CN100560133C - Magnetic polylactic acid-phenylarsine glycolate nano microsphere and pharmaceutical applications thereof - Google Patents
Magnetic polylactic acid-phenylarsine glycolate nano microsphere and pharmaceutical applications thereof Download PDFInfo
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- CN100560133C CN100560133C CNB2006100246609A CN200610024660A CN100560133C CN 100560133 C CN100560133 C CN 100560133C CN B2006100246609 A CNB2006100246609 A CN B2006100246609A CN 200610024660 A CN200610024660 A CN 200610024660A CN 100560133 C CN100560133 C CN 100560133C
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Abstract
The present invention relates to a kind of application with magnetic polylactic acid-phenylarsine glycolate nano microsphere and treatment liver cancer thereof of magnetic responsiveness.At first prepare the magnetic polylactic acid-phenylarsine glycolate nano microsphere by ultrasonic emulsification-solvent evaporation method, microsphere is a kernel with ferroso-ferric oxide, Arsenosobenzene, with polylactic acid-glycolic guanidine-acetic acid copolymer integument is shell, the part by weight of Arsenosobenzene and polylactic acid-glycolic guanidine-acetic acid copolymer is 1: 50 to 25: 50, and microspherulite diameter is the 140-500 nanometer in the time of 20 ℃.Because at hepatocarcinoma diseased region externally-applied magnetic field, make the magnetic nano drug major part concentrate on the hepatocarcinoma district, reach targeting administering effect in the body, the drug level of raising liver target spot that can be bigger, improve the anti-hepatocarcinoma curative effect of Arsenosobenzene, reduce the medicament contg of other internal organs, thereby reduce medicine whole body toxicity.
Description
Technical field
The present invention relates to a kind of newtype drug dosage form and uses thereof, be specially the magnetic polylactic acid-phenylarsine glycolate nano microsphere and the treatment liver cancer application.
Background technology
Primary hepatocarcinoma is still one of modal malignant tumor of China, belongs to late period during discovery more, 1 year with 5 years to become to deposit rate all lower.Over year, inoperable liver cancer treatment has been obtained some progress, comprise embolism chemical therapeutic, local anhydrous alcohol injection for curing etc., but clinical practice has certain limitation surplus in the of nearly ten; Though new chemotherapeutics is developed, because the whole body effect is undesirable and side effect is big, lack hepatic targeting, at present clinically do not adopt substantially.
Recently people such as Konig and Koshiuka reports that respectively organo-arsenic class medicine has better therapeutic effect for suppressing leukemia and breast carcinoma in vivo and in vitro, and toxic and side effects is less, but does not see that so far organic arsenic preparation is used for the research report of liver cancer treatment.
Recently, the magnetic drug-carrying system that the nano-carrier that gets up based on Nano-technology Development mediates, under the effect of externally-applied magnetic field, can realize site-specific target administration purpose, help improving the local drug concentration of lesions position, the drug level of non-treated area is reduced, thereby further improve curative effect, reduce toxic and side effects, this magnetic drug-supplying system has external controllability, is the research direction of hepatoma-targeting treatment.
The present invention prepares the magnetic polylactic acid-phenylarsine glycolate nano microsphere by ultrasonic emulsification-solvent evaporation method, be used for anti-liver cancer treatment research, under the condition of externally-applied magnetic field, can improve the drug level of selective oxidation phenol arsenic preferably, strengthen therapeutic effect, and can reduce the whole body toxic and side effects greatly, not appear in the newspapers both at home and abroad so far.
Summary of the invention
The objective of the invention is to use the magnetic polylactic acid-phenylarsine glycolate nano microsphere,, can improve the medicine solubility of diseased region preferably, strengthen therapeutic effect, reduce the whole body toxicity at hepatocarcinoma diseased region externally-applied magnetic field.
The above-mentioned magnetic polylactic acid-phenylarsine glycolate nano microsphere that the present invention proposes adopts ultrasonic emulsification-solvent evaporation method preparation synthetic, its composition comprises polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA), ferroso-ferric oxide, Arsenosobenzene (PAO), it is characterized in that with ferroso-ferric oxide, Arsenosobenzene be kernel, with polylactic acid-glycolic guanidine-acetic acid copolymer integument is shell, the part by weight of Arsenosobenzene and polylactic acid-glycolic guanidine-acetic acid copolymer is 1: 50 to 25: 50, and microspherulite diameter is the 140-500 nanometer in the time of 20 ℃.
