 50～1000nm; Disperse medium is the phosphate buffered solution of water, normal saline or pH7.4.
Above-mentioned comonomer is at least a in acrylamide, the N-acrylamide, acrylic acid, methacrylic acid, acrylate and the methacrylate that replace.
The temperature sensing nano gel system that is used for vascular suppository material of the present invention is to have the nanogel particle suspension of three-dimensional net structure in aqueous dispersion medium, adds micronized heavy metal inorganic particulate or magnetic particle or iohexol simultaneously and plays the development effect.Nanogel particle wherein has temperature-sensing property, and single particle varies with temperature swelling-contraction that volume can take place, and its stereomutation amount can change several times to tens times because of the difference of the consumption of the cross-linking agent of adding.And the temperature-sensitive nano-gel dispersion of nano-particles body of higher concentration is when varying with temperature, and the transformation of colloidal sol-gel has promptly taken place in mobile-noncurrent transformation that general performance goes out.The temperature sensing nano gel system that is used for vascular suppository material that the present invention proposes is with variation of temperature, the difference difference of nanogel content in the difference of difference, dosage of crosslinking agent and kind that the mostly transformation mutually of experience swell gel-fluid-contractions gel, the temperature of two transformation are formed because of the nanogel comonomer, the system.Both can adjust swell gel-fluidic transition temperature is body temperature, and the transition temperature of also adjustable rectification body-contraction gel is a body temperature.So can utilize swell gel-fluidic transformation, promptly high temperature is fluid, be injected into the reduction of back Yin Wendu in the body and form swell gel, play the effect of occluding vascular; Also can utilize fluid-contraction gel conversion, promptly room temperature is a fluid, is injected into the gel that back Yin Wendu raises and formation is shunk in the body, uses as vascular suppository material.
The temperature sensing nano gel system that is used for vascular suppository material that the present invention proposes because dispersion is the small-particle of nano-scale, is different from the microgranules (more than the 50 μ m) such as gelatin, the Pseudobulbus Bletillae (Rhizoma Bletillae) of clinical use, and is easy to injection and more is applicable to terminal blood vessel embolism.In addition, because dispersive nanoparticle is the temperature sensitive type gel, it is the regulation and control factor with the temperature only that colloidal sol-gel conversion takes place, and has avoided organic solvent or micromolecule cross-linking agent or the monomeric use adopted in some embolism materials, has reduced toxicity.
The temperature-sensitive nano-gel granule that uses in the vascular suppository material that the present invention proposes, severally compare as the temperature sensitive type vascular suppository material with reported with linear temperature sensitive polymer solution, under the identical situation of temperature sensitive polymer concentration, because (the former is crosslinked network to the difference of both structures, and the latter is a spherical structure), nano gel system has lower viscosity during collosol state, and gel state has higher modulus of elasticity; Has better temperature sensitivity simultaneously.In addition, people's such as Tanaka result of study shows, to a spherical gel particles, expands or shrinks square being directly proportional of required time and particle radius, and promptly the size of spherical gel is more little, and is fast more to the response speed of environment.So the temperature sensing nano gel system as vascular suppository material that the present invention proposes has short gelation time.
To be temperature sensing nano gel systems of being used for vascular suppository material be the fluid of good fluidity external to characteristics of the present invention, be injected into the blood vessel of tumor locus through intubate after, owing to the change of inside and outside temperature takes place to change mutually, form gel and make blood vessel embolism, blood flow stops, cancerous cell supplies to be cut off " dying of hunger " because of blood, thereby reaches the purpose of treatment.Advantage of the present invention is: its collosol state has lower viscosity, thixotropy and fast gelation speed preferably; Because of being temperature sensitive property material, its colloidal sol-gel conversion is the regulation and control factor with the temperature only, has avoided the use of organic solvent and small molecule monomer, has reduced toxicity simultaneously; In addition, nanogel is a kind of as hydrogel, also has excellent biological compatibility.
