CN101690831A - Temperature-sensitive nano-gel vascular embolic materials, preparation method and application thereof - Google Patents
Temperature-sensitive nano-gel vascular embolic materials, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a vascular embolic material for intervention, which consists of poly(N-isopropylacrylamide) (PNIPAAm) polymeric temperature-sensitive nano-gels, and a water-soluble iodic contrast medium injection or a diluent thereof. The poly(N-isopropylacrylamide) (PNIPAAm) polymeric nano-gels are copolymerized gels of N-isopropylacrylamide and hydrophobic allyl monomers, and the grain diameter of the nano-gels is between 60 and 400nm. The vascular embolic material has the advantages of low concentration of the temperature-sensitive nano-gels, capacity of developing, simple preparation method, good room temperature fluidity, high body-temperature gel strength, long embolization time, non-adhesion, suitable terminal embolism and the like. The vascular embolic material can be used for the treatment of various diseases of tumor sites such as vascular embolization, arteriovenous malformation and the like.
Description
Technical field
The present invention relates to a kind of intervention vascular suppository material, particularly a kind of temperature-sensitive nano-gel vascular embolic materials and its production and application.
Background technology
Embolotherapy is meant embolism materials optionally is injected in the supply blood vessel of a certain diseased organ by conduit, make corresponding vascular occlusion, interrupt blood for and reach therapeutic purposes.Wherein embolism materials and thromboembolism technology are its important ingredients, and the effect of embolization of vascular suppository material has directly determined the quality of therapeutic outcome.
At present, the main dependence on import of China's vascular suppository material, price is very expensive.Therefore, the research of vascular suppository material, exploitation and application are one of developing groundworks of interventional neuroradiology.Ideal embolism materials should possess following condition at least: 1. good biological safety; 2. thromboembolism lesion vessels securely; 3. nontoxic or low toxicity; 4. obtain easily; 5. easy to operate, controlled; 6. can produce non-infringement inflammation, bring out thrombosis; 7. have a development.Now existing multiple intervention vascular suppository material mainly comprises 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 the clinical suppository the most widely that is used for malignant tumor arteries thromboembolism is an iodized oil, but its time of keeping thromboembolism in vivo be generally for 2 weeks～February, need repeatedly thromboembolism; Its viscosity height in addition, be difficult for injecting and medicine carrying (Jiang Xiaoliang etc., modern tumor medical science .2006,14 (1): 112), also backflow easily and thromboembolism after easily form collateral circulation etc., had a strong impact on the thromboembolism curative effect of tumor locus.
The variation of temperature sensitive type poly compound energy sense ambient temperature, in very narrow temperature range, take place to change mutually, utilizing it is that flowable fluid is easy to inject, the generation sol-gel changes mutually when body temperature when room temperature, original position forms the characteristic of gel, now as injectable materials, field (Hao Jianyuan etc., the CN1958074 such as immobilization, organizational project of pharmaceutical carrier, enzyme have been widely used in; King Chang Yong etc., CN101288779; Jiang Zhi is strong etc., CN1916050).Poly-(N-N-isopropylacrylamide) (PNIPAAm) base polymer studies focus owing to its phase transition temperature becomes one near human body temperature.1233), (LiX, etal.Biomaterials.2005,26:7002 such as Liu Wenguang (Sheng Xizhong etc., practical radiology magazine .2005,21 (12): such as Sheng Xizhong; Liu Wen is wide etc., CN 1679620A, CN 1546057A, CN 101053681) 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 embolism materials has non-adhesive, zoopery has obtained better effects.In addition, as vascular suppository material,, avoided the use of organic solvent and cross-linking agent owing to only with the regulation and control factor of temperature as sol-gel transition with the temperature sensitive type material, safer.
