CN102151336B - Active targeting drug conveying system for crossing blood brain barrier through mediation of acetylcholine receptor - Google Patents
Active targeting drug conveying system for crossing blood brain barrier through mediation of acetylcholine receptor Download PDFInfo
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- CN102151336B CN102151336B CN201010110665XA CN201010110665A CN102151336B CN 102151336 B CN102151336 B CN 102151336B CN 201010110665X A CN201010110665X A CN 201010110665XA CN 201010110665 A CN201010110665 A CN 201010110665A CN 102151336 B CN102151336 B CN 102151336B
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Images
Abstract
The invention relates to an active targeting drug conveying system for crossing a blood brain barrier through mediation of an acetylcholine receptor, belonging to the field of pharmacy. In the invention, after a biotinylation derivative of the acetylcholine receptor is coupled with streptavidin-based fluorescein by utilizing polypeptide KC2S with high appetency with the acetylcholine receptor, cell specificity ingestion and in vivo brain distribution results show that the KC2S can mediate protein molecules across the blood brain barrier; when the KC2S is modified to albumin nanoparticles, a 125I labeled object biodistribution shows that the KC2S can promote a nano drug conveying system across the blood brain barrier; when the KC2S is modified into polyethylene glycol-polylactic acid and is established into micelle with the polyethylene glycol-polylactic acid, a fluorescent tracing result shows that the KC2S can mediate brain targeting of the drug conveying system; and when the KC2S- polyethylene glycol-polylactic acid micelle is used for entrapping taxol, the life cycle of an in-situ model nude mouse with brain glioma can be remarkably prolonged.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of brain targeting complex and nanoscale medicine delivery system that strides across blood brain barrier, be specifically related to the active targeting drug delivery system that a kind of acetylcholine receptor mediated is crossed over blood brain barrier.
Background technology
Studies show that nAChR (nAChRs) is a kind of door-control type ion channel receptor, highly express the central nervous system, at cerebral tissue, comprise the equal wide expression of brain capillary endotheliocyte that forms blood brain barrier.
Snake venom neurotoxin mainly is divided into short neurotoxin and long neurotoxin venom, the protein molecular that the former mainly refers to contain 60-62 aminoacid, forms 4 pairs of disulfide bond; The protein molecular that the latter refers to contain 71-74 aminoacid, forms 5 pairs of disulfide bond.There are some researches show, some poisonous snakes, such as Naja, Agkistrodon halys and Bungarus fasciatus etc., the neurotoxin of its secretion in venom can with acetylcholinergic receptor specific binding (K
D=10
-9-10
-10M).Snake venom neurotoxin belongs to three finger type structures, has structure shown in Figure 1.Wherein, in three rings that snake venom neurotoxin forms (loopI, loopII and loopIII), loopII is the main region of being combined with nAChRs, and the molecular level experimental result shows that neurotoxin loopII aminoacid sequence and nAChRs have high-affinity.KC2S is the LoopII zone aminoacid sequence of long neurotoxin venom O.Hannah toxin b, comprises 20 aminoacid.Its aminoacid sequence is YTKTWCDGFCSSRGKRIDLG, and 6 and 10 s' cysteine forms disulfide bond, Thomas L.Lentz[Biochemistry, 1991,30,10949-10957] chemosynthesis KC2S, and investigated the structure activity relationship of itself and rabies virus glycoprotein polypeptide fragment.
Blood brain barrier is to hinder the major obstacle that medicine enters brain tissue, and research and development can penetrate the targeted molecular of blood brain barrier, assists medicine or pharmaceutical carrier to pass blood brain barrier, thereby reaches the interior transmission of brain of medicine, has realistic meaning.
Summary of the invention
Purpose of the present invention is for seeking the targeted molecular that can penetrate blood brain barrier, assist medicine or pharmaceutical carrier to pass blood brain barrier, thereby reach the delivery system that transmits in the brain of medicine, be specifically related to the active targeting drug delivery system that a kind of acetylcholine receptor mediated is crossed over blood brain barrier.
The present invention with polypeptide KC2S as the targeted molecular that can penetrate blood brain barrier, utilize itself and acetylcholinergic receptor to have high-affinity and by the characteristic of brain capillary endothelial cell specific picked-up, with fluorescent probe and nano-carrier system or nanoscale medicine delivery system targeted delivery to animal brain.
