CN105348506A - Preparation of glutamic acid-TPGS block copolymer and application thereof to targeted drug delivery - Google Patents
Preparation of glutamic acid-TPGS block copolymer and application thereof to targeted drug delivery Download PDFInfo
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- CN105348506A CN105348506A CN201510869800.1A CN201510869800A CN105348506A CN 105348506 A CN105348506 A CN 105348506A CN 201510869800 A CN201510869800 A CN 201510869800A CN 105348506 A CN105348506 A CN 105348506A
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- tpgs
- glutamic acid
- liposome
- segmented copolymer
- drug
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33344—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carbamate group
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterized by the type of post-polymerisation functionalisation
- C08G2650/04—End-capping
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
- C08G2650/50—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type containing nitrogen, e.g. polyetheramines or Jeffamines(r)
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to preparation of a glutamic acid-TPGS block copolymer and application of amphipathic targeted material modified liposome to disease targeted delivery. For the amphipathic targeted material, glutamic acid is used as a target head, the flexibility of the target head is improved through polyethylene glycol and hydrophobic alpha-tocopherol ester used is a riveted part of phospholipid. The targeted material modified liposome can be used as a targeted delivery carrier of multiple anti-tumor drugs, and interacts with a big neutral amino acid transporter 1 highly expressing on a blood brain barrier and a tumor cell membrane through surface modified glutamic acid, so that the blood brain barrier crossing capacity as well as cell uptake and anti-tumor activity of liposome are effectively improved. The liposome is good in stability, high in safety, and excellent in targeting, can be used for intravenous injection and has a larger market application prospect.
Description
Technical field
The invention belongs to the new auxiliary material of pharmaceutical preparation and novel form field, relate to the preparation of amphipathic nature polyalcohol L-glutamic acid-TPGS, and as the application of target material in active targeting drug delivery system.
Background technology
The wettability growth of cerebral tumor and hemato encephalic barrier have had a strong impact on the clinical therapeutic efficacy of brain tumor.Chemotherapy is the conventional means of brain tumor treatment, but most small-molecule drug and all macromolecular drugs across hemato encephalic barrier poor ability, the high antitumor drug of many activity is owing to just announcing failure across hemato encephalic barrier ability in early days in exploitation.Therefore, on hemato encephalic barrier, some acceptors of high expression level and nutritional type transporter become research focus, as: VITAMIN transporter, amino acid transporter, glucose transporter.These nutritional type transporters indispensable on tumor locus and hemato encephalic barrier can be developed as the novel targets of cerebral tumor active targeting treatment.Nano-carrier is owing to can improving the curative effect of cancer therapy drug and reducing drug side effect and be widely used in targeted drug delivery system, the nano-carrier of PEGization more can demonstrate the superiority of some uniquenesses, as: extend the circulation time in vivo of nanometer formulation, the snappiness increasing part and targeting etc.Taking nano-carrier as drug delivery machinery, for target spot, is one brain targeted drug delivery system effectively with high expression level transporter while of hemato encephalic barrier and tumour.
In recent years, more and more sight is transferred to the research of the nano particle preparations of tumour transporter target, they are by carrying out the finishing of transporter substrate to nanometer formulation, substrate is when touching transporter, by transporter, high-affinity identification, combination carried out to the substrate on its surface, then cave in, enter born of the same parents.Nanometer formulation can rely on the transporter of high expression level on tumor cell membrane to reach raising cellular uptake amount, increases the object of tumor killing effect.In addition, some nutritional type transporters are high expression level on hemato encephalic barrier simultaneously, targeted nano preparation first rely on the transporter of high expression level on hemato encephalic barrier promote medicine across hemato encephalic barrier ability, then by identical target spot, further target is carried out to brain tumor.At this, we are intended to the nanometer formulation of the neutral amino acid transporter body 1 (LAT1) developing high expression level on target hemato encephalic barrier and cerebral glioma, study its target ability across hemato encephalic barrier ability and cerebral glioma.
Summary of the invention
The object of the present invention is to provide a kind of have high across hemato encephalic barrier ability, tumor-targeting, prolong drug transformation period, not only self self-assembly micella can be formed but also can make the amphipathic nature material-L-glutamic acid-TPGS of nanometer formulation modifier.