PNIPAAm class temperature-sensitive nano-gel vascular suppository material is compared with the above-mentioned temperature sensitive type linear polymer embolism materials of having reported, under the identical situation of temperature sensitive polymer concentration, because (nanogel is crosslinked network to the difference of both structures, and linear polymer is a spherical structure), nano gel system has lower viscosity during collosol state, and gel state has higher modulus of elasticity; Have better temperature sensitivity (Stieger M, et al.Langmuir.2004,20:7283 simultaneously; Macromolecules.2003,36:8811).Compare with the microspheric embolism materials with other granule,, have the advantage that is easy to inject and more is applicable to terminal thromboembolism because dispersion is the small-particle of nano-scale; Compare with other liquid embolizing agent, then have the thromboembolism time long, do not have and backflow and advantage such as collateral circulation.We can say the advantage that has had liquid embolizing agent and embolism agent of granule concurrently, overcome deficiency separately, is very promising vascular suppository material.On basis of experimental, the applicant proposed the patent application that name is called " temperature sensing nano gel system that is used for vascular suppository material " (publication number is CN1923303) on the 15th in JIUYUE in 2006.
But since during as embolism materials the concentration of temperature-sensitive nano-gel big (Wang Q, et al.Colloid Polym.Sci.2007,285 (5), 515-521.), and PNIPAAm class temperature-sensitive nano-gel is difficult for a large amount of preparations, has limited its application.In addition, as vascular suppository material, also need it to have development, so that clinical manipulation.
Summary of the invention
The object of the present invention is to provide a kind of temperature-sensitive nano-gel vascular embolic materials with the quick nanogel concentration of lower temperature, further purpose of the present invention is to provide a kind of temperature-sensitive nano-gel vascular embolic materials that develops; The present invention also provides this preparation methods and application.
For realizing first purpose of the present invention, temperature-sensitive nano-gel vascular embolic materials provided by the invention, it is characterized in that, it comprises poly-(N-N-isopropylacrylamide) base polymer nanogel and disperse medium, wherein, the mass percent concentration of poly-(N-N-isopropylacrylamide) base polymer nanogel is 3～10%, and surplus is a disperse medium;
The chemical constitution skeleton symbol of poly-(N-N-isopropylacrylamide) base polymer nanogel is: poly (A-co-B), its particle diameter is 60～400nm, wherein, A is the N-N-isopropylacrylamide, B is a hydrophobicity allylic comonomer, the molar percentage of A, B is 80～100: 0～20, and cross-linking agent is the bisacrylamide compounds that N-replaces, and dosage of crosslinking agent is 0.1～5% of A and a B total mole number;
Disperse medium is that water solublity contains diodone injection or its diluent, and content of iodine is 50～350mg in every 1mL disperse medium, and the diluent of diluent is that water for injection, normal saline or pH value are a kind of in 4～9 the buffer solution.
For realizing second purpose of the present invention, in above-mentioned temperature-sensitive nano-gel vascular embolic materials, content of iodine is 180～350mg in every 1mL disperse medium.
In above-mentioned two technical schemes, in poly-(N-N-isopropylacrylamide) base polymer nanogel, acrylamide, acrylate or methacrylate that the preferred N-of comonomer replaces, preferred iohexol of contrast-medium injection liquid or ioversol.
The preparation method of above-mentioned temperature-sensitive nano-gel vascular embolic materials, its step comprises:
(1) takes by weighing poly-(N-N-isopropylacrylamide) base polymer nanogel lyophilized powder, add disperse medium, at room temperature be stirred to abundant swelling, through the emulsifying of high shear homogenizer it be uniformly dispersed again, centrifugally leave standstill after removing bubble, obtain the temperature-sensitive nano-gel dispersion;
(2), seal the back and use with above-mentioned finely dispersed temperature-sensitive nano-gel dispersion
60The Co irradiation sterilization, room temperature storage.
Above-mentioned temperature-sensitive nano-gel vascular embolic materials can be used as the vascular suppository material of tumor locus and vascular malformation.
A kind of temperature-sensitive nano-gel vascular embolic materials of the present invention is the nanogel particle suspending that will have a three-dimensional net structure in containing the aqueous medium that water solublity contains diodone.Water solublity wherein contains diodone when adding minute quantity, can significantly reduce the concentration of temperature-sensitive nano-gel in the temperature-sensitive nano-gel suspended substance with effect of embolization.Simultaneously, water solublity contain diodone to the phase transition temperature of temperature-sensitive nano-gel with to change behavior mutually influential.The use that water solublity contains diodone reduces the minimum gelation concentration of temperature-sensitive nano-gel dispersion, and has reduced the consumption of temperature-sensitive nano-gel; Simultaneously, the gel that forms at body temperature does not almost have dehydration property; The phase transition temperature of nanogel dispersion is raise.This may be because the water solublity that adds contains diodone such as iohexol etc. for containing a plurality of hydroxyls and amino chemical compound, except that the contribution of the intergranular hydrophobic interaction of temperature-sensitive nano-gel, also comprise between contrast agent and the nanogel, the hydrogen bond action between contrast agent and the water near the formation of the gel body temperature.
