CN103751797B - A kind of enzyme with dual activity touches release preparation, its preparation method and application - Google Patents
A kind of enzyme with dual activity touches release preparation, its preparation method and application Download PDFInfo
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- CN103751797B CN103751797B CN201310751673.6A CN201310751673A CN103751797B CN 103751797 B CN103751797 B CN 103751797B CN 201310751673 A CN201310751673 A CN 201310751673A CN 103751797 B CN103751797 B CN 103751797B
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Abstract
The present invention relates to a kind of pharmaceutical preparation, especially a kind of enzyme with dual activity touches release preparation, its preparation method and application, belongs to pharmaceutical technology sectors.The present invention by A, B, C, D tetra-part form, described part A is gold nanorods, and part B is Polyethylene Glycol, and C part be matrix metalloproteinase specific recognition peptide, and D is partly methylprednisolone.Non-steroidal anti-inflammatory drug methylprednisolone is passed through matrix metalloproteinase specific recognition peptide as linking arm by the present invention, be connected to Polyethylene Glycol-gold nanorods surface, build methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods targeting drug delivery system, thus the enzyme realizing having Drug therapy and thermotherapy dual activity touches release delivery system.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, especially a kind of enzyme with dual activity touches release preparation, its preparation method and application, belongs to pharmaceutical technology sectors.
Background technology
Rheumatoid arthritis (rheumatoid arthritis, RA) is the chronic autoimmune disease in a kind of connective tissue place, and its pathogeny is unknown.Arthritis can cause the pain of bone joint, enlargement, stiff and functional forfeiture.RA still lacks the means of healing, and clinical treatment comprises Drug therapy and thermotherapy.Drug therapy is mainly nonsteroidal and corticosteroid anti-inflammatory agent, and as ibuprofen, Methylprednisolone succinate (MPS) etc., methylprednisolone is a kind of Aeroseb-Dex, is mainly used in anaphylaxis and diseases associated with inflammation.Methylprednisolone is insoluble in water, what commercial preparation adopted is that Urbason Solubile (prednisolone) is for arthritic treatment, but this medicine lacks targeting in vivo, vein gives rapidly the anaphylaxis that general may occur heavy dose, there is more serious toxic and side effects, methylprednisolone molecular structural formula:
Conventional thermotherapy comprises: hot compress, near-infrared light irradiation and microwave diathermy.Thermotherapy all achieves good curative effect on relief of symptoms and raising knee joint function, and relative to Drug therapy, thermotherapy side effect is lower, but its treatment degree of depth is limited, is difficult to the deep layer position being heated to knee.Therefore, also need clinically to find new thermotherapy means to improve arthritis thermotherapy curative effect.Thermotherapy and Drug combination, dual-target arthritis, perhaps synergistic therapeutic action occurs is one " key " of dealing with problems.Therefore, the two targeting drug delivery systems providing a kind of novel thermotherapy to be combined with Drug therapy for the treatment of RA are extremely urgent.
Summary of the invention
The object of the invention is the defect existed for prior art, propose a kind of enzyme with dual activity and touch release preparation, its preparation method and application, the treatment for rheumatoid arthritis provides new medicine.
The present invention is technical solution problem by the following technical programs: a kind of enzyme with dual activity touches release preparation, by A, B, C, D tetra-part form, described part A is gold nanorods, and part B is Polyethylene Glycol, C part is matrix metalloproteinase specific recognition peptide, and D part is methylprednisolone.