Described its aminoacid sequence of polypeptide KC2S is YTKTWCDGFCSSRGKRIDLG.
Described KC2S polypeptide and acetylcholinergic receptor have high combination activity.
Among the present invention, utilize solid phase synthesis to prepare the biotin derivative of KC2S, this derivant can with fluorescein-labelled Streptavidin coupling, the brain distribution results shows in cell-specific picked-up and body, KC2S has the feature of carrying fluorescence molecule leap blood brain barrier; Utilize the biotinstreptatin system, KC2S modified albumin (BSA) nanoparticle surface,
125The brain abundance of I labelling increases presentation of results, and KC2S can promote the brain targeting of nanoparticulate carriers system; React with the KC2S sulfhydrylation and with maleimide, modify on polyethylene glycol-polylactic acid (PEG-PLA) material, the micelle that makes up can carry fluorescent dye or antitumor drug into brain, prolong the life cycle of cerebral tumor animal pattern, shows that KC2S can mediate nano-micelle delivery system brain targeting and anti-cerebral tumor effect.
KC2S of the present invention can utilize the mode of biotinstreptatin and fluorescent material FITC to form complex, but is not limited only to FITC, and nir dye Cy5.5 and IR820 can profit form complex with KC2S in the same way; KC2S not only can modify the polyethylene glycol-polylactic acid micelle administration system by sulfhydrylation, can also modify polyethylene glycol-polylactic acid-polyglycolic acid, PEG-PCL and PEG2000-DSPE; Behind the described KC2S biotinylation, can also modify bovine serum albumin nanoparticle, human serum albumin nanoparticle, polyethylene glycol-polylactic acid nanoparticle, poly-Polyethylene Glycol-lactic acid-polyglycolic acid nanoparticle, the own interior nanoparticle of polyethylene glycol-and PEG2000-DSPE nanoparticle; Described KC2S modifies have brain targeting feature delivery system be not limited only to bag and carry the antitumor drug such as paclitaxel, amycin and itraconazole, can also wrap the medicine such as the bilobalide brain drug delivery that carry the treatment neurodegenerative diseases.
Among the present invention, its N end of described KC2S polypeptide is coupled with the Streptavidin derivant behind biotinylation, obtains fluorescently-labeled KC2S-Biotin-Streptavidin-X complex, and wherein X is fluorescent material, is selected from FITC or nir dye IR820.The KC2S-Biotin-Streptavidin-FITC of gained can be used for the stripped spike of brain diseases, and KC2S-Streptavidin-IR820 can be used as the live body diagnosis of brain diseases.
Among the present invention; described polypeptide KC2S; wherein cysteine sulfydryl is protected with Acm; its N end is connected upper cysteine; obtain the sulfhydrylation polypeptide, be connected with the amphipathy macromolecule micelle material that contains maleimide-Polyethylene Glycol, after the iodine oxidation; obtain micelle material KC2S-PEG-Y complex, wherein Y is polylactic acid (PLA), polylactic acid-polyglycolic acid (PLGA), polycaprolactone (PCL) or DSPE (DSPE).The micelle material KC2S-PEG-Y complex of gained comprises KC2S-PEG-PLA, KC2S-PEG-PLGA, KC2S-PEG-PCL and KC2S-PEG-DSPE, and it can wrap and carry insoluble drug.Described insoluble drug comprises paclitaxel, amycin, itraconazole and bilobalide.Above-mentioned micelle material KC2S-PEG-Y complex has brain targeting feature, and drug-carrying passes through blood brain barrier to brain drug delivery.