A kind of temperature-sensitive nano-gel vascular embolic materials of the present invention, its phase transition temperature and a required minimum nanogel content of effect of embolization, except that can also regulating and control by the kind and factor regulation and control such as consumption, dosage of crosslinking agent that change comonomer in the nanogel by the kind and the content of contrast agent.Be colloidal sol when utilizing its room temperature, be injected into back Yin Wendu rising formation gel in the body, and play the thromboembolism effect.
A kind of temperature-sensitive nano-gel vascular embolic materials of the present invention, when the content of contrast agent wherein is enough big, in embolism materials temperature-sensitive nano-gel concentration low, also have the property of development, and be convenient to clinic observation and operation.
The preparation method of a kind of temperature-sensitive nano-gel vascular embolic materials of the present invention is simple, only needs the temperature-sensitive nano-gel lyophilized powder is scattered in to contain in the disperse medium that water solublity contains diodone to get final product.
The applied range of above-mentioned vascular suppository material in addition 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.In addition, because the non-degradable of temperature-sensitive nano-gel material itself is a kind of permanent embolic type vascular suppository material.
In a word, low, the collosol state of the concentration of temperature-sensitive nano-gel has lower viscosity, thixotropy and fast gelation speed, tool development preferably in the temperature-sensitive nano-gel vascular embolic materials provided by the invention; Because of being temperature sensitive property material, its sol-gel transition 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 temperature-sensitive nano-gel vascular embolic materials that develops of the present invention 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 suspended substance of the temperature-sensitive nano-gel that develops that is in collosol state.
Description of drawings
Fig. 1 be 6wt/v% the temperature-sensitive nano-gel aqueous dispersion (a, b) and contain dispersion (content of iodine is 180mg/mL) (c, d) photo under different temperatures of iohexol.a，c：T＝25℃；b，d：T＝37℃
The influence that Fig. 2 changes the aqueous dispersion (content of iodine is 150mg/mL) that contains ioversol mutually for temperature-sensitive nano-gel concentration.■: swell gel temperature GT, ●: turbidization temperature CPT; ▲: shrink gelling temperature ST
The influence that Fig. 3 changes the aqueous dispersion (content of iodine is 300mg/mL) that contains iohexol mutually for temperature-sensitive nano-gel concentration.■：GT；●：CPT；▲：ST
Fig. 4 is right segmental renal artery thromboembolism digital subtraction angiography (DSA) sheet of temperature-sensitive nano-gel vascular suppository material.Figure A: normal right renal artery radiography; B: right segmental renal artery radiography behind the thromboembolism; C:35 days check radiographies; D:60 days check radiographies
Fig. 5 is a matched group PVA particulate embolization renal artery DSA sheet.A: right segmental renal artery radiography behind the thromboembolism; B:35 days check radiographies; C:60 days check radiographies
Fig. 6 is rabbit VX2 liver cancer model hepatic artery embolism hepatic arteriography figure.A-C is respectively 14 days hepatic arteriographies behind radiography behind tumor Hepar Leporis seu Oryctolagi angiography, the temperature-sensitive nano-gel thromboembolism, the thromboembolism; D-F is respectively 14 days hepatic arteriographies behind radiography behind tumor Hepar Leporis seu Oryctolagi angiography, the super liquid iodized oil thromboembolism, the thromboembolism
Fig. 7 is the observation figure under low power lens and high power lens respectively of tumor tissue section of temperature-sensitive nano-gel embolization group.A: low power lens (HE X40); B: high power lens (HE X200)
Fig. 8 is the observation figure under low power lens and high power lens respectively of tumor tissue section of iodized oil embolization group.A: low power lens (HEX40); B: high power lens (HE X200)
The specific embodiment
The present invention obtains the temperature-sensitive nano-gel vascular embolic materials quick nanogel concentration of lower temperature, that can develop on to the implementation method of development, basis that contrast agent is studied the influence of thermo-responsive hydro gelization.The following example only is used to further specify the present invention, the composition of the temperature-sensitive nano-gel of open herein and explanation, the kind of contrast agent and content can be with identical the replacing of other effect, those skilled in the art can make countless variations, improvement and replacement, and can not break away from the present invention.