The present invention selects gold nanorods (AuNR) as pharmaceutical carrier.Gold nanorods has major diameter (LP) and minor axis (TP), has two plasma resonance absorption peaks respectively between 650-950nm with 520nm place TP.AuNR surface plasma body resonant vibration can cause it to the scattering of light of near infrared band specific wavelength and absorption, and this part energy absorbed is converted into heat energy by the relaxation of lattice the most at last, makes gold nanorods have effect of heat-therapeutic action.In order to reduce gold nanorods toxicity, adopting Polyethylene Glycol-mercaptan (PEG-thiol) to its finishing, obtaining that there is thermotherapy effect, hypotoxic Polyethylene Glycol-gold nanorods.Secondly, research finds, the inflammation of RA mainly occurs in place of synovial tissue, along with edema and blood vessel hyperplasia, forms pannus.The inflammatory cell that pannus contains macrophage, fibroblast and invades profit as the T be activated and bone-marrow-derived lymphocyte, and can discharge multiple inflammatory factor and interleukin.Under the impact of inflammatory factor, synovial fluid can produce a large amount of proteolytic enzyme (mainly matrix metalloproteinase by specificity, MMPs), therefore, arthritis place can specific expressed go out higher than the MMP-2 of normal structure level, discharge at arthritis site specific to make medicine, adopt matrix metalloproteinase specific recognition peptide (MMP specific peptide) as linking arm, methylprednisolone is connected to Polyethylene Glycol-gold nanorods surface, after this delivery system targeting to arthritis affected part, under MMP-2 (MMP-2) effect, MMP specificpeptide is cut off, medicine is from the release of AuNRs surface, reach the object that enzyme touches release.Concrete preparation method is as follows: a kind of enzyme with dual activity touches the preparation method of release preparation, comprises the following steps:
Step one, employing seed mediated growth method prepare the gold nanorods of cetyl trimethyl ammonium bromide as stabilized zone, first according to a conventional method seed liquor is prepared, then join in growth-promoting media under seed liquor being stirred, keep 3h, solution is that brilliant violet is red, the centrifugal 10min of 11000rpm, separation is concentrated obtains CTAB-AuNR.CTAB-AuNR being dispersed in 4mL concentration is in the Polyethylene Glycol-mercaptan aqueous solution of 250 μMs, stirs hatching 1h, and through deionized water dialysis 24h, centrifugal removing CTAB obtains Polyethylene Glycol-gold nanorods;
Step 2, get the obtained Polyethylene Glycol-gold nanorods of 5mL step one, add 98.5mg1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, stirring at room temperature activation is spent the night, add 57.5mg N-hydroxy-succinamide, 50mg methylprednisolone-matrix metalloproteinase specific recognition peptide again, 4 DEG C are stirred 6h, reactant liquor is collected gold nanorods at the centrifugal 10min of 11000rpm, again gold nanorods is dispersed in 2mL deionized water, obtains methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods.
The described step of said method is a kind of, and the Ratio of long radius to short radius of Polyethylene Glycol-gold nanorods is 4:1.Polyethylene Glycol-thiol molecule amount is 400,600,2000 or 5000.
In described step 2, prednisolone-matrix metalloproteinase specific recognition peptide and Polyethylene Glycol-gold nanorods form amido link by esterification or ester bond is connected.
The present invention further provides the enzyme with dual activity and touch the application of release preparation in the medicine of preparation treatment rheumatoid arthritis.
Non-steroidal anti-inflammatory drug methylprednisolone is passed through matrix metalloproteinase specific recognition peptide as linking arm by the present invention, be connected to Polyethylene Glycol-gold nanorods surface, build methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods targeting drug delivery system, thus the enzyme realizing having Drug therapy and thermotherapy dual activity touches release delivery system.
Accompanying drawing explanation
Fig. 1 is the structure chart of invention formulation.
Fig. 2 is Electronic Speculum figure and the ultra-violet absorption spectrum of Polyethylene Glycol-gold nanorods.
Fig. 3 is that the enzyme of embodiment one touches drug release profiles.
Fig. 4 is the thermotherapy experimental temperature variation diagram of embodiment one.
Fig. 5 is the interior curative effect figure of embodiment one.