Among the present invention, described biotinylation polypeptide KC2S prepares the KC2S-Z nanoparticle by Biotin-Streptavidin mechanism.Wherein, the Z nanoparticle is selected from bovine serum albumin (BSA) nanoparticle, human serum albumin (HSA) nanoparticle, polyethylene glycol-polylactic acid (PEG-PLA) nanoparticle, poly-Polyethylene Glycol-lactic acid-polyglycolic acid (PEG-PLGA) nanoparticle, own interior (PEG-PCL) nanoparticle of polyethylene glycol-and PEG2000-DSPE (PEG-DSPE) nanoparticle.The KC2S-Z nanoparticle of gained comprises KC2S-BSA nanoparticle, KC2S-HSA nanoparticle, KC2S-PEG-PLA nanoparticle, KC2S-PEG-PLGA nanoparticle, KC2S-PEG-PCL nanoparticle and KC2S-PEG-DSPE nanoparticle, have brain targeting feature, drug-carrying passes through blood brain barrier to brain drug delivery.The medicine that described nanoparticle bag carries comprises paclitaxel, amycin, itraconazole and bilobalide.
The present invention is through the inside and outside test of body, the result shows, polypeptide KC2S can carry molecule, nanoparticle and micelle carrier system and cross over blood brain barrier, increases fluorescence or nano-carrier system concentration in brain, and makes the nanoscale medicine delivery system of bag carrying anti-tumor medicine have good anti-cerebral glioma effect.
Description of drawings
Fig. 1 is three finger type snake venom neurotoxin structural representations.
The HPLC of Fig. 2, KC2S and ESI-MS collection of illustrative plates,
Wherein, chromatographic process chromatographic column: YMC C18 5 μ 150 * 4.6mm; Mobile phase A: water (containing 0.1% trifluoroacetic acid); Mobile phase B: acetonitrile (containing 0.1% trifluoroacetic acid); Elution program: 0-45 minute 5%B-65%B; Flow velocity: 0.7ml/ minute; Column temperature: 40 ℃; Detect: UV280nm, TKC2S:14.199 minute.ESI-MS?KC2S：2292.1。
Fig. 3, KC2S competition suppresses curve.
Fig. 4, BCECs (A, B) and HeLa (C, D) cellular uptake result,
Wherein, figure below numeral represents respectively cell fluorescence labelling ratio and fluorescence intensity,
A and C are KC2S-FITC-Streptavidin conjugate picked-up result, and B and D are FITC-Streptavidin picked-up result, and E is the flow cytometer detection result.
Bio distribution figure in Fig. 5, the KC2S body,
Wherein, A, B are respectively negative control FITC-Streptavidin internal organs imaging and fluorescence semi-quantitative results, C, D are respectively the imaging of KC2S-Biotin-Streptavidin-FITC internal organs and fluorescence semi-quantitative results, and internal organs are respectively 0.5h, 1h, 2h and 4h from left to right.
Bio distribution figure in Fig. 6, the KC2S-BSA nanometer plastochondria,
Wherein, A is
125The I-BSA nanoparticle is bio distribution in vivo, and B is KC2S-BSA-
125The I nanoparticle is bio distribution in vivo, and C is KC2S-BSA-
125I nanoparticle brain targeting efficient;
Te=(KC2S-BSA-
125The I brain distributes)/(
125The I-BSA brain distributes).
Bio distribution figure in Fig. 7, the KC2S-PEG-PLA glue bundle body,
Wherein, upper row distributes for common PE G-PLA micelle carries the Coumarin-6 brain, and lower row distributes for KC2S-PEG-PLA carries the Coumarin-6 brain; Be from left to right: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h and 24h.
The survival curve of Fig. 8, antigen position Brain Glioma Model nude mice,
Wherein, PEG-PLA and the KC2S-PEG-PLA micelle group mean survival time of normal saline group, Taxol group, year paclitaxel are 34,38.5,41.5 and 47.5 days.
The specific embodiment
To help further to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1KC2S preparation and sign
Adopt solid-phase synthesis, with PAM-Gly-Boc resin trifluoroacetic acid (TFA) deprotection 1 minute, twice.React successively with the Boc protected amino acid, after reaction was finished, after trifluoroacetic acid took off the Boc protection, the piperidines DMF solution with 20% removed the CHO protecting group 15 minutes, twice.With Fluohydric acid. polypeptide is cut down, form intramolecular disulfide bond, acetonitrile/water (containing 0.1%TFA) system separation and purification with the 20%DMSO oxidation.HPLC and ESI-MS characterize purity and the molecular weight of KC2S.The result as shown in Figure 1, the molecular weight of KC2S is 2292.1.