A kind of temperature-sensitive nano-gel vascular embolic materials of the present invention can be implemented in the following manner:
1. the preparation of the present invention's temperature-sensitive nano-gel lyophilized powder
The precipitation polymerization method or the emulsion polymerization preparation of pressing bibliographical information gather (N-N-isopropylacrylamide) (PNIPAAm) class temperature-sensitive nano-gel (Wang Q, et al.Colloid Polym Sci, 2007,285:515-521.Pelton R H, etal.Colloids Surf, 1986,20:247-256.), the nanogel dispersion that reaction obtains is stored in the exsiccator standby through dialysis, lyophilizing.
2. the preparation of the temperature-sensitive nano-gel vascular embolic materials of the quick nanogel concentration of the present invention's lower temperature
(1) commodity being contained the diodone injection with water solublity is that 4～9 buffer solution is diluted to desired concn with diluent-water for injection or normal saline or pH;
(2) take by weighing a certain amount of temperature-sensitive nano-gel lyophilized powder, add commodity and contain diodone injection or above-mentioned contrast agent diluent with water solublity, at room temperature be stirred to abundant swelling, through the emulsifying of high shear homogenizer it be uniformly dispersed again, centrifugally leave standstill after removing bubble, obtain the temperature-sensitive nano-gel dispersion of required mass percentage concentration;
(3), seal the back and use with above-mentioned finely dispersed temperature-sensitive nano-gel dispersion
60The Co irradiation sterilization, room temperature storage.
3. the preparation of the quick nanogel concentration of the present invention's the existing lower temperature temperature-sensitive nano-gel vascular embolic materials that can develop again
(1) commodity being contained the diodone injection with water solublity is that 4～9 buffer solution is diluted to desired concn (content of iodine is greater than 180mg/mL) with diluent-water for injection or normal saline or pH;
(2) take by weighing a certain amount of temperature-sensitive nano-gel lyophilized powder, add commodity and contain diodone injection or above-mentioned contrast agent diluent with water solublity, at room temperature be stirred to abundant swelling, through the emulsifying of high shear homogenizer it be uniformly dispersed again, centrifugally leave standstill after removing bubble, obtain the temperature-sensitive nano-gel dispersion of required mass percentage concentration;
(3), seal the back and use with above-mentioned finely dispersed temperature-sensitive nano-gel dispersion
60The Co irradiation sterilization, room temperature storage.
4. the preparation of the temperature-sensitive nano-gel vascular embolic materials of the present invention's medicine carrying
Method one:
(1) commodity being contained the diodone injection with water solublity is that 4～9 buffer solution is diluted to desired concn with diluent-water for injection or normal saline or pH;
(2) take by weighing a certain amount of temperature-sensitive nano-gel lyophilized powder, with a certain amount of water soluble drug, add commodity and contain diodone injection or above-mentioned contrast agent diluent with water solublity, at room temperature be stirred to abundant swelling, through the emulsifying of high shear homogenizer it be uniformly dispersed again, centrifugally leave standstill after removing bubble, obtain the temperature-sensitive nano-gel dispersion of required mass percentage concentration;
(3), seal the back and use with the temperature-sensitive nano-gel dispersion of above-mentioned finely dispersed medicine carrying
60The Co irradiation sterilization, room temperature storage.
Method two:
Prepare the not temperature-sensitive nano-gel vascular embolic materials of medicine carrying as stated above earlier, toward the water soluble drug that wherein adds convention amount, ultrasonic, mix homogeneously seals again,
60The Co sterilization, room temperature storage.
5. the application of the present invention's the temperature-sensitive nano-gel vascular embolic materials that can develop
Adopt the method for interventional therapy, microtubular is inserted the target organ feeding artery, use earlier the cool brine irrigating catheter, the back is at the descending angiography of perspective, the temperature-sensitive nano-gel class embolism materials of the degree (from the peripheral vessel to the aorta) of thromboembolism injection aequum as required is generally 0.5-5mL again.