The water-insoluble developing agent that adds among the present invention has no adverse reaction to human body.After joining in the temperature-sensitive nano-gel dispersion behavior of transformation mutually of temperature sensing nano gel system is not had influence, have the development effect simultaneously.When making developing agent, the phase transition temperature of nano gel system is raise, be lower than 37 ℃ thermosensitive hydrogel system so iohexol is applicable to self phase transition temperature with iohexol.
The temperature sensing nano gel system that is used for vascular suppository material of the present invention can carry the water solublity medicine easily, and has sustained release performance preferably.
The temperature sensing nano gel system that is used for vascular suppository material of the present invention can be used for the blood vessel embolism at kinds of tumors position, as entity tumors such as hepatocarcinoma, renal carcinoma, pulmonary carcinoma, hysteromyoma, the blood vessel embolism that also can be used for multiple vascular conditions is as arteriovenous malformation of brain, facial vessels deformity etc.
Description of drawings
Fig. 1 is the surface topography map of temperature-sensitive nano-gel;
Fig. 2 is temperature-sensitive nano-gel colloidal sol-gel conversion phasor;
Fig. 3 is temperature-sensitive nano-gel colloidal sol-gel conversion phasor;
Fig. 4 is temperature-sensitive nano-gel rheological curves, wherein ■: G ', ▲: G ";
Fig. 5 is the outer drug release curve of medicine carrying temperature sensing nano gel.
The specific embodiment
The vascular suppository material that the present invention proposes be a kind of be the temperature sensing nano gel system of basic material with poly-N-isopropyl acrylamide (PNIPAAm) base polymer, comprise PNIPAAm class temperature-sensitive nano-gel and disperse medium.Wherein, PNIPAAm class temperature-sensitive nano-gel quality percentage composition is 3～20%, and surplus is a disperse medium.The temperature-sensitive nano-gel particle size range is 50～1000nm.Preferred 50～the 300nm of temperature-sensitive nano-gel particle diameter.
The chemical structural formula of PNIPAAm base polymer nanogel is abbreviated as in the above-mentioned temperature sensing nano gel system: poly (A-co-B).Wherein, A is NIPAAm, gives the polymer temperature-sensing property, and B is a comonomer, is the acrylic acid or derivatives thereof, is used to adjust the phase transition temperature of polymer, and wherein monomer molar percentage ratio (A:B) is 80～99:1～20.The bisacrylamide compounds that cross-linking agent adopts N-to replace, dosage of crosslinking agent is 0.2～10mol% of A and B consumption sum.
Disperse medium is the phosphate buffered solution (PBS) of water or normal saline or pH7.4 in the above-mentioned temperature sensing nano gel system.
Acrylic acid or derivatives thereof comonomer in the above-mentioned temperature sensing nano gel system can be selected in acrylamide, acrylic acid, methacrylic acid, acrylate and the methyl acrylic ester etc. that acrylamide, N-replace one or more for use.
The bisacrylamide compounds cross-linking agent that the N-of PNIPAAm base polymer nanogel replaces in the above-mentioned temperature sensing nano gel system, preferred N, N '-methylene-bisacrylamide (MBAAm).
When the body vascular suppository material is gone in above-mentioned temperature sensing nano gel system conduct, also comprise developing agent, the quality percentage composition of developing agent is 10～50%.
The developing agent that adopts in the above-mentioned temperature sensing nano gel system comprises water-insoluble developing agent such as micronize tantalum powder, tantalum oxide, barium sulfate, magnetic particle Fe
3O
4Deng, water miscible developing agent of also optional usefulness such as iohexol.When adopting non-water soluble substance to be developing agent in the above-mentioned temperature sensing nano gel system, PNIPAAm class temperature-sensitive nano-gel quality percentage composition is 2.7～18% in the temperature sensing nano gel system.
Above-mentioned temperature sensing nano gel system is the direct vascular embolization of medicine carrying not, also can carry the water solublity medicine as required, as Bleomycin A5, and mitomycin, amycin etc.Its medicine carrying process is simple, promptly directly medicine is dissolved in the temperature sensing nano gel system that is in collosol state.We studies show that this temperature-sensitive nano-gel has medicament slow release ability preferably.