Embodiment 2KC2S competition is tested in conjunction with acetylcholine receptor activity
Isolate rapidly Hippocampus after Wister rat (220～260 gram) sacrificed by decapitation, add Tris-HCl buffer (50mM Tris-HCl, the 5mM MgCl of 10 times of volumes after the weighing
26H
2O, 1mM EDTA, 0.5% (W/V) BSA, 1mM PMSF, 3 μ g/ml protease inhibitor, 0.1%NaN
3, 0.32M sucrose, pH7.4), carry out homogenate with 15000 rev/mins of homogenizers, each 30 seconds, totally 5 times.Homogenate centrifugal 10 minutes through 1000 * g, get supernatant and used again 39000 * g centrifugal 10 minutes, collecting precipitation, with 10 times of volume Tris-HCl pH of buffer 7.4 of former weight again suspension, used again 39000 * g centrifugal 10 minutes, get precipitation and wash with same buffer again, centrifugal 10 minutes of 39000 * g, the precipitation that will obtain at last suspends with above buffer, is divided in-80 ℃ and saves backup, and measures protein content with the Fotin method.
Put test tube in 37 ℃ of reactors, all Guan Zhongjun add 50 μ g acetylcholinergic receptor (nAChRs) protein contents.Add successively the certain density KC2S of 20 μ l in the testing tube, (α-Bgt), final concentration is 10 μ M, reacts in advance 50 minutes to add 50 μ l non-marked part α-Bungarotoxin in the non-specific binding pipe.All test tube adds 30 μ l successively
125I-α-Bgt, final concentration are 2nM.Supplying all reaction tube volumes with Tris-HCl pH of buffer 7.4 is 200 μ l.Reaction is 2 hours under 37 ℃ of reaction conditions.Point sample is on 49 type glass fiber filters, and negative pressure leaching washs 10 times with ice-cold buffer again, and each 2ml drains filter membrane, after the oven dry, is placed in the scintillation vial, adds the 1ml scintillation solution, measures radioactive intensity with LS6500 type liquid flashing counting device.KC2S when variable concentrations to nAChR with
125I-α-Bgt binding competition inhibitory action result as shown in Figure 2.The IC50 of KC2S is 42.66nM.
Embodiment 3KC2S brain capillary endothelial cell (BCECs) picked-up test
Connect biotin at the KC2S molecule, prepare biotinylated KC2S (KC2S-Biotin).With BCECs and HeLa cell according to 2 * 10
5Cells/well density kind on 6 orifice plates, adherent 24h.Streptavidin and the biotinylation KC2S of FITC labelling are dissolved among the PBS (pH7.4), and vortex 30 minutes prepares the FITC-Streptavidin-Biotin-KC2S complex.Before the cellular uptake experiment, 1%BSA solution and cell are hatched 4h, saturated albumen non-specific binding.BCECs and HeLa cell are hatched 2h (final concentration of KC2S is 2.5 μ M) with 800 μ l FITC-Streptavidin or FITC-Streptavidin-Biotin-KC2S complex solution respectively.With phosphate buffer (PBS, pH7.4) washed cell 3 times, with fluorescence microscope cellular uptake situation, experimental result is seen accompanying drawing 2.Simultaneously, after BCECs and the enzymic digestion of HeLa cell tryptase, 1600 rev/mins centrifugal 10 minutes, with PBS washing 3 times, vortex disperses, flow cytometer detection by quantitative, detection by quantitative the results are shown in accompanying drawing 3.The BCECs cell-specific picked-up that KC2S is had nAChRs to express, and absorb without specificity at the HeLa cell that does not have nAChRs to express.Experimental result shows that the KC2S cellular level has the brain targeting feature.
Bio distribution test in the embodiment 4KC2S-Streptavidin composite body
FITC-Streptavidin or FITC-Streptavidin-Biotin-KC2S complex Kunming mouse (～25 gram) tail vein injection 100 μ l (final concentration of KC2S is 2.5 μ M), respectively 0.5,1, used etherization in 2 and 4 hours, use the normal saline cardiac perfusion, core respectively, liver, spleen, lung, the major organs such as kidney and brain, with living imaging instrument (in-vivoImaging System, FX Pro, Kodak, USA) detect the fluorescence distribution of each internal organs, carry out sxemiquantitative according to fluorescence intensity simultaneously and calculate, experimental result as shown in Figure 4.Experimental result shows, tail vein KC2S-Streptavidin complex, in 0.5 hour to 4 hours, mainly be distributed in brain and kidney, wherein kidney is its main metabolic pathway, and negative control FITC-Streptavidin does not distribute in brain, illustrates that KC2S can promote FITC-Streptavidin to cross over blood brain barrier.