Embodiment 1
Take by weighing 4.526gN-N-isopropylacrylamide (NIPAAm), 0.006 gN, N-methylene-bisacrylamide (being the 0.1mol% of NIPAAm), 0.196g sodium lauryl sulphate, join in the three-necked bottle of 500mL, add ultra-pure water 326mL, precipitation polymerization method or emulsion polymerization by bibliographical information prepare PNIPAAm temperature-sensitive nano-gel (Wang Q, et al.ColloidPolym Sci, 2007,285:515-521.Pelton R H, et al.Colloids Surf, 1986,20:247-256.), the nanogel dispersion that obtains of the reaction fortnight of in ultra-pure water, dialysing, stay 5mL to do the particle diameter test, lyophilized powder is collected in all the other lyophilizing, is stored in the exsiccator standby.
The mensuration of the particulate mean diameter of PNIPAAm nanogel: adopt dynamic light scattering method, measure with Nano-ZS 90 laser particle analyzers (Britain Malvern company), light source is He-Ne Lasers (λ=633nm), detect 90 ° at angle, specimen is the nanogel dialysis solution, dilutes with ultra-pure water.Recording its particle diameter in the time of 20 ℃ is 115.3nm.
Embodiment 2-6
Press comonomer kind shown in the table 1 and proportioning, dosage of crosslinking agent, precipitation polymerization method or emulsion polymerization by bibliographical information prepare PNIPAAm class temperature-sensitive nano-gel (Wang Q, et al.Colloid Polym Sci, 2007,285:515-521.Pelton R H, et al.Colloids Surf, 1986,20:247-256.), the nanogel dispersion that obtains of the reaction fortnight of dialysing in ultra-pure water stays 5mL to do particle diameter test, all the other lyophilizing, collect lyophilized powder, be stored in the exsiccator standby.Prepare in the method for PNIPAAm class temperature-sensitive nano-gel at this, also can regulate and control the particle diameter of nanogel by the consumption of regulation and control emulsifying agent.The particle diameter of each PNIPAAm class temperature-sensitive nano-gel that records with dynamic light scattering method in the time of 20 ℃ sees Table 1.
Table 1 temperature-sensitive nano-gel is formed and particle diameter
Annotate: MAA, BMA, iPA, NiPAAm and NEAAm are respectively methyl methacrylate, butyl methacrylate, isopropyl acrylate, N-isopentyl acrylamide, N-ethyl acrylamide.
Embodiment 7
It is 50mg/mL that iohexol 300 injection are diluted to content of iodine with water for injection.After take by weighing the temperature-sensitive nano-gel lyophilized powder of 0.5g by embodiment 2 preparation, add above-mentioned iohexol diluent 5mL, be stirred to abundant swelling under the room temperature, through the emulsifying of high shear homogenizer it be uniformly dispersed again, centrifugally leave standstill after removing bubble, obtain temperature-sensitive nano-gel concentration and be 10% dispersion.
Take by weighing the temperature-sensitive nano-gel lyophilized powder of 0.6g by embodiment 4 preparations, add 10mL ioversol 350 injection, at room temperature be stirred to abundant swelling, through the emulsifying of high shear homogenizer it be uniformly dispersed again, centrifugally leave standstill after removing bubble, obtaining content of iodine is the temperature-sensitive nano-gel dispersion of developing (temperature-sensitive nano-gel concentration is 6%) of 350mg/mL.
Embodiment 9
Take by weighing the temperature-sensitive nano-gel lyophilized powder of 0.3g by embodiment 6 preparations, (normal saline and iohexol inj volume ratio are 1: 2 to the iohexol 350 injection 10mL that adding is diluted with normal saline, this moment, iodine concentration was 233.3mg/mL), at room temperature be stirred to abundant swelling, through the emulsifying of high shear homogenizer it be uniformly dispersed again, centrifugally leave standstill after removing bubble, obtain the temperature-sensitive nano-gel dispersion (temperature-sensitive nano-gel concentration is 3%) that to develop.
