CN109568598A - Placenta targeted nano particle and its preparation method and application for drug abortion - Google Patents
Placenta targeted nano particle and its preparation method and application for drug abortion Download PDFInfo
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Abstract
The present invention provides a kind of placenta targeted nano particles, it can be used for drug abortion, it includes hydrophobic cores, the single layer lipid molecule layer and hydrophily shell for wrapping up hydrophobic cores, and hydrophobic cores include the target delivery object of hydrophobic polymer and its load, and it includes abortifacient that target, which delivers object,；The ingredient of hydrophily shell is the polypeptide grafted amphiphilic macromolecular compound for targeting placenta sample chondroitin sulfate A (CSA), the hydrophobic side of amphiphilic macromolecular compound is interspersed in single layer lipid molecule layer, the water-wet side and polypeptide of amphiphilic macromolecular compound are keyed by amide, polypeptide is exposed to outside single layer lipid molecule layer, wherein, the amino acid sequence of polypeptide is selected from one of amino acid sequence shown in SEQ ID NO:1-SEQ ID NO:3 or a variety of.The present invention also provides the preparation method of the placenta targeted nano particle and its applications in preparation mammal abortifacient.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, in particular to a kind of placenta targeted nano particle for drug abortion and its
Preparation method and application.
Background technique
World Health Organization's estimation, there are 75,000,000 unexpected pregnancies in the whole world every year, and the pact to be come to an end with induced abortion
There are 26,000,000 to 53,000,000.Under the premise of so high ratio of induced abortion, safer effective induced abortion technology is urgently
It is to be developed.Existing induced abortion technology is broadly divided into two classes: drug abortion and negative pressure inhale palace Surgical abortion.But both technologies are all
There are larger disadvantages.Although Surgical abortion success rate is high, the time is short, its surgical pain sense is high and with postoperative complication；Medicine
Although logistics production has many advantages, such as that method is simple, pain is small, there are certain proportion incomplete abortion, Ineffective abortion and have drug pair work
Risk.Relative to the more artificial uncertain factor that has of Surgical abortion, the innovation room for promotion of drug abortion is more broad.
The research of the targeted nano particle based on nanotechnology brings new opportunity to drug abortion in recent years.It can be incited somebody to action
Therapeutic agent is transported to target organ to the maximum extent, and influences very little to non-target organ, to reach the treatment effect of high-efficiency low-toxicity
Fruit, and nano material itself has the advantages such as slow controlled capability, transmucosal, transdermal, is of great importance to drug abortion.Wherein,
It can be with target cell (brain microvessel endothelial cells in vitro for constituting blood-brain barrier) specific binding by the connection of drug-loading nanoparticles surface
Ligand, such as antibody, peptide chain are delivered to nano particle by Nano medication by receptor-mediated transcytosis specific
Position is more common technology.
Therefore, researching and developing a kind of high miscarriage success rate, the novel nano abortifacient of low side effect is expected to break through existing people simultaneously
The bottleneck of work miscarriage.But have not yet to see the nano particle to the targeting of placenta height.
Summary of the invention
In view of this, the present invention provides a kind of nano particle of placenta targeting, for solving drug stream in the prior art
The shortcomings that failure rate of production is higher, incomplete abortion, while miscarriage efficiency is improved, reduce drug side-effect.
In a first aspect, the present invention provides a kind of polypeptides for targeting placenta sample chondroitin sulfate A (CSA) (pl-CSA), wherein institute
The amino acid sequence for stating polypeptide is selected from one of amino acid sequence shown in SEQ ID NO:1-SEQ ID NO:3 or a variety of.
Wherein, amino acid sequence shown in SEQ ID NO:1 is LKPSHEKKNDDNGKKLCKAC.
Amino acid sequence shown in SEQ ID NO:2 is EDVKDINFDTKEKFLAGCLIVSFHEGKC.
Amino acid sequence shown in SEQ ID NO:3 is GKKTQELKNIRTNSELLKEWIIAAFHEGKC.
The polypeptide can be modified in polymer (such as polyethyleneimine, chitosan), liposome, gold nano grain, two
On the common pharmaceutical carrier or genophore such as silica, seralbumin, for the tissue of targeted expression pl-CSA, such as placenta
Cell.
Second aspect, the present invention provides a kind of placenta targeted nano particles, are used for drug abortion, and the placenta targeting is received
Rice grain includes outside the hydrophily of hydrophobic cores, the single layer lipid molecule layer of the package hydrophobic cores and targeting placenta
Shell, the hydrophobic cores include the target delivery object of the hydrophobic polymer and its load, and the target delivers object and includes
Abortifacient；The ingredient of the hydrophily shell is the polypeptide grafted amphiphilic macromolecular compound for targeting pl-CSA, described
The hydrophobic side of amphiphilic macromolecular compound is interspersed in the single layer lipid molecule layer, the amphiphilic macromolecular compound
Water-wet side and the polypeptide are keyed by amide, and the polypeptide is exposed to outside the single layer lipid molecule layer, wherein described more
The amino acid sequence of peptide is selected from one of amino acid sequence shown in SEQ ID NO:1-SEQ ID NO:3 or a variety of.