Detailed description of the invention
Below in conjunction with embodiments of the invention and accompanying drawing, enforcement of the present invention is elaborated; following examples implement under premised on the present invention program; give detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment one
The present embodiment is prepared the enzyme with dual activity by the following method and is touched release preparation:
Step one, Polyethylene Glycol-gold nanorods preparation: adopt seed mediated growth method to prepare the gold nanorods of cetyl trimethyl ammonium bromide (CTAB) as stabilized zone.First according to a conventional method prepare seed liquor, then join in growth-promoting media by under seed liquor vigorous stirring, keep 3h, solution is that brilliant violet is red, and the centrifugal 10min of 11000rpm is separated to concentrate and obtains CTAB-AuNR.CTAB-AuNR being dispersed in 4mL concentration is in Polyethylene Glycol-mercaptan (PEG-thiol) aqueous solution of the molecular weight 5000 of 250 μMs, stirs hatching 1h, deionized water dialysis 24h, centrifugal removing CTAB obtains Polyethylene Glycol-gold nanorods, major diameter is 40nm, and minor axis is 10nm, as shown in Figure 2.
Step 2, the preparation of methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods delivery system: get the Polyethylene Glycol gold nanorods that 5mL step one is obtained, add 98.5mg1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, stirring at room temperature activation is spent the night, add 57.5mg N-hydroxy-succinamide again, 50mg methylprednisolone-matrix metalloproteinase specific recognition peptide, 4 DEG C are stirred 6h, reactant liquor is collected gold nanorods at the centrifugal 10min of 11000rpm, be dispersed in 2mL deionized water, obtain methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods.
Methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods vitro enzyme touches drug release:
Investigate the performance that methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods enzyme touches drug release, it is in the bag filter of 10000 that a certain amount of target conjugate is loaded interception, add MMP-2 (MMP-2), 37 DEG C of shaking baths are hatched, in 1h, 2h, 4h, 6h, 10h, 14h, 20h, 28h, 36h, 44h and 56h, take out 20 μ L hydrolyzed solutions and inject HPLC systems axiol-ogy methylprednisolone burst size, result as shown in Figure 3.
Thermotherapy effect experiment in body:
1. animal
The model of arthritic mice is set up: Kunming mouse, body weight 18-20g, and 4-6 point subcutaneous injection cattle II Collagen Type VI acetic acid and Freund's complete adjuvant mixed solution are got in back, 200 μ L altogether, mice joint motion is obstructed, toe and redness and swelling of joints, show that model is successfully established, for targeting experiment in body.
2. thermotherapy experiment in body
Dosage regimen: methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods, tail vein injection enters in arthritis Mice Body, and matched group is: methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol.Adopt near-infrared laser to irradiate joint after 24h respectively, result as shown in Figure 4.
The scorching therapeutic effect of body intrinsic articulation:
1. animal
The model of arthritic mice is set up: Kunming mouse, body weight 18-20g, and 4-6 point subcutaneous injection cattle II Collagen Type VI acetic acid and Freund's complete adjuvant mixed solution are got in back, 200 μ L altogether, mice joint motion is obstructed, toe and redness and swelling of joints, show that model is successfully established, for targeting experiment in body.
2. interior therapeutic experiment
Dosage regimen: arthritic mice tail vein injection methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods, dosage be 1mg/kg/ weekly, continuous injection 6 weeks, methylprednisolone commercial preparation is matched group, dosage is 1mg/kg/ days, and injection investigates therapeutic effect in 6 weeks respectively continuously.Result presses the marking of arthritis treatment mark, and 0 is without congested NIP, and 1 is congested micro-swelling, 2 is that ankle swelling is congested, and 3 is that toe swelling ankle swelling is congested, and 4 is that the overall swelling of foot is congested, once result was recorded every 3 days, as shown in Figure 5 after treatment starts.