Embodiment 10
Take by weighing the temperature-sensitive nano-gel lyophilized powder of 0.75g by embodiment 6 preparations, add the 10mL pH value and be ioversol 320 injection that 9 buffer solution dilutes, wherein content of iodine is 120mg/mL, at room temperature be stirred to abundant swelling, through the emulsifying of high shear homogenizer it be uniformly dispersed again, centrifugally leave standstill after removing bubble, obtain temperature-sensitive nano-gel concentration and be 7.5% temperature-sensitive nano-gel dispersion.
Embodiment 11
Take by weighing the temperature-sensitive nano-gel lyophilized powder of 0.06g by embodiment 3 preparations, add the 1.0mL pH value and be the iohexol solution that 7.4 phosphate buffered solution is diluted, wherein content of iodine is 180mg/mL, prepares the dispersion that nanogel concentration is 6wt/v% by the method for embodiment 7.Adopt the temperature sensitive phase behavior of visual method, change photo mutually as shown in Figure 1 in conjunction with bottle roll back method mensuration temperature-sensitive nano-gel dispersion.Accompanying drawing 1 explanation nanogel concentration is that the aqueous dispersion of 6wt/v% can not form gel at 37 ℃, but and the dispersion that contains iohexol of identical nanogel concentration 37 ℃ of gelations.
Embodiment 12
Take by weighing that a certain amount of (0.02～0.08g) the temperature-sensitive nano-gel lyophilized powder of pressing embodiment 4 preparation is in the 5mL plastic tube, adding with pH is that 4 buffer solution dilutes 1 times ioversol 300 injection 1.0mL, press the method for embodiment 7, the different temperature-sensitive nano-gel dispersion (content of iodine is 150mg/mL) of preparation temperature-sensitive nano-gel mass percentage concentration.Make disperse medium with iohexol 300 injection 1.0mL in addition, the preparation content of iodine is the temperature-sensitive nano-gel dispersion of the different temperature-sensitive nano-gel mass percentage concentration of 300mg/mL.Adopt visual method each phase transition temperature in conjunction with bottle roll back method working sample: swell gel temperature GT, turbidization temperature CPT and contraction gelling temperature ST, Range of measuring temp is 5～45 ℃.Its result is respectively shown in accompanying drawing 2 and accompanying drawing 3.The mass concentration that accompanying drawing 2 and accompanying drawing 3 shows temperature-sensitive nano-gel in the temperature-sensitive nano-gel dispersions not simultaneously, it changes the behavior difference mutually with variation of temperature.Its phase transition temperature is relevant with the quality percentage composition of temperature-sensitive nano-gel with phase.Near the gel strength that the temperature-sensitive nano-gel dispersion that content of iodine is high in addition (accompanying drawing 2) forms body temperature is good, and does not have the dehydration phenomenon.
Embodiment 13
Take by weighing 0.5g by the prepared temperature-sensitive nano-gel lyophilized powder of embodiment 6 in the 10mL color comparison tube, adding 1mL ioversol 240 injection is disperse medium, prepares the temperature-sensitive nano-gel dispersion by the method for embodiment 7.Add the 1.0mg Bleomycin A5, ultra-sonic dispersion promptly gets the temperature-sensitive nano-gel dispersion of developing of medicine carrying.
Embodiment 14
Toward by the doxorubicin hydrochloride that adds therapeutic dose in the temperature-sensitive nano-gel vascular embolic materials that develops of embodiment 8 preparations, ultrasonic, mix homogeneously, standby.
Embodiment 15-18
To seal warp by the prepared temperature-sensitive nano-gel dispersion of embodiment 7-10
60The Co irradiation sterilization, room temperature storage, stand-by.
Embodiment 19
Zoopery is carried out according to " Hubei Province's management of laboratory animal regulations ", and ratifies through Medical Ethics committee of Tongji Medical Institute.
Purebred, as to clean new zealand white rabbit, about body weight 3.0kg, male and female are not limit, and are provided by Tongji Medical College, Huazhong Science and Technology Univ.'s Experimental Animal Center.