The present invention's second object is the preparation method providing above-mentioned L-glutamic acid-TPGS segmented copolymer.
3rd object of the present invention is to provide the effect of L-glutamic acid-TPGS segmented copolymer in targeted drug transmits.
The present invention is achieved through the following technical solutions above-mentioned purpose:
L-glutamic acid-TPGS segmented copolymer is using L-glutamic acid as target head, and polyoxyethylene glycol is water-wet side, provides the snappiness of target head, and hydrophobic alpha-tocopherol esters is hydrophobic side, with the holdfast position of other medicines carrier kernel.It is the good active targeting material of a kind of good stability, targeting.
The structural formula general formula of described L-glutamic acid-TPGS segmented copolymer is as follows:
Described target material, n is 11-110, and the molecular weight of polyoxyethylene glycol is 500-5000, is preferably 500-1000.
Its preparation process: by the L-glutamic acid of carboxyl and amido protecting; as: N-carbobenzoxy-(Cbz)-Pidolidone-1-benzyl ester (Z-Glu-OBzl; I); be dissolved in the organic good solvent such as q. s. methylene chloride, dimethyl sulfoxide (DMSO); under the effect of catalyzer; as: 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) and DMAP (DMAP); lucifuge ice bath 1h-2h; then under 30 DEG C of N2 protect, react 12h-48h with TPGS (II), obtain III of faint yellow solid through separation and purification.III compound, through palladium carbon reduction reaction, takes off the blocking group of L-glutamic acid, then obtains final compound-glutamate-TPGS segmented copolymer (Glu-TPGS, IV) through further separation and purification.
This segmented copolymer is faint yellow solid, is soluble in the organic solvents such as methylene dichloride, N, dinethylformamide, dimethyl sulfoxide (DMSO).
Described L-glutamic acid-TPGS segmented copolymer is the good active targeting material of a kind of good stability, targeting.
Described L-glutamic acid-TPGS segmented copolymer may be used for modifying the arbitrary material or derivatives thereof in bag loaded taxane class, camptothecin, Anthraquinones antitumour drug or dihydropyridines, NSAID (non-steroidal anti-inflammatory drug); Gene class medicine is the liposome of DNA or SiRNA, its modifying method can adopt film dispersion method to prepare, and adopt following step: by phosphatide, cholesterol and L-glutamic acid-TPGS segmented copolymer (30-40:1-2:2-4, w/w/w) be dissolved in completely in appropriate methylene dichloride, at moderate temperatures, be spin-dried for film forming, add 2-5mL hydrated agent aquation, and after Probe Ultrasonic Searching, obtain the liposome with brain targeting.
The present invention has following beneficial effect: prepare the strong amphipathic nature polyalcohol of a kind of novel targeting-L-glutamic acid-TPGS segmented copolymer, and carrier preparation process is gentle, easy to operate.The liposome that prepared L-glutamic acid-TPGS modifies, prepare easy, particle diameter is less and homogeneous, and encapsulation rate is high, good stability, and targeting is good.Prove that the liposome that L-glutamic acid-TPGS of the present invention modifies has preferably across hemato encephalic barrier ability and tumor-targeting across hemato encephalic barrier ability in In vitro cell experiment and body.