The temperature sensing nano gel system that is made of temperature-sensitive nano-gel and disperse medium etc. of the present invention prepares in accordance with the following methods:
The preparation of temperature-sensitive nano-gel:
In monomer ratio (A:B) is that the ratio of 80～99:1～20 takes by weighing two kinds of comonomers, be dissolved in the water of certain volume, making monomeric concentration is 0.1～0.2mol/L, add 0.2～10% cross-linking agent that accounts for total moles monomer, emulsifying agent adopts anion surfactant, and emulsifier concentration is 0.5～5mmo/L.Emulsifying agent preferably sodium dodecyl sulfate (SDS).Behind the logical nitrogen 30min, add the water solublity radical initiator under the magnetic agitation, reaction temperature is 20～90 ℃, and N is adopted in reaction
2Gas shiled, the response time is 4～24h.The nanogel dispersion that reaction obtains is stored in the exsiccator standby through dialysis, lyophilizing.Employed initiator concentration is 1～5mmol/L in the said process, and initiator can be selected potassium peroxydisulfate (KPS), Ammonium persulfate .-tetramethylethylenediamine or potassium peroxydisulfate-tetramethylethylenediamine for use.
The dispersion of temperature-sensitive nano-gel:
Add the PBS of disperse medium-water or normal saline or pH7.4 in certain amount of nano gel lyophilized powder, placement is spent the night, and makes it abundant swelling, obtains the temperature-sensitive nano-gel dispersion of different quality percentage concentration (3～20%).
The preparation of the temperature sensing nano gel system that can develop:
Add 10～50% water-insoluble developing agent such as micronize tantalum powder, tantalum oxide, barium sulfate or magnetic particle Fe in the temperature-sensitive nano-gel dispersion of above-mentioned preparation
3O
4Deng, through ultrasonic mix homogeneously.Or iohexol (10～50%) mixed as cosolvent with water disperse temperature-sensitive nano-gel.
Temperature-sensitive nano-gel colloidal sol-gel transition temperature in the above-mentioned temperature sensing nano gel system can be regulated between 30～42 ℃ by the kind, ratio, the consumption of cross-linking agent and the content of temperature-sensitive nano-gel etc. of monomer A in temperature-sensitive nano-gel is formed that change comonomer.
The preparation of the temperature sensing nano gel system of medicine carrying:
In the temperature-sensitive nano-gel dispersion of above-mentioned preparation, add water soluble drug, ultra-sonic dispersion.
The following example only is used to further specify the present invention, and persons skilled in the art can adopt other multiple mode specifically to implement the present invention according to the disclosed content of this description.
Embodiment 1
With 2.263g NIPAAm (20mmol), 0.014gAAm (0.2mmol), 0.031g MBAAm (0.2mmol) and 0.030g SDS join in the three-necked bottle of the 250mL that reflux condensing tube and gas operated device are housed, dissolve under magnetic agitation with the 171.3mL ultra-pure water.In above-mentioned reaction system, feed high purity nitrogen 30min earlier, be heated to 70 ℃ then, and add 0.0452g KPS initiated polymerization.At N
2In the atmosphere, 70 ± 1 ℃ of down reactions 4.5 hours.Obtain white opacity nanogel suspension.With this nanogel suspension fortnight of in ultra-pure water, dialysing, stay 5mL to test, lyophilized powder is collected in all the other lyophilizing.
The mensuration of the particulate mean diameter of nanogel: adopt Nano-ZS90 laser particle analyzer (Britain Malvern company) to measure, light source is helium-Ne laser (λ=633nm), detect 90 ° at angle.Specimen is the nanogel dialysis solution, dilutes with ultra-pure water.This sample particle diameter is 226.2nm when recording 20 ℃.
With 1.488g NIPAAm (13mmol), 0.182gN-n-pro-pyl acrylamide (NNPAAm) (1.6mmol), 0.176g MBAAm (1.09mmol) and 0.030g SDS join in the three-necked bottle of the 250mL that reflux condensing tube and gas operated device are housed, dissolve under magnetic agitation with the 125mL ultra-pure water.In above-mentioned reaction system, feed high purity nitrogen 30min earlier, add 0.050g Ammonium persulfate. and 100 μ L tetramethylethylenediamines and come initiated polymerization.At N
2Reaction is 24 hours in the atmosphere, under the room temperature.Obtain the nanogel suspension.With this nanogel suspension fortnight of in ultra-pure water, dialysing, stay 5mL to test, lyophilized powder is collected in all the other lyophilizing.