The normal rabbits thrombosis of renal artery is tested: get 40 of new zealand white rabbits, test fasting in preceding 12 hours, water, weigh the rabbit body weight before the art, anaesthetize preceding 30 minutes intramuscular injection atropine 0.05rag/kg,, keep respiratory passage unblocked to reduce salivary gland secretion.Sleep with the speed of 0.2mL/kg then and newly carry out the right thigh intramuscular anesthesia, after treating rabbit pain sensation loss for reaction after 5～10 minutes, lie on the back and be fixed on homemade four jiaos of planks that have a nail, plank is positioned over the angiography operating-table, and skin of groin is cut in right side groin preserved skin and sterilization, the femoral artery that exposes right common femoral artery and expose with the mosquito forceps separation, two ends put silk thread, mention the two ends silk thread, and femoral artery is separated with muscular tissue on every side.Then with 18G lancet puncture femoral artery after puncture needle is directly inserted the coaxial microtubular of 3F, microtubular is placed ventral aorta hand push contrast agent radiography, select intubate to right renal artery through ventral aorta microtubular behind the clear and definite right renal artery opening, manual injection contrast agent iohexol, row right renal artery radiography, wherein 20 rabbit will be injected right renal artery, row tip arterial thrombosis through microtubular by temperature-sensitive nano-gel vascular suppository material injection speed with 0.1mL/s under perspective of embodiment 7 preparations with the 1mL syringe; In addition go thrombosis of renal artery at different levels respectively for 15, and use digital subtraction angiography (DSA) machine radiography respectively, all use 4 ℃ of normal saline washing pipes before and after the thromboembolism, stop up to prevent microtubular; 5 rabbit of matched group are used the suspension thromboembolism right renal artery of PVA fine grained and iohexol.EO is removed pipe back ligation point of puncture far-end femoral artery, sews up the back and continues to raise.Postoperative was observed ordinary circumstances such as rabbit spirit, diet in 3 days.
Statistical method: experimental data is represented with x ± s, use SPSS11.5 statistical software analyzing and processing, enumeration data is used chi-square criterion and the accurate probabilistic method of Fiher, and measurement data is that difference has significance with independent sample t check and two-way analysis of variance with P＜0.05.
Its DSA sheet is seen attached Figure 4 and 5.Found that plugging and anti-flow phenomenon do not appear in this temperature-sensitive nano-gel vascular embolic materials The book of Changes interposing catheter injection during injection, postoperative is cut conduit open, does not see in its inwall that temperature-sensitive nano-gel adheres to tube wall.This temperature-sensitive nano-gel vascular embolic materials is slightly that the high density shadow flows to the renal artery tip gradually, quickly the thromboembolism peripheral arteriole; Continue injected plug agent, thromboembolism renal artery branches at different levels and main renal artery successively according to identical injection speed.Rabbit spirit behind the thromboembolism, diet are normal, and it is normal that renal function can recover in 14 days; Gel is thromboembolism tremulous pulsies at different levels as required, and the thromboembolism peripheral vessel is firm, and 60 days check radiographies find not had logical by the renal artery distal vessels of thromboembolism again; Rabbit does not have obvious toxicity behind the thromboembolism; Infarction promptly occurred in 3 days behind the pathologic finding right renal artery thromboembolism, hepatic tissue occurs downright bad after 14 days; After 35 days by the hepatic tissue of gel embolism and nephridial tissue diffuse necrosis is appearred all; And matched group PVA group check in 35 days radiography is found to be led to by the upper pole of kidney tremulous pulse of thromboembolism part again, and excess of the kidney matter is partly developed; 60 days check radiographies, logical again by the upper pole of kidney arteries of thromboembolism, excess of the kidney matter is developed.
(1) laboratory animal is with embodiment 19.
(2) experiment material: the strain of subcutaneous VX2 tumor tumor is introduced by U.S. ATCC company, and Concord Hospital goes down to posterity the several years in Wuhan.Rabbit anesthesia is slept new II by the veterinary institute examination development of military supplies university of PLA with speed, and every milliliter of speed is slept and newly contained the peaceful 60mg in Baoding, dihydroetorphine hydrochlorate 4 μ g, haloperidol 2.5mg.Omnipaque (iohexol) is available from German Bei Lang company (B.Braun AG).