Accompanying drawing explanation
Fig. 1 is the L-glutamic acid-TPGS block copolymer structure of the embodiment of the present invention 1
1hNMR spectrogram
Fig. 2 is Dynamic Light Scattering Determination micella grain-size graph and the perspective Electronic Speculum figure of the docetaxel liposome (DTX-TGL) that the L-glutamic acid-TPGS of the embodiment of the present invention 2 modifies
Fig. 3 is the DSC figure of the docetaxel liposome/of the embodiment of the present invention 2 L-glutamic acid-TPGS modification and the docetaxel liposome (DTX-TGL/DTX-TL) of TPGS modification
A: docetaxel, B: the docetaxel liposome that docetaxel physical mixture C:TPGS modifies, the docetaxel liposome that D:TPGS-Glu modifies
Fig. 4 is the plasma stability assay of the docetaxel liposome of the L-glutamic acid-TPGS modification of the embodiment of the present invention 2 and the docetaxel liposome (DTX-TGL/DTX-TL) of TPGS modification
the docetaxel liposome change of size that DTX-TLTPGS modifies
the docetaxel liposome change of size that DTX-TGLTPGS-Glu modifies
The docetaxel liposome polydispersity index change that-DTX-TLPDITPGS modifies
The docetaxel liposome polydispersity index change that-DTX-TGLPDITPGS-Glu modifies
Fig. 5 is the dilution stability test of the docetaxel liposome of the L-glutamic acid-TPGS modification of the embodiment of the present invention 2 and the docetaxel liposome (DTX-TGL/DTX-TL) of TPGS modification
the docetaxel liposome change of size that DTX-TLTPGS modifies
the docetaxel liposome change of size that DTX-TGLTPGS-Glu modifies
The docetaxel liposome polydispersity index change that-DTX-TLPDITPGS modifies
The docetaxel liposome polydispersity index change that-DTX-TGLPDITPGS-Glu modifies
Fig. 6 is the extracorporeal releasing test of the docetaxel liposome of the embodiment of the present invention 2 L-glutamic acid-TPGS modification and the docetaxel liposome (DTX-TGL/DTX-TL) of TPGS modification
the docetaxel liposome that DTX-TL7.4TPGS modifies is in the release of pH7.4
the docetaxel liposome that DTX-TGL7.4TPGS-Glu modifies is in the release of pH7.4
Fig. 7 be the embodiment of the present invention 2 L-glutamic acid-TPGS modify docetaxel liposome and TPGS modify docetaxel liposome (DTX-TGL/DTX-TL) to the cell toxicant 72h of brain glioblastoma cell C6
the docetaxel liposome that DTX-TLTPGS modifies
the docetaxel liposome that DTXTGLTPGS-Glu modifies
dTX-Sol docetaxel DMSO solution
Fig. 8 be the embodiment of the present invention 2 L-glutamic acid-TPGS modify docetaxel liposome and TPGS modify docetaxel liposome (DTX-TGL/DTX-TL) to the cell toxicant 96h of brain glioblastoma cell C6
the docetaxel liposome that DTX-TLTPGS modifies
the docetaxel liposome that DTX-TGLTPGS-Glu modifies
oTX-Sol docetaxel DMSO solution
Fig. 9 is that the brain glioblastoma cell C6 of the docetaxel liposome of the L-glutamic acid-TPGS modification of the embodiment of the present invention 2 and the coumarin 6 liposome (C6-TGL/C6-TL) of TPGS modification absorbs situation
the coumarin 6 liposome that C6TLTPGS modifies
the coumarin 6 liposome that C6TGLTPGS-Glu modifies
Figure 10 is that the L-glutamic acid-TPGS density of the embodiment of the present invention 2 absorbs situation to the brain glioblastoma cell C6 of the coumarin 6 liposome that L-glutamic acid-TPGS modifies
Figure 11 is the impact that on the coumarin 6 liposome modified L-glutamic acid-TPGS of the different aminoacids substrate of the embodiment of the present invention 2 and glioma C 6 cell film, neutral large amino acid transporter 1 (LAT1) absorbs
Figure 12 be the embodiment of the present invention 2 L-glutamic acid-TPGS/TPGS modify DIR liposome across hemato encephalic barrier ability
The DIR liposome that DIR:DIR solution TGL:TPGS-Glu modifies
The DIR liposome that TL:TPGS modifies.
Embodiment
Mode below by embodiment further illustrates the present invention, but therefore invention is not limited among described scope of embodiments.
Embodiment 1
The preparation of L-glutamic acid-TPGS segmented copolymer.
By the L-glutamic acid of carboxyl and amido protecting; as: N-carbobenzoxy-(Cbz)-Pidolidone-1-benzyl ester (Z-Glu-OBzl; I); be dissolved in q. s. methylene chloride; at 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) and DMAP (DMAP); lucifuge ice bath 1h, then reacts 12h with TPGS (II), obtains III of faint yellow solid through separation and purification under 30 DEG C of N2 protect.III compound, through palladium carbon reduction reaction, takes off the blocking group of L-glutamic acid, then obtains final compound-glutamate-TPGS segmented copolymer (Glu-TPGS, IV) through further separation and purification.Reaction formula is as follows:
In step, the molecular weight of polyoxyethylene glycol is 1000, but is not limited to this, polyoxyethylene glycol of the present invention also one end be the polyoxyethylene glycol of hydroxyl modified, but be not limited to above material.The molecular weight of polyoxyethylene glycol can be within the scope of 500-5000.