The mensuration of the particulate mean diameter of nanogel: adopt Nano-ZS90 laser particle analyzer (Britain Malvern company) to measure, light source is helium-Ne laser (λ=633nm), detect 90 ° at angle.Specimen is the nanogel dialysis solution, dilutes with ultra-pure water.This sample particle diameter is 225.3nm when recording 20 ℃.
Embodiment 3-8
Press comonomer kind shown in the table 1 and proportioning, dosage of crosslinking agent, prepare temperature-sensitive nano-gel by the method for embodiment 1 or embodiment 2, the particle diameter when surveying its 20 ℃ the results are shown in Table 1.
Table 1 temperature-sensitive nano-gel prescription and performance
Annotate: MAA, HEMA, HEA are respectively methacrylic acid, hydroxyethyl methylacrylate, 2-(Acryloyloxy)ethanol.
To dilute by the nanogel dialysis solution of embodiment 6 preparations, and warp
0.45 the membrane filtration of μ m is drawn 2 nanogel dilution drops on firm dissociated mica sheet, makes it to sprawl film forming as far as possible.Air drying.Adopt the micro-mode scanning imaging of dynamic force of vibration mode, sweep speed 2Hz observes in the atmosphere.Test result is seen Fig. 1.The nanogel mean diameter is 232.2nm among the figure, is regular elliposoidal.
Take by weighing 0.15g by the nanogel lyophilized powder of embodiment 5 preparation in the 5mL plastic tube, the PBS that adds 1mLpH7.4 is a disperse medium, placement is spent the night, and makes it abundant swelling, obtains the nanogel dispersion.
Embodiment 11
Take by weighing 0.03g by the nanogel lyophilized powder of embodiment 1 preparation in the 5mL plastic tube, adding the 1mL normal saline is disperse medium, placement is spent the night, and makes it abundant swelling, obtains the nanogel dispersion.
Take by weighing 0.25g by the nanogel lyophilized powder of embodiment 8 preparation in the 5mL plastic tube, adding the 1mL ultra-pure water is disperse medium, post-heating to 40 ℃, ultra-sonic dispersion.
Take by weighing-quantitatively (0.03～0.25g) the nanogel lyophilized powder of press embodiment 5 preparations is in the 5ml plastic tube, and the PBS of adding 1ml pH7.4 is a disperse medium, is mixed with the different nanogel dispersion of mass percentage concentration by the method for embodiment 10.Adopt the volume phase transition temperature of visual method, and draw temperature-sensitive nano-gel colloidal sol-gel conversion phasor in conjunction with bottle roll back method working sample.Range of measuring temp is 5～50 ℃.Its result as shown in Figure 2.Fig. 2 shows with variation of temperature, the transformation of nanogel dispersion experience swell gel-colloidal sol-contraction gel.Transition temperature is relevant with the quality percentage composition of nanogel.
Embodiment 14
Take by weighing that a certain amount of (0.03～0.25g) the nanogel lyophilized powder of pressing embodiment 8 preparation is in the 5ml plastic tube, and adding the 1ml ultra-pure water is disperse medium, is mixed with the different nanogel dispersion of mass percentage concentration by the method for embodiment 12.Adopt the volume phase transition temperature of visual method, and draw temperature-sensitive nano-gel colloidal sol-gel conversion phasor in conjunction with bottle roll back method working sample.Range of measuring temp is 5～50 ℃.Its phasor as shown in Figure 3.Fig. 3 shows with variation of temperature, the transformation of nanogel dispersion experience swell gel-colloidal sol-contraction gel.Transition temperature is relevant with the quality percentage composition of nanogel.