(3) experimental technique: 50 new zealand white rabbits are set up VX2 transplanted hepatoma model, row CT and MRI check after 14 days, open the abdominal cavity through median abdominal incision, after exposing Hepatic artery, close the temporary transient folder of ramus dexter arteriae hepaticae propriae with the temporary transient folder of bulldog clamp during treatment and close ramus dexter arteriae hepaticae propriae, make the super thromboembolism leftlobe of liver tumor vessel of selecting of intubate.Be divided into following 2 groups of treatments then, 25 every group.The A group: trans-hepatic artery injects and carries out thromboembolism by the embodiment 9 prepared temperature-sensitive nano-gel dispersions of developing; The B group: trans-hepatic artery injects super liquid iodized oil.2 weeks of postoperative are carried out following detection:
A. capable CT and MRI check.Experimental result is seen accompanying drawing 6.The preceding visible tumor vessel traveling of rabbit VX2 hepatocarcinoma arterial phase of accompanying drawing 6 explanation temperature-sensitive nano-gel thromboembolisms is irregular, and arrangement disorder, part feeding artery are forced into " embracing spherical " by the tumor body, visible nodositas tumor staining.Inject temperature-sensitive nano-gel through fine duct and see that tumor and on every side little blood vessel thereof are all by thromboembolism.14 days neoplasm necrosises behind the thromboembolism.And the iodized oil thromboembolism is the part neoplasm necrosis after 14 days.
B. pathology detect.Experimental result is shown in accompanying drawing 7 and 8.Its tumor boundary clear when accompanying drawing 7 explanation temperature-sensitive nano-gel embolization group are observed under low power lens, the tumor nest is less and lack, similar round, tumor is coagulation necrosis; High power lens observation is down found tumor cell karyopycnosis, cracked, dissolving disappearance, does not see the tumor cell of survival in the necrosis region.Find that its tumor tumor nest is bigger when accompanying drawing 8 explanation iodized oil embolization group are observed under low power lens, still clear with the normal liver tissue boundary, tumor is based on coagulation necrosis, and visible a large amount of fibrous tissue form, visible a little incomplete tumor in necrotic area; High power lens is observed down, and a large amount of fibrous tissue form in the visible necrosis region, see the survival tumor cell in the necrotic area.
Claims (6)
1. temperature-sensitive nano-gel vascular embolic materials, it is characterized in that, it comprises poly-(N-N-isopropylacrylamide) base polymer nanogel and disperse medium, wherein, the mass percent concentration of poly-(N-N-isopropylacrylamide) base polymer nanogel is 3～10%, and surplus is a disperse medium;
The chemical constitution skeleton symbol of poly-(N-N-isopropylacrylamide) base polymer nanogel is: poly (A-co-B), its particle diameter is 60～400nm, wherein, A is the N-N-isopropylacrylamide, B is a hydrophobicity allylic comonomer, the molar percentage of A, B is 80～100: 0～20, and cross-linking agent is the bisacrylamide compounds that N-replaces, and dosage of crosslinking agent is 0.1～5% of A and a B integral molar quantity;
Disperse medium is that water solublity contains diodone injection or its diluent, and content of iodine is 50～350mg in every 1mL disperse medium, and the diluent of diluent is that water for injection, normal saline or pH value are a kind of in 4～9 the buffer solution.
2. a kind of temperature-sensitive nano-gel vascular embolic materials according to claim 1 is characterized in that, content of iodine is 180～350mg in every 1mL disperse medium.
3. temperature-sensitive nano-gel vascular embolic materials according to claim 1 and 2, it is characterized in that, in poly-(N-N-isopropylacrylamide) base polymer nanogel, comonomer is any in the N-acrylamide, acrylate and the methacrylate that replace.
4. a kind of temperature-sensitive nano-gel vascular embolic materials according to claim 1 and 2 is characterized in that, contrast-medium injection liquid is iohexol or ioversol.
5. the preparation method of the described temperature-sensitive nano-gel vascular embolic materials of claim 1, its step comprises:
(1) takes by weighing poly-(N-N-isopropylacrylamide) base polymer nanogel lyophilized powder, add disperse medium, at room temperature be stirred to abundant swelling, through the emulsifying of high shear homogenizer it be uniformly dispersed again, centrifugally leave standstill after removing bubble, obtain the temperature-sensitive nano-gel dispersion;
(2) above-mentioned finely dispersed temperature-sensitive nano-gel dispersion is sealed, through 60Co irradiation sterilization, room temperature storage.
6. the described temperature-sensitive nano-gel vascular embolic materials of claim 1 is as the application in the vascular suppository material of tumor locus and vascular malformation.
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