Embodiment two
The present embodiment is prepared the enzyme with dual activity by the following method and is touched release preparation:
Step one, Polyethylene Glycol-gold nanorods preparation: adopt seed mediated growth method to prepare the gold nanorods of cetyl trimethyl ammonium bromide (CTAB) as stabilized zone.First according to a conventional method prepare seed liquor, then join in growth-promoting media by under seed liquor vigorous stirring, keep 3h, solution is that brilliant violet is red, and the centrifugal 10min of 11000rpm is separated to concentrate and obtains CTAB-AuNR.CTAB-AuNR being dispersed in 4mL concentration is in Polyethylene Glycol-mercaptan (PEG-thiol) aqueous solution of the molecular weight 2000 of 250 μMs, stirs hatching 1h, deionized water dialysis 24h, and centrifugal removing CTAB obtains Polyethylene Glycol-gold nanorods;
Step 2, the preparation of methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods delivery system: get the Polyethylene Glycol gold nanorods that 5mL step 1 is obtained, add 98.5mg1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, stirring at room temperature activation is spent the night, add 57.5mg N-hydroxy-succinamide again, 50mg methylprednisolone-matrix metalloproteinase specific recognition peptide, 4 DEG C are stirred 6h, reactant liquor is collected gold nanorods at the centrifugal 10min of 11000rpm, be dispersed in 2mL deionized water, obtain methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods.
Therapeutic effect and the embodiment one of the present embodiment are similar, repeat no more.
Embodiment three
The present embodiment is prepared the enzyme with dual activity by the following method and is touched release preparation:
Step one, Polyethylene Glycol-gold nanorods preparation: adopt seed mediated growth method to prepare the gold nanorods of cetyl trimethyl ammonium bromide (CTAB) as stabilized zone.First according to a conventional method prepare seed liquor, then join in growth-promoting media by under seed liquor vigorous stirring, keep 3h, solution is that brilliant violet is red, and the centrifugal 10min of 11000rpm is separated to concentrate and obtains CTAB-AuNR.CTAB-AuNR being dispersed in 4mL concentration is in Polyethylene Glycol-mercaptan (PEG-thiol) aqueous solution of the molecular weight 600 of 250 μMs, stirs hatching 1h, deionized water dialysis 24h, and centrifugal removing CTAB obtains Polyethylene Glycol-gold nanorods;
Step 2, the preparation of methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods delivery system: get the Polyethylene Glycol gold nanorods that 5mL step 1 is obtained, add 98.5mg1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, stirring at room temperature activation is spent the night, add 57.5mg N-hydroxy-succinamide again, 50mg methylprednisolone-matrix metalloproteinase specific recognition peptide, 4 DEG C are stirred 6h, reactant liquor is collected gold nanorods at the centrifugal 10min of 11000rpm, be dispersed in 2mL deionized water, obtain methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods.
Therapeutic effect and the embodiment one of the present embodiment are similar, repeat no more.
Embodiment four
The present embodiment is prepared the enzyme with dual activity by the following method and is touched release preparation:
Step one, Polyethylene Glycol-gold nanorods preparation: adopt seed mediated growth method to prepare the gold nanorods of cetyl trimethyl ammonium bromide (CTAB) as stabilized zone.First according to a conventional method prepare seed liquor, then join in growth-promoting media by under seed liquor vigorous stirring, keep 3h, solution is that brilliant violet is red, and the centrifugal 10min of 11000rpm is separated to concentrate and obtains CTAB-AuNR.CTAB-AuNR being dispersed in 4mL concentration is in Polyethylene Glycol-mercaptan (PEG-thiol) aqueous solution of the molecular weight 400 of 250 μMs, stirs hatching 1h, and deionized water dialysis 24h, centrifugal removing CTAB obtains Polyethylene Glycol-gold nanorods.