Take by weighing 1.0g and be scattered among the PBS of 10mLpH7.4, go up its linear-viscoelastic behavior of test at ARES 2000 Rheometer flow graphs (TA) by the nanogel lyophilized powder that embodiment 8 prepares.Probe temperature is 15～50 ℃, parallel-plate anchor clamps (Φ 25mm), spacing 0.9～1.1mm.3 ℃/min of heating rate, rate of scanning are 1.0rad/s, and selected linear zone strain is 3%.Its storage modulus (G ') and loss modulus (G ") with variation of temperature be rheological curve as shown in Figure 4.Among the figure during low temperature, G "〉G ', interpret sample is a viscous liquid.During high temperature, G '〉G ", be elastic solid (Hookean body).G '=G " time temperature be phase transition temperature, this system is 37 ℃.
Embodiment 16
Take by weighing 0.15g by the prepared nanogel lyophilized powder of embodiment 3 in the 5mL plastic tube, adding 0.57mL iohexol and 0.43mL water is disperse medium, placement is spent the night, and makes it abundant swelling, makes the temperature-sensitive nano-gel dispersion that contains the developing agent iohexol.
Embodiment 17
Add 0.13g micronize tantalum powder in the prepared temperature-sensitive nano-gel dispersion of embodiment 10 toward pressing, ultra-sonic dispersion makes the temperature-sensitive nano-gel dispersion that contains developing agent tantalum powder.
Add 0.26g micronize tantalum powder in the prepared temperature-sensitive nano-gel dispersion of embodiment 12 toward pressing, ultra-sonic dispersion makes the temperature-sensitive nano-gel dispersion that contains developing agent tantalum powder.
Embodiment 19
Take by weighing 0.2g by the prepared nanogel lyophilized powder of embodiment 2 in the 10mL color comparison tube, adding the 1mL ultra-pure water is disperse medium, the preparation of nano gel dispersion, placement is spent the night, and makes it abundant swelling.Add the 1.0mg Bleomycin A5, ultra-sonic dispersion places 37 ℃ water-bath then, and the medicament-carried nano gel dispersion loses flowability immediately, becomes semisolid.Continue hatching 10min.Add the 10.0mL ultra-pure water then as release medium.Regularly pipette 1.0mL solution, and replenish the fresh release medium of 1.0mL immediately.Be determined at the 295nm place and pipette solution absorbency.Add the 10mL release medium in the microgel dispersion of medicine carrying not, timing sampling is as reference.Its drug release curve is seen Fig. 5.As shown in Figure 5, its pharmaceutical release time reached more than 10 days, illustrated that this temperature-sensitive nano-gel has medicament slow release performance preferably.
Take by weighing 0.15g by the prepared nanogel lyophilized powder of embodiment 7 in the 10mL color comparison tube, adding 1mLPBS is a disperse medium, the preparation of nano gel dispersion, placement is spent the night, and makes it abundant swelling.Add the 1.0mg mitomycin, ultra-sonic dispersion places 37 ℃ water-bath then, and the medicament-carried nano gel dispersion loses flowability immediately, becomes semisolid.Continue hatching 10min.Add 10.0mLPBS then as release medium.Regularly pipette 1.0mL solution, and replenish the fresh release medium of 1.0mL immediately.Be determined at the 363nm place and pipette solution absorbency.Add the 10mL release medium in the microgel dispersion of medicine carrying not, timing sampling is as reference.
Take by weighing 0.10g by the prepared nanogel lyophilized powder of embodiment 4 in the 10mL color comparison tube, adding the 1mL normal saline is disperse medium, the preparation of nano gel dispersion, placement is spent the night, and makes it abundant swelling.Add the 1.0mg doxorubicin hydrochloride, ultra-sonic dispersion places 37 ℃ water-bath then, and the medicament-carried nano gel dispersion loses flowability immediately, becomes semisolid.Continue hatching 10min.Add the 10.0mL normal saline then as release medium.Regularly pipette 1.0mL solution, and replenish the fresh release medium of 1.0mL immediately.Be determined at the 234nm place and pipette solution absorbency.Add the 10mL release medium in the microgel dispersion of medicine carrying not, timing sampling is as reference.