Concrete preparation process is as follows:
Arsenosobenzene and polylactic acid-glycolic guanidine-acetic acid copolymer in the constant weight ratio, are dissolved in the dichloromethane fully, add the inorganic magnetic ferroferric oxide nano granules again, ultra-sonic dispersion forms oil phase.Oil phase is added in 4% polyvinyl alcohol water solution, and ultrasonic emulsification presents even emulsus after 5 minutes.Under stirring condition, above-mentioned emulsion slowly is added drop-wise in 0.3% polyvinyl alcohol water solution, continue to stir 5 hours, whole whipping process carries out under 37 ℃ of water-baths.After stirring end, the gained suspension is placed on the Magnet, remove supernatant, reuse distilled water wash, high speed centrifugation, 3 times repeatedly.With the lyophilization of gained precipitate, vacuum drying, sterilization, promptly get the magnetic polylactic acid-phenylarsine glycolate nano microsphere.
Nano medication of the present invention is to be integument with polylactic acid-glycolic guanidine-acetic acid copolymer, is the polymer microballoon of nuclear with ferriferrous oxide nano microgranule and Arsenosobenzene dispersion.This kind Nano microsphere is synthetic by ultrasonic emulsification-solvent evaporation method, and its particle diameter is the 140-500 nanometer at 20 ℃, and has magnetic preferably, has magnetic targeting preferably under the condition of externally-applied magnetic field.
The polymer integument of above-mentioned microsphere is a polylactic acid-glycolic guanidine-acetic acid copolymer.
Above-mentioned kernel is ferriferrous oxide nano microgranule and Arsenosobenzene dispersion.
Above-mentioned Nano microsphere has the magnetic core, has magnetic responsiveness preferably, so under the condition of externally-applied magnetic field, can realize the targeted therapy effect of medicine.
Among the present invention, used magnetic nanoparticle can be wherein a kind of such as ferroso-ferric oxide, r-iron sesquioxide.
Among the present invention, used oil phase is a dichloromethane, and water is a polyvinyl alcohol water solution.
Among the present invention, adopt ultrasonic emulsification-solvent evaporation method to prepare the magnetic polylactic acid phenylarsine glycolate nano microballoon, ultrasonic time should be not too short, more than 5 minutes for well.
The magnetic polylactic acid-phenylarsine glycolate nano microsphere with magnetic of the present invention's development, its diameter is the 140-500 nanometer at 20 ℃.Can be by the adjusting ultrasonic time, the consumption of polylactic acid-glycolic guanidine-acetic acid, oil-water ratio is controlled the size of its particle diameter.Ultrasonic time prolongs in the certain limit, and particle diameter increases; Polylactic acid-glycolic guanidine-acetic acid consumption increases, and particle diameter increases; Oil-water ratio increases, and particle diameter increases.
The magnetic polylactic acid-phenylarsine glycolate nano microsphere with magnetic of the present invention development, its envelop rate, drug loading can be by changing Arsenosobenzene, polylactic acid-glycolic guanidine-acetic acid consumption, oil-water ratio, the solubility of polyvinyl alcohol regulate and control.
The present invention is in the above-mentioned scope that feeds intake, and the copolymer coated ferroferric oxide of development, the microsphere of Arsenosobenzene are a kind of nanoparticles with magnetic, and its diameter is in the 140-500 nanometer, and drug loading and envelop rate are all controlled.
This medicine has magnetic targeting and slow-releasing preferably, can be used for site-specific delivery of drugs in the body, under the condition of externally-applied magnetic field, can reduce the whole body toxic and side effects and the administration number of times of Arsenosobenzene greatly, simultaneously can increase target drug concentration preferably, improve therapeutic effect.
We have carried out following research work, by Flow Cytometry, the outer anti-liver cancer efficacy of mtt assay checking magnetic polylactic acid-phenylarsine glycolate nano microsphere.Set up the kunming mice liver cancer model, magnetic polylactic acid-phenylarsine glycolate nano microsphere group is adding under the magnetic field condition, compares with simple Arsenosobenzene medicine group, can better improve the life cycle of mice.
We adopt the anti-liver cancer treatment of polylactic acid-phenylarsine glycolate nano microballoon, and its concrete steps are as follows:
(1) prepares the magnetic polylactic acid-phenylarsine glycolate nano microsphere by ultrasonic emulsification-solvent evaporation method.