Step 2, the preparation of methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods delivery system: get the Polyethylene Glycol gold nanorods that 5mL step 1 is obtained, add 98.5mg1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, stirring at room temperature activation is spent the night, add 57.5mg N-hydroxy-succinamide again, 50mg methylprednisolone-matrix metalloproteinase specific recognition peptide, 4 DEG C are stirred 6h, reactant liquor is collected gold nanorods at the centrifugal 10min of 11000rpm, be dispersed in 2mL deionized water, obtain methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods.
Therapeutic effect and the embodiment one of the present embodiment are similar, repeat no more.
Except above-mentioned enforcement, the present invention can also have other embodiments.All employings are equal to the technical scheme of replacement or equivalent transformation formation, all drop on the protection domain of application claims.
Claims (4)
1. an enzyme with dual activity touches the preparation method of release preparation, the described enzyme with dual activity touches release preparation, by A, B, C, D tetra-part form, described part A is gold nanorods, part B is Polyethylene Glycol, C part is matrix metalloproteinase specific recognition peptide, and D part is methylprednisolone; Its preparation method comprises the following steps:
Step one, employing seed mediated growth method prepare the gold nanorods of cetyl trimethyl ammonium bromide as stabilized zone, first according to a conventional method seed liquor is prepared, then join in growth-promoting media under seed liquor being stirred, keep 3 h, solution is that brilliant violet is red, centrifugal 10 min of 11000 rpm, be separated to concentrate and obtain CTAB-AuNR, CTAB-AuNR being dispersed in 4 mL concentration is in the Polyethylene Glycol-mercaptan aqueous solution of 250 μMs, stir hatching 1h, to dialyse 24 h through deionized water, centrifugal removing CTAB obtains Polyethylene Glycol-gold nanorods;
Step 2, get the obtained Polyethylene Glycol-gold nanorods of 5 mL steps one, add 98.5 mg 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, stirring at room temperature activation is spent the night, add 57.5 mg N-hydroxy-succinamides, 50 mg methylprednisolones-matrix metalloproteinase specific recognition peptide again, 4
oc stirs 6 h, reactant liquor is collected gold nanorods at centrifugal 10 min of 11000 rpm, then is dispersed in by gold nanorods in 2 mL deionized waters, obtain methylprednisolone-matrix metalloproteinase specific recognition peptide-Polyethylene Glycol-gold nanorods.
2. the enzyme according to claim 1 with dual activity touches the preparation method of release preparation, it is characterized in that: in described step one, and the Ratio of long radius to short radius of Polyethylene Glycol-gold nanorods is 4:1.
3. the enzyme according to claim 2 with dual activity touches the preparation method of release preparation, it is characterized in that: Polyethylene Glycol-thiol molecule amount is 400,600,2000 or 5000.
4. the enzyme according to claim 1 with dual activity touches the preparation method of release preparation, it is characterized in that: in described step 2, methylprednisolone-matrix metalloproteinase specific recognition peptide and Polyethylene Glycol-gold nanorods form ester bond to be connected by esterification.
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| CN101528691A (en) * | 2006-08-22 | 2009-09-09 | 兰贝克赛实验室有限公司 | Matrix metalloproteinase inhibitors |
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| CN101528691A (en) * | 2006-08-22 | 2009-09-09 | 兰贝克赛实验室有限公司 | Matrix metalloproteinase inhibitors |
Non-Patent Citations (3)
| Title |
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| Gold Nanorods Conjugated with Doxorubicin and cRGD for Combined Anti-cancer Drug Delivery and PET Imaging;Yuling Xiao et al.;《Theranostics》;20120806;第2卷(第8期);摘要、图1和图S1 * |
| Matrix Metalloproteinase Sensitive Gold Nanorod for Simultaneous Bioimaging and Photothermal Therapy of Cancer;Dong Kee Yi et al.;《Bioconjugate Chemistry》;20100911;第21卷;2173页及图示1 * |
| 不同表面化学修饰金纳米棒的血液相容性;李媛 等;《国际药学研究杂志》;20130430;第40卷(第2期);228-232页 * |
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