Distribution test in the embodiment 5KC2S-BSA nanometer plastochondria
Utilize precipitation-solidification method to prepare the BSA nanoparticle.BSA is dissolved in PBS (pH9.0), adds while stirring 2.5 times of ethanol, 1ml/ minute.The glutaraldehyde that adds the equimolar ratio example solidifies, and rotary evaporation is removed ethanol, and SephadexG-50 removes residual glutaraldehyde, lyophilizing.10mg BSA nanoparticle is dispersed in 1ml PBS (pH9.0), adds NHS-Biotin at 1: 4 according to mol ratio, room temperature reaction 2h, Sephadex G-50 post eluting is removed residual active ester.
0.5ml biotinylation nanoparticle (1mg/ml) mixes with 0.75ml Streptavidin solution (2mg/ml), stirring at room 30 minutes, and centrifugal (12000 rev/mins, 10 minutes) are removed not in conjunction with albumen for three times.The biotinylation KC2S that adds equimolar ratio, stirring at room 30 minutes is removed not Binding peptide, is prepared the KC2S-BSA nanoparticle for centrifugal three times.
The Iodogen method is carried out the BSA nanoparticle
125The I labelling is removed free
125I, respectively preparation
125The I-BSA nanoparticle and
125The I-KC2S-BSA nanoparticle.
The kunming mice tail vein injection
125The I-BSA nanoparticle and
125The I-KC2S-BSA nanoparticle, 200 μ l/ are (～20 μ Ci) only.1h and 12h collect blood sample, etherization, and the normal saline cardiac perfusion is cored, the internal organs such as lung, liver,spleen,kidney and brain, and the gamma enumerator detects activity and also calculates %ID/g.Result of the test as shown in Figure 5, result of the test shows, after KC2S modified, the BSA nanoparticle enters brain at 1h and 12h all to be strengthened.
Bio distribution test in the embodiment 6KC2S-PEG-PLA glue bundle body
During solid phase synthesis KC2S, the cysteine in the sequence is protected sulfydryl with Acm, connection cysteine after sequence is finished.KC2S (Acm)
2-Cys reacts with maleimide-polyethylene glycol-polylactic acid (Maleimide-PEG-PLA) in the PBS of pH8.0, and dialysis was removed micromolecule, KC2S (Acm) after reaction was finished
2-Cys-PEG-PLA continues to obtain intramolecular disulfide bond with the iodine oxidation.The KC2S-PEG-PLA (1mg) of preparation and PEG-PLA (19mg) are dissolved in the 3ml acetonitrile, add 15 μ g 6-coumarins (Coumarin-6), decompression film forming 2h, aquation, the CL-4B post is removed free Coumarin-6, prepare the peptide modified micelle of embedding Coumarin-6, with the standby common micelle of PEG-PLA that carries Coumarin-6 of legal system, with KM Mus (～25g) tail vein injection 100 μ l.Used etherization at 5 minutes～24 hours respectively, 40ml normal saline cardiac perfusion is cored respectively, the major organs such as liver, spleen, lung, kidney and brain, detects the fluorescence distribution of each internal organs with the living imaging instrument, and experimental result as shown in Figure 6.With common micellar phase ratio, the KC2S-PEG-PLA micelle is strong in the brain fluorescence distribution, illustrates that KC2S can promote the PEG-PLA carrier system to penetrate blood brain barrier.