Embodiment 22
The internal diameter that one end is had stop,threeway is 0.5mm, and the silica gel tube of long 50cm places 37 ℃ thermostatic water bath, and with 4F intubate 10cm in silica gel tube is inserted in threeway, from the PBS of another three ports injection by the pH7.4 of water pump supply, flow velocity is 20mL/min.Inject the temperature-sensitive nano-gel dispersion for preparing by embodiment 10 from the 4F intubate, observe the situation of colloidal sol in silica gel tube.Experiment is found to form gel in silica gel tube, and cuts off current, and the suitable embolism materials of doing uses.
Embodiment 23
Choose 6 of adult healthy rabbit, body weight 2.0～2.5kg.After the fasting 6 hours, the positive small incision of the descending xiphoid-process lower abdomen of general anesthesia planting rabbit VX2 tubercle piece on the left liver leaf of rabbit, is set up rabbit VX2 tumor model.Big through 2～3 all tumor block lengths.Art pre-treatment routinely after the CT scan, row median abdominal incision operation for the second time separates the exposure gastroduodenal artery, and intubate is after microtubule injects the colloidal sol 0.2～0.5mL of the temperature sensing nano gel system of pressing embodiment 16 preparations, this tremulous pulse of ligation.Rabbit death of postoperative.All the other survival conditions are good.CT examination after 5～7 days.CT shows that tumor locus has the gel calmness, compares tumor with CT before the art and reduces or increase not obvious.
Claims (10)
1. a temperature sensing nano gel system that is used for vascular suppository material is characterized in that, this temperature sensing nano gel system has three-dimensional net structure, and it comprises poly-N-isopropyl acrylamide base polymer nanogel and disperse medium, wherein,
The mass percent concentration of poly-N-isopropyl acrylamide base polymer nanogel is 3～20%, surplus is a disperse medium, the chemical constitution skeleton symbol of poly-N-isopropyl acrylamide base polymer nanogel is: poly (A-co-B), wherein, A is the N-N-isopropylacrylamide, B is a comonomer, be the acrylic acid or derivatives thereof, the molar percentage of A, B is 80～99:1～20, cross-linking agent is the bisacrylamide compounds that N-replaces, dosage of crosslinking agent is 0.2～10mol% of A and B consumption sum, and the particle diameter of nanogel is 50～1000nm;
Disperse medium is the phosphate buffered solution of water, normal saline or pH7.4.
2. the temperature sensing nano gel system that is used for vascular suppository material according to claim 1, it is characterized in that comonomer is at least a in acrylamide, the N-acrylamide, acrylic acid, methacrylic acid, acrylate and the methacrylate that replace.
3. the temperature sensing nano gel system that is used for vascular suppository material according to claim 1 and 2 is characterized in that it also comprises developing agent, and the mass percent concentration of developing agent is 10～50%.
4. the temperature sensing nano gel system as vascular suppository material according to claim 1 and 2 is characterized in that, the particle diameter of nanogel is 50～300nm.
5. the temperature sensing nano gel system as vascular suppository material according to claim 1 and 2 is characterized in that, also contains the water solublity medicine of effective dose in this gel rubber system.
6. the temperature sensing nano gel system that is used for vascular suppository material according to claim 1 and 2 is characterized in that, cross-linking agent is N, N '-methylene-bisacrylamide.
7. the temperature sensing nano gel system as vascular suppository material according to claim 3 is characterized in that, developing agent is water-insoluble developing agent micronize tantalum powder, tantalum oxide, barium sulfate, magnetic particle Fe
3O
4Or water miscible developing agent iohexol; When developing agent was non-water soluble substance, poly-N-isopropyl acrylamide class temperature-sensitive nano-gel quality percentage composition was 2.7～18%.
8. the temperature sensing nano gel system that is used for vascular suppository material according to claim 7 is characterized in that, cross-linking agent is N, N '-methylene-bisacrylamide.
9. the temperature sensing nano gel system as vascular suppository material according to claim 8 is characterized in that, the particle diameter of nanogel is 50～300nm.