(2) liver target Journal of Sex Research: 12 SD rats are divided into 2 groups at random, and 6 every group, male and female half and half.Behind the pentobarbital sodium intraperitoneal injection of anesthesia, rat is fixed on fixing head.21 milligrams of magnetic polylactic acid-phenylarsine glycolate nano microspheres of tail vein injection, 1 group of rat hepatic region adds big or small 4500 gauss magnetic fields, and another group does not add magnetic field.After 30 minutes, put to death rat, core respectively, liver, lung, kidney device, detect Arsenosobenzene content.
(3) the outer anti-hepatoma carcinoma cell effect research of magnetic polylactic acid-phenylarsine glycolate nano microsphere: adopt mtt assay, Flow Cytometry to observe the magnetic polylactic acid-phenylarsine glycolate nano microsphere to the effect of hepatoma carcinoma cell (SMMC-7721) inhibition of proliferation.
(4) liver cancer model kunming mice survival period is observed: extract hepatic ascites model Kunming kind Mus (the shanghai Medicine industrial research provides) ascites, after ascites and normal saline were diluted by 1: 1, the 0.1ml mixing material was injected in every mice oxter.After ten days, divide two groups with the mice that grows the cancer piece, one group of hepatocarcinoma district adds 4500 gauss magnetic fields, and the tail vein gives the magnetic polylactic acid-phenylarsine glycolate nano microsphere, and another group gives pure zirconia phenol arsenic medicine, observes the mice mouse storaging current.
Studies show that magnetic polylactic acid-phenylarsine glycolate nano microsphere of the present invention, its medicine active ingredient is an Arsenosobenzene, and medicine of the present invention can better improve hepatocarcinoma district drug level, reduces the whole body toxic and side effects, is used for liver cancer treatment.
Description of drawings
Fig. 1 is adding under the magnetic field condition and is giving the Arsenosobenzene medicine merely and compare liver cancer model kunming mice survival period and observe for the magnetic polylactic acid-phenylarsine glycolate nano microsphere
The specific embodiment
Following test example can illustrate in greater detail the present invention, but does not limit the present invention in any form.
Test example 1. liver target Journal of Sex Researchs
Laboratory animal: the SD rat, male and female half and half, Mus 4-6 in age week, body weight 175-200 gram, 12 of quantity are provided by the The 2nd Army Medical College Experimental Animal Center.
Test method: 12 SD rats are divided into 2 groups at random, and 6 every group, male and female half and half.Behind the pentobarbital sodium intraperitoneal injection of anesthesia, rat is fixed on fixing head.21 milligrams of magnetic polylactic acid-phenylarsine glycolate nano microspheres of tail vein injection, 1 group of rat hepatic region adds big or small 4500 gauss magnetic fields, and another group does not add magnetic field.After 30 minutes, put to death rat, core respectively, liver, lung, kidney device, detect Arsenosobenzene content, result such as table 1.
Table 1 Arsenosobenzene drug level (n=6)
Test shows, under the condition of externally-applied magnetic field, the magnetic polylactic acid-phenylarsine glycolate nano microsphere has targeting preferably, the drug level of raising liver target spot that can be bigger, reduce the medicament contg of other internal organs, thereby reduce medicine whole body toxicity.
Test example 2. magnetic polylactic acid-phenylarsine glycolate nano microspheres are to hepatoma carcinoma cell (SMMC-7721) inhibitory action.
Adopt mtt assay to observe the inhibitory action of magnetic polylactic acid-phenylarsine glycolate nano microsphere to hepatoma cell proliferation.Trial drug group concentration is respectively: 1, Arsenosobenzene 0.1umol/L, 1.0umol/L, 10umol/L, 100umol/L; 2, magnetic polylactic acid-phenylarsine glycolate nano microsphere valid density 0.1umol/L, 1.0umol/L, 10umol/L, 100umol/L, with the suspending agent dilution, hepatoma carcinoma cell is with 5 * 10
4/ ml is inoculated in 96 orifice plates, and 3 multiple holes are established for every group in the 200ul/ hole, change the complete culture solution that is added with medicinal liquid behind the inoculation 24h, 100ul/ hole, the blank microsphere of a negative control group addition polymerization lactic-co-glycolic acid.After the dosing respectively at 24,48,72h adds MTT solution 20ul/ hole, after continuing to cultivate 4h, adds the DMSO100ul/ hole, after 37 ℃ of placements, detects the absorbance (A) of each hole at 570nm place with the porous microplate reader, the calculating suppression ratio.The absorbance of suppression ratio=(matched group absorbance-experimental group absorbance)/matched group.The results are shown in Table 2.