Adopt nuclear magnetic resonance measuring
1h-NMR hydrogen spectrum determines the structure of target material in embodiment 1, and the solvent selected is d-DMSO, and result is as Fig. 1.4.2ppm is the H on L-glutamic acid on-CH-, and the proton peak between 3.52-3.75ppm is the H in PEG.Below 3.0ppm is the typical proton H peak in VE-succinate.
Embodiment 2
The liposome that the L-glutamic acid-TPGS that docetaxel or coumarin 6 are carried in film dispersion method preparation modifies and the liposome that TPGS modifies
Take 1mg docetaxel or coumarin 6, be dissolved in q. s. methylene chloride, add L-glutamic acid-TPGS or TPGS prepared by 2mg embodiment 1, and the soybean phospholipid of 30mg and the cholesterol of 1mg.Be spin-dried for film forming, add the deionized water aquation 30min of 2mL, Probe Ultrasonic Searching 300W, 5min, adopt mini-column centrifugation to remove the medicine do not wrapped up.
The liposome of preparation in embodiment 2 is measured size and the form of liposome by dynamic light scattering and perspective Electronic Speculum.Result is as Fig. 2, and the particle diameter of liposome is about 80nm, narrow diameter distribution; Perspective Electronic Speculum figure shows that drug-loaded liposome is the spherical of uniform particle diameter.
Table 1 be the embodiment of the present invention 2 L-glutamic acid-TPGS modify docetaxel liposome and TPGS modify docetaxel liposome (DTX-TGL/DTX-TL) to the IC of brain glioblastoma cell C6 at 72h and 96h
50value.
Table 1 docetaxel solution, the docetaxel liposome that TPGS modifies and the docetaxel liposome that TPGS-Glu modifies are to the IC of C6 glioma cell
50value.
Embodiment 3
The DSC figure of the docetaxel liposome that L-glutamic acid-TPGS modifies and the docetaxel liposome (DTX-TGL/DTX-TL) that TPGS modifies
The docetaxel liposome of L-glutamic acid-TPGS/TPGS modification is prepared according to example 2; and be that lyophilized vaccine carries out freeze-drying with N.F,USP MANNITOL; by the existence of dsc analysis DTX in liposome; analytic sample comprises: DTX bulk drug; DTX bulk drug and blank liposome physical mixture, DTX-TGL and DTX-TL of freeze-drying.
Fig. 3 result shows that DTX is wrapped in phospholipid bilayer with unformed or molecular state.
Embodiment 4
The docetaxel liposome that L-glutamic acid-TPGS modifies and the docetaxel liposome that TPGS modifies
(DTX-TGL/DTX-TL) stability test in blood plasma
Prepare the docetaxel liposome of L-glutamic acid-TPGS modification and the docetaxel liposome of TPGS modification according to example 2, liposome is placed in the high sugared nutrient solution of DMEM containing 10%FBS, by Dynamic Light Scattering Determination liposome at 0h, 1h, 2h, 4h, 6h, the particle diameter of 8h, 10h, 12h and 24h.
Fig. 4 result shows that the docetaxel liposome that L-glutamic acid-TPGS/TPGS modifies has good plasma stability.
Embodiment 5
The dilution stability of the docetaxel liposome that L-glutamic acid-TPGS modifies and the docetaxel liposome (DTX-TGL/DTX-TL) that TPGS modifies
Prepare the docetaxel liposome of L-glutamic acid-TPGS modification and the docetaxel liposome of TPGS modification according to example 2, liposome PBS is diluted different multiples, and passes through the particle diameter of Dynamic Light Scattering Determination liposome.
Fig. 5 result shows that the docetaxel liposome that L-glutamic acid-TPGS modifies and the docetaxel liposome that TPGS modifies have good dilution stability.