10. the temperature sensing nano gel system as vascular suppository material according to claim 9 is characterized in that, also contains the water solublity antitumor drug of effective dose in this gel rubber system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101245393A CN100502957C (en) | 2006-09-15 | 2006-09-15 | Temperature sensing nano gel system for blood vessel embolism material |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101245393A CN100502957C (en) | 2006-09-15 | 2006-09-15 | Temperature sensing nano gel system for blood vessel embolism material |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1923303A CN1923303A (en) | 2007-03-07 |
| CN100502957C true CN100502957C (en) | 2009-06-24 |
Family
ID=37816244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101245393A Active CN100502957C (en) | 2006-09-15 | 2006-09-15 | Temperature sensing nano gel system for blood vessel embolism material |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100502957C (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101053681B (en) * | 2007-04-10 | 2010-05-19 | 天津大学 | Temperature sensitive MPC-b-NIPAM biblock star type polymer for vessel embolism material and preparation method and application |
| CN101890185B (en) * | 2010-05-21 | 2012-12-12 | 天津大学 | ZnO quantum dot vector/DNA composite-containing collagen-based composite cornea substitute, and preparation method and application thereof |
| CN102250277A (en) * | 2011-05-17 | 2011-11-23 | 郑隆泗 | Macromolecular polymer capable of carrying medicine and used for embolism |
| CN105663033B (en) * | 2016-02-25 | 2019-04-19 | 华中科技大学 | Intratumor injection temperature sensitive polymer gel nano-composition in situ and application |
| CN107754025B (en) * | 2016-08-20 | 2020-11-27 | 天津大学 | Temperature-responsive supramolecular copolymer hydrogel embolization material and preparation method thereof |
| CN106334213B (en) * | 2016-08-31 | 2019-07-26 | 安疗生命科学（武汉）有限公司 | A kind of vascular suppository material, preparation method and the purposes in medicine preparation |
| CN106620826B (en) * | 2016-11-04 | 2019-11-01 | 华中科技大学 | It is a kind of can long-term autography temperature sensitive vascular suppository material and preparation method thereof |
| CN110215542A (en) * | 2018-03-02 | 2019-09-10 | 成都远睿生物技术有限公司 | A method of forming the interim obturator of blood vessel |
| CN112940176A (en) * | 2021-01-22 | 2021-06-11 | 广东广纳安疗科技有限公司 | Temperature-sensitive nano material and preparation method thereof |
| CN113284388B (en) * | 2021-05-26 | 2023-05-26 | 广东广纳安疗科技有限公司 | In-vitro vascular embolism simulation system and method |
| CN114042042B (en) * | 2021-11-29 | 2023-07-25 | 广东粤港澳大湾区国家纳米科技创新研究院 | W/O/W type temperature-sensitive embolic agent |
| CN114272430B (en) * | 2022-01-24 | 2023-01-24 | 科睿驰（深圳）医疗科技发展有限公司 | Thermo-sensitive embolism microsphere and preparation method thereof |
| CN115845117B (en) * | 2022-11-21 | 2024-02-20 | 赛克赛斯生物科技股份有限公司 | Embolic agent |
| CN116003683A (en) * | 2022-12-19 | 2023-04-25 | 华中科技大学 | Nano gel blocking material, tumor multi-step therapy series medicine based on RES-block strategy and application thereof |
| CN115895124A (en) * | 2023-01-03 | 2023-04-04 | 中化泉州能源科技有限责任公司 | Antibacterial and antifouling foamed polypropylene material and preparation method thereof |
-
2006
- 2006-09-15 CN CNB2006101245393A patent/CN100502957C/en active Active
Non-Patent Citations (6)
| Title |
|---|
| N-异丙基丙烯酰胺高分子水凝胶研究进展. 史海营，李瑞霞，吴大诚.广东化工，第33卷第153期. 2006 |
| N-异丙基丙烯酰胺高分子水凝胶研究进展. 史海营，李瑞霞，吴大诚.广东化工，第33卷第153期. 2006 * |
| 温敏凝胶微粒的制备、性质与应用. 吴红，张镇西.中国药学杂志，第40卷第24期. 2005 |
| 温敏凝胶微粒的制备、性质与应用. 吴红，张镇西.中国药学杂志，第40卷第24期. 2005 * |
| 表面强化交联聚（N-异丙基丙烯酰胺）水凝胶的温敏和浓缩分离性能. 黄健，黄志明，包永忠，单国荣，翁志学.化工学报，第57卷第4期. 2006 |