Table 2 magnetic polylactic acid-phenylarsine glycolate nano microsphere is to the inhibitory action of hepatoma carcinoma cell
Test shows that the magnetic polylactic acid-phenylarsine glycolate nano microsphere is in the external inhibitory action that has hepatoma carcinoma cell, and its inhibition degree changes with action time, drug level.
Test example 3: liver cancer model kunming mice survival period is observed
Experimental animal: kunming mice, male and female half and half, body weight 16-20 gram, 40 of quantity, kunming mice is provided by the The 2nd Army Medical College zooscopy.
Experimental technique: extract hepatic ascites model Kunming kind Mus (the shanghai Medicine industrial research provides) ascites, by 1: 1 dilution proportion, the 0.1ml mixing material was injected in every mice oxter with normal saline.After ten days, divide two groups with the mice that grows the cancer piece, one group of hepatocarcinoma district adds 4500 gauss magnetic fields, presses 3.6mg/kg the efficient oxidation phenol arsenic content, and the tail vein gives the magnetic polylactic acid-phenylarsine glycolate nano microsphere; Another group is by same content, and only the tail vein gives the Arsenosobenzene medicine, observes mouse storaging current, and record as shown in Figure 1.
Experimental result shows, magnetic polylactic acid-phenylarsine glycolate nano microsphere of the present invention is adding under the magnetic field condition and is giving the Arsenosobenzene medicine merely and compare, because at hepatocarcinoma diseased region externally-applied magnetic field, make the magnetic nano drug major part concentrate on the hepatocarcinoma district, reach targeting administering effect in the body, reduce the toxic and side effects and the administration number of times of Arsenosobenzene, increase hepatocarcinoma district medicine solubility, improve the anti-hepatocarcinoma curative effect of Arsenosobenzene, can obviously prolong the mice time-to-live.
Claims (2)
1. magnetic polylactic acid-phenylarsine glycolate nano microsphere, its composition comprises polylactic acid-glycolic guanidine-acetic acid copolymer, ferroso-ferric oxide, Arsenosobenzene, it is characterized in that microsphere is that what to adopt that ultrasonic emulsification-solvent evaporation method makes is kernel with ferroso-ferric oxide, Arsenosobenzene, with polylactic acid-glycolic guanidine-acetic acid copolymer integument is shell, the part by weight of Arsenosobenzene and polylactic acid-glycolic guanidine-acetic acid copolymer is 1: 50 to 25: 50, and microspherulite diameter is the Nano microsphere of 140-500 nanometer in the time of 20 ℃;
Described ultrasonic emulsification-solvent evaporation method concrete steps are as follows:
With Arsenosobenzene and polylactic acid-glycolic guanidine-acetic acid copolymer by weight proportion, be dissolved in fully in the dichloromethane, add the inorganic magnetic ferroferric oxide nano granules again, ultra-sonic dispersion forms oil phase;
Oil phase is added in 4% polyvinyl alcohol water solution, and ultrasonic emulsification presents even emulsus after 5 minutes; Under stirring condition, above-mentioned emulsion slowly is added drop-wise in 0.3% polyvinyl alcohol water solution, continue to stir 5 hours, whole whipping process carries out under 37 ℃ of water-baths;
After stirring end, the gained suspension is placed on the Magnet, remove supernatant, reuse distilled water wash, high speed centrifugation, 3 times repeatedly;
With the lyophilization of gained precipitate, vacuum drying, sterilization, promptly get the magnetic polylactic acid-phenylarsine glycolate nano microsphere.
2. a kind of magnetic polylactic acid-phenylarsine glycolate nano microsphere according to claim 1 is adding the application that is used for the medicine of targeting drug treatment hepatocarcinoma in the body under the magnetic field condition in preparation.
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| CN101757718B (en) * | 2009-12-31 | 2012-11-14 | 重庆大学 | Preparation method of implanted magnetic control drug microchip |
| CN102091027B (en) * | 2011-01-14 | 2012-10-31 | 华南理工大学 | Method for preparing antitumor small interfering RNA carrying magnetic nano probe |
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| 氧化酚砷对血液肿瘤细胞系的体外效应. 孙岳平等.癌症，第19卷第1期. 2000 * |
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