Pharmacodynamics test in 7 years paclitaxel KC2S-PEG-PLA of embodiment glue bundle body
KC2S-PEG-PLA (1mg) and PEG-PLA (19mg) are dissolved in the 3ml acetonitrile, add the 10mg paclitaxel, decompression film forming 2h, aquation, 0.22 μ m water film filtering is removed free paclitaxel, prepare the KC2S modification micelle that bag carries paclitaxel, standby PEG-PLA carries the common micelle of paclitaxel with legal system, tumor in situ model nude mice tail vein injection 100 μ l carry KC2S-PEG-PLA and the PEG-PLA micelle of paclitaxel, and Taxol (normal saline dilution) and normal saline, the dosage of formulation for paclitaxel is 10mg/kg, respectively behind tumor planting the 7th, 12, administration in 17 and 22 days, the life span of record nude mice.The nude mice survival curve is compared with other groups as shown in Figure 7, carries paclitaxel KC2S-PEG-PLA micelle significant prolongation tumor in situ nude mice life span.
Claims (11)
1. an acetylcholine receptor mediated is crossed over the active targeting drug delivery system of blood brain barrier, it is characterized in that, prepare by following method: utilize polypeptide KC2S with its biotinylation derivant and the coupling of streptavidin fluorescein, or polypeptide KC2S modified on the albumin nano granular, or modify polypeptide KC2S on the polyethylene glycol-polylactic acid and be built into micelle and make the active targeting drug delivery system of crossing over blood brain barrier; Described its aminoacid sequence of polypeptide KC2S is YTKTWCDGFCSSRGKRIDLG.
2. cross over the active targeting drug delivery system of blood brain barrier by acetylcholine receptor mediated claimed in claim 1, it is characterized in that, its N end of described polypeptide KC2S is coupled with the Streptavidin derivant behind biotinylation, makes fluorescently-labeled KC2S-Biotin-Streptavidin-X complex; Wherein X is fluorescent material FITC or nir dye IR820; Described complex is KC2S-Biotin-Streptavidin-FITC or KC2S-Biotin-Streptavidin-IR820.
3. an acetylcholine receptor mediated is crossed over the active targeting drug delivery system of blood brain barrier, it is characterized in that, cysteine sulfydryl in its sequence of polypeptide KC2S is protected with Acm, its N end connects upper cysteine, obtain the sulfhydrylation polypeptide, be connected with the amphipathy macromolecule micelle material that contains maleimide-Polyethylene Glycol, after the iodine oxidation, obtain micelle material KC2S-PEG-Y complex; Wherein Y is polylactic acid PLA, polylactic acid-polyglycolic acid PLGA, polycaprolactone (PCL) or DSPE DSPE; Described its aminoacid sequence of polypeptide KC2S is YTKTWCDGFCSSRGKRIDLG.
4. cross over the active targeting drug delivery system of blood brain barrier by acetylcholine receptor mediated claimed in claim 3, it is characterized in that, described KC2S-PEG-Y complex forms polymer micelle, and bag carries insoluble drug.
5. cross over the active targeting drug delivery system of blood brain barrier by acetylcholine receptor mediated claimed in claim 4, it is characterized in that the insoluble drug that described polymer micelle bag carries comprises paclitaxel, amycin, itraconazole and bilobalide.
6. cross over the active targeting drug delivery system of blood brain barrier by acetylcholine receptor mediated claimed in claim 1, it is characterized in that described polypeptide KC2S prepares the KC2S-Z nanoparticle by Biotin-Streptavidin mechanism; Wherein the Z nanoparticle is bovine serum albumin BSA nanoparticle or human serum albumin HSA nanoparticle.
7. cross over the active targeting drug delivery system of blood brain barrier by acetylcholine receptor mediated claimed in claim 6, it is characterized in that described KC2S-Z nanoparticle has brain targeting feature, drug-carrying passes through blood brain barrier to brain drug delivery.
8. cross over the active targeting drug delivery system of blood brain barrier by acetylcholine receptor mediated claimed in claim 7, it is characterized in that the medicine that described nanoparticle bag carries comprises paclitaxel, amycin, itraconazole and bilobalide.
9. KC2S-Biotin-Streptavidin-FITC claimed in claim 2 is for the preparation of the purposes in the stripped spike preparation of brain diseases.
KC2S-Biotin-Streptavidin-IR820 claimed in claim 2 the preparation brain diseases the live body diagnostic preparation in purposes.
11. the purposes of KC2S-PEG-Y complex claimed in claim 4 in the active targeting drug delivery system of preparation leap blood brain barrier.
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