| 表面强化交联聚(N-异丙基丙烯酰胺)水凝胶的温敏和浓缩分离性能. 黄健，黄志明，包永忠，单国荣，翁志学.化工学报，第57卷第4期. 2006 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1923303A (en) | 2007-03-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100502957C (en) | Temperature sensing nano gel system for blood vessel embolism material | |
| Cazares-Cortes et al. | Doxorubicin intracellular remote release from biocompatible oligo (ethylene glycol) methyl ether methacrylate-based magnetic nanogels triggered by magnetic hyperthermia | |
| Coughlan et al. | Effect of drug physicochemical properties on swelling/deswelling kinetics and pulsatile drug release from thermoresponsive poly (N-isopropylacrylamide) hydrogels | |
| Fan et al. | Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique | |
| Prasad et al. | Microspheres as drug delivery system-a review | |
| Carreira et al. | Temperature and pH responsive polymers based on chitosan: applications and new graft copolymerization strategies based on living radical polymerization | |
| Liang et al. | Novel method using a temperature-sensitive polymer (methylcellulose) to thermally gel aqueous alginate as a pH-sensitive hydrogel | |
| Kozlovskaya et al. | Self-assemblies of thermoresponsive poly (N-vinylcaprolactam) polymers for applications in biomedical field | |
| Ghugare et al. | Temperature-sensitive poly (vinyl alcohol)/poly (methacrylate-co-N-isopropyl acrylamide) microgels for doxorubicin delivery | |
| Zhang et al. | Highly stable and degradable multifunctional microgel for self-regulated insulin delivery under physiological conditions | |
| Li et al. | Polymer nanogels as reservoirs to inhibit hydrophobic drug crystallization | |
| Bian et al. | One-pot synthesis of redox-labile polymer capsules via emulsion droplet-mediated precipitation polymerization | |
| Cao et al. | Near-Infrared Light-, Magneto-, and pH-Responsive GO–Fe3O4/Poly (N-isopropylacrylamide)/alginate Nanocomposite Hydrogel Microcapsules for Controlled Drug Release | |
| Zhao et al. | Synthesis of surfactant-free hydroxypropyl methylcellulose nanogels for controlled release of insulin | |
| CN101690831A (en) | Temperature-sensitive nano-gel vascular embolic materials, preparation method and application thereof | |
| TW200902097A (en) | Method of formation of viscous, shape conforming gels and their uses as medical prosthesis | |
| Town et al. | Dual-stimuli responsive injectable microgel/solid drug nanoparticle nanocomposites for release of poorly soluble drugs | |
| CN103830752B (en) | A kind of preparation method and applications of degradable polymer nano microcapsule | |
| Sarfraz et al. | Synthesis of co-polymeric network of carbopol-g-methacrylic acid nanogels drug carrier system for gastro-protective delivery of ketoprofen and its evaluation | |
| Sivakumaran et al. | Temperature-induced assembly of monodisperse, covalently cross-linked, and degradable poly (N-isopropylacrylamide) microgels based on oligomeric precursors | |
| CN103965421A (en) | Preparation method and product of thermo-sensitive amphipathic block copolymer with nucleocapsid structure | |
| Simpson et al. | Narrowly dispersed, degradable, and scalable poly (oligoethylene glycol methacrylate)-based nanogels via thermal self-assembly | |
| JP5718815B2 (en) | Polymer particles prepared from polymerizable alkylene glycol (meth) acrylate monomers | |
| Al-Tikriti et al. | Drug-eluting polyacrylate microgels: loading and release of amitriptyline | |
| US20070224274A1 (en) | Polymer Particles Containing Active Agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20070307 Assignee: Life Science (Wuhan) Co., Ltd. Assignor: Huazhong University of Science and Technology Contract record no.: 2017420000001 Denomination of invention: Temperature sensing nano gel system for blood vessel embolism material Granted publication date: 20090624 License type: Exclusive License Record date: 20170122 |
|
| EE01 | Entry into force of recordation of patent licensing contract |