Embodiment 6
The docetaxel liposome that L-glutamic acid-TPGS modifies and docetaxel liposome (DTX-TGL/DTX-TL) extracorporeal releasing test that TPGS modifies
Dialysis method investigation example 2 is adopted to prepare the tablets in vitro feature of the docetaxel liposome of L-glutamic acid-TPGS modification and the docetaxel liposome of TPGS modification.Pipette polypeptide drug-loaded micelle solution containing 150 μ g in dialysis tubing, dialysis tubing two ends clamp, be placed in the Erlenmeyer flask of the release medium containing 30mLpH7.4PBS (containing 0.5%Tween80) respectively, in 37 DEG C of constant temperature oscillators, carry out vitro release investigation with 100r/min.Respectively 1,2,4,6,8,10,12,24h and 48h sample 2mL, supplement 2mL fresh dissolution medium, sample, through 0.45 μm of filtering with microporous membrane, is got 20 μ L and is carried out HPLC mensuration simultaneously.
Fig. 6 result shows the docetaxel liposome that L-glutamic acid-TPGS modifies and the docetaxel liposome release that TPGS modifies slowly, is conducive to more medicine and reaches tumor locus.
Embodiment 7
Cytotoxicity experiment
To the brain glioblastoma cell (C6) of logarithmic phase be in 3.5 × 10
4the high sugared nutrient solution of DMEM of/hole/0.1mL is embedded in 96 orifice plates, the docetaxel liposome that L-glutamic acid-TPGS embodiment 2 prepared after 24h modifies and the docetaxel liposome that TPGS modifies add each hole respectively with different concns, every hole adds 100 μ L containing liposome solutions, each concentration 3 parallel holes, put in incubator and hatch.After cultivating 72h and 96h, take out 96 orifice plates, every hole adds the 5mg/mLMTT of 20 μ L, hatch 4h in incubator, knockout plate, 96 orifice plate back-offs are fully blotted residual liquid in filter paper, every hole adds 150 μ LDMSO and to vibrate in vibrator 10min, and microplate reader measures the absorbancy at 492nm place, each hole.Calculate inhibiting rate:
Inhibiting rate (%)=(1-A
medicine feeding hole/ A
control wells) × 100%
Mtt assay measures liposome cytotoxicity result as Fig. 7 and Fig. 8, after different concns drug-loaded liposome acts on C6 cell strain 72h and 96h, cell inhibitory rate increases with drug level and incubation period and increases, and strengthens due to the targeting of L-glutamic acid the restraining effect of cell.The IC of each preparation that table 1 calculates
50value also embodies the advantage of L-glutamic acid modified liposome.
Embodiment 8
Cellular uptake is tested
By the C6 cell of LAT1 high expression level with 2 × 10
5the RPMI-1640 of/hole/0.1mL and DMEM nutrient solution are embedded in 96 orifice plates, the coumarin 6 liposome that L-glutamic acid-TPGS embodiment 2 prepared after 24h modifies and the coumarin 6 liposome that TPGS modifies, the concentration of being diluted identical coumarin 6 by HBSS damping fluid adds in each hole, every hole 100 μ L, parallel 3 holes, put in incubator and hatch 1h and 3h.Abandon supernatant, every hole adds in the PBS solution juxtaposition shaking table of 50 μ l0.5%TrtionX-100 (containing 0.2NNaOH) and acts on 1h.Subsequently, be 458nm in excitation wavelength, emission wavelength is that 525nm measures intensity of cellular fluorescence, and carries out determining the protein quantity to every hole, and calculates intake.In order to screen optimum target density, preparation simultaneously has the coumarin 6 liposome that different L-glutamic acid-TPGS density is modified, and carries out cellular uptake investigation according to above-mentioned.
Cellular uptake the results are shown in Figure 9, Figure 10, in the strain of LAT1 high expression level knurl, L-glutamic acid-TPGS modify coumarin 6 liposome cellular uptake amount all than TPGS modify coumarin 6 lipid height.And along with the increase of density modified by target material, cellular uptake increases, and reaches maximum at 10% cellular uptake.
Embodiment 9
The impact experiment of the coumarin 6 liposome picked-up that the L-glutamic acid-TPGS that different aminoacids substrate mediates LAT1 modifies
By the C6 cell of LAT1 high expression level with 2 × 10
5the RPMI-1640 of/hole/0.1mL and be embedded in 96 orifice plates, the coumarin 6 liposome that L-glutamic acid-TPGS embodiment 2 prepared after 24h modifies, after being diluted by HBSS damping fluid, after mixing with different aminoacids, add in each hole, every hole 100 μ L, parallel 3 holes, put in 37 DEG C and hatch 3h.Abandon supernatant, every hole adds in the PBS solution juxtaposition shaking table of 50 μ l0.5%TrtionX-100 (containing 0.2NNaOH) and acts on 1h.Subsequently, be 458nm in excitation wavelength, emission wavelength is that 525nm measures intensity of cellular fluorescence, and carries out determining the protein quantity to every hole, and calculates intake.
Picked-up affects experimental result and sees Figure 11, and result shows as LAT1 high affinity substrate, and leucine and the cohesive process of phenylalanine to liposome and LAT1 have obvious restraining effect, proves the identification of targeting lipids physical efficiency and in conjunction with LAT1, promotes cellular uptake.
Embodiment 10
L-glutamic acid-TPGS modify DIR liposome and TPGS modify DIR liposome across hemato encephalic barrier ability
Adopt living imaging method investigate example 2 prepare DIR liposome that L-glutamic acid-TPGS/TPGS modifies and DIR solution across hemato encephalic barrier ability.Give with 2mg/kg tail vein the liposome that KM mouse is loaded with DIR, after 8h, by the heart of mouse, liver, spleen, lung, kidney and brain take out, and are observed the distribution situation of liposome by living imaging instrument.
See Figure 12 across hemato encephalic barrier capacity experimental result, result shows that the liposome modified as L-glutamic acid-TPGS has better across hemato encephalic barrier ability.
Claims (10)
1. L-glutamic acid-TPGS segmented copolymer, is characterized in that: take polyoxyethylene glycol as water-wet side, and alpha-tocopherol esters is hydrophobic side, and L-glutamic acid is target head, and general structure is as follows:
Wherein, n is 11-110, and the molecular weight of polyoxyethylene glycol is 500-5000.
2. L-glutamic acid-TPGS segmented copolymer according to claim 1, is characterized in that, described L-glutamic acid-TPGS segmented copolymer is AB block copolymer, and molecular weight polyethylene glycol scope is at 500-1000.
3. the preparation method of L-glutamic acid-TPGS segmented copolymer according to claim 1, is characterized in that adopting following steps preparation:
By the L-glutamic acid of carboxyl and amido protecting, be dissolved in the organic good solvent such as q. s. methylene chloride, dimethyl sulfoxide (DMSO), under the effect of catalyzer, lucifuge ice bath 1h-2h, then under 30 DEG C of N2 protect, react 12h-48h with TPGS, obtain faint yellow solid through separation and purification;
By this faint yellow solid through palladium carbon reduction reaction, take off the blocking group of L-glutamic acid, then obtain final compound-glutamate-TPGS segmented copolymer (Glu-TPGS) through further separation and purification.
4. preparation method according to claim 3, is characterized in that, the L-glutamic acid of carboxyl and amido protecting is N-carbobenzoxy-(Cbz)-Pidolidone-1-benzyl ester.
5. preparation method according to claim 3, is characterized in that, described catalyzer is one or both in 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride or DMAP.
6. the application of L-glutamic acid-TPGS segmented copolymer in drug delivery system described in claim 1 or 2.
7. the application in hemato encephalic barrier and tumor-targeting are sent as pharmaceutical carrier or modifier of the L-glutamic acid-TPGS segmented copolymer described in claim 1 or 2.
8. the application in the neutral large amino acid transporter 1 of target as pharmaceutical carrier or modifier of the L-glutamic acid-TPGS segmented copolymer described in claim 1 or 2.
9. a drug-carrying nanometer particle, is characterized in that, with the L-glutamic acid-TPGS segmented copolymer described in claim 1 or 2 for modifier, take liposome as drug-reservoir.
10. drug-carrying nanometer particle according to claim 9, it is characterized in that: the medicine in liposome is hydrophobic drug, wetting ability medicine or gene class medicine, described hydrophobic drug is the arbitrary material or derivatives thereof in taxanes, camptothecin, Anthraquinones antitumour drug or dihydropyridines, NSAID (non-steroidal anti-inflammatory drug); Hydrophilic medicament is Zorubicin, hydroxycamptothecine, cis-platinum class; Gene class medicine is DNA or SiRNA.
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