In the present invention, the polypeptide be can be such as SEQ ID NO:1, SEQ ID NO:2 or as shown in SEQ ID NO:3
A kind of sequence, can also be a variety of in the sequence as shown in SEQ ID NO:1-SEQ ID NO:3.
Preferably, the diameter of the placenta targeted nano particle is 80~150nm.The partial size is aobvious using transmitted electron
Micro mirror measures.
Preferably, the hydrophobic polymer, single layer lipid molecule, the amphiphilic macromolecular compound mass ratio be
1:(0.04-0.2): (0.1-0.4).Under the mass ratio, shape can be formed between each component of the placenta targeted nano particle
Looks are relatively regular, favorable dispersibility, the more uniform structure of particle diameter distribution, and the stable structure of the placenta targeted nano particle is not easy
It by human body fluid dilution, dissolves and disintegrates, be conducive to the placenta targeted nano particle and be targeted to the host cell for constituting placenta
(such as trophoblast).
Preferably, the single layer lipid molecule is selected from least one of lecithin and cephalin (phosphatidyl-ethanolamine),
The lecithin is selected from one of soybean lecithin, hydrogenated soy phosphatidyl choline, egg yolk lecithin and phosphatidyl choline or a variety of.
It is further preferred that the single layer lipid molecule is with the hydrophobic part towards the hydrophobic cores and towards the nanometer
Hydrophilic segment outside grain.
Preferably, the mass ratio of the amphiphilic macromolecular compound and the polypeptide is 1:(1-4).In the mass ratio
Under, polypeptide is higher to the grafting rate of the amphiphilic macromolecular compound.
As described in the present invention, the polypeptide grafted amphiphilic macromolecular compound layer includes amphiphilic macromolecular chemical combination
Object and polypeptide, the water-wet side that the amphiphilic macromolecular compound has hydrophobic side and connect with the rouge end.In the present invention, institute
The hydrophobic side for stating amphiphilic macromolecular compound can help the amphiphilic macromolecular compound to be inserted into the single layer lipid point
Sublayer, and the water-wet side and the polypeptide grafted branches and the outside for extending in the nano particle.
Preferably, the amphiphilic macromolecular compound is polyglycol derivatization phospholipid, the polyglycol derivatization
Phosphatide is connected to obtain by covalent bond by polyethylene glycol and its derivative with phospholipid substance.At this point, the amphiphilic macromolecular
The hydrophobic side of compound is the phospholipid substance, and the water-wet side is carboxyl or amido modified polyethylene glycol or is band
There is the polyethyleneglycol derivative of other active function groups.
Wherein, the molecular weight of the polyethylene glycol is preferably 200~20000.Specifically, the molecular weight of peg molecule
It can be 200,500,1000,2000,5000,7000,10000,15000 or 20000.The phospholipid substance can be artificial
Phosphatide existing for synthesize or nature, the phospholipid substance can be but be not limited to Distearoyl Phosphatidylethanolamine
(DSPE), distearoylphosphatidylglycerol (DSPG) or cholesterol.
It is further preferred that the amphiphilic macromolecular compound is distearoylphosphatidylethanolamine-polyethylene glycol-carboxylic
Acid copolymerization (DSPE-PEG-COOH, also known as phosphatide-PEG- carboxyl), distearoylphosphatidylethanolamine-polyethylene glycol-amino
It is copolymerized (DSPE-PEG-NH2, also known as phosphatide-PEG- amino) or distearoylphosphatidylethanolamine-polyethylene glycol-Malaysia acyl
Amine.
Preferably, the hydrophobic polymer be selected from poly lactide-glycolide acid (also known as poly (glycolide-co-lactide),
Be abbreviated as PLGA), polylactic acid and polycaprolactone it is one or more, but not limited to this.
It is further preferred that the hydrophobic polymer is poly lactide-glycolide acid (being abbreviated as PLGA), it is described
The molecular weight of PLGA is 7000-17000.Wherein, the copolymerization ratio of monomer lactic acid and hydroxyacetic acid is 50:50.
In the application, the target delivery object (containing abortifacient) collectively forms described hydrophobic with the hydrophobic polymer
Property kernel.Hydrophobic polymer can adsorb or wrap up target and deliver object composition hydrophobic cores, it is possible to prevente effectively from load
Target delivers object and occurs to assemble before reaching placenta cells or reveal, the stability of the delivery object of proof load.
Preferably, it further includes one of contrast agent and fluorescence tracer or a variety of that the target, which delivers object,.
Preferably, it is 1:(0.1-0.8 that the hydrophobic polymer and the target, which deliver the mass ratio of object).It is further excellent
It is selected as 1:(0.1-0.6), more preferably 1:(0.1-0.2).Most preferably 1:(0.1-0.16).
It is further preferred that the target is delivered in object, the abortifacient and the fluorescence tracer and/or contrast agent
Mass ratio be 1:(0.1-0.8).
Preferably, the abortifacient is selected from mifepristone, Misoprostol, Gemeprost, sulprostone, triphen oxygen
One of amine, Letrozole and methotrexate (MTX) are a variety of, but not limited to this.
Preferably, the fluorescence tracer is selected from indocyanine-green, Evans blue, isosulfan blue, patent blue, methylenum careuleum, tonka-bean
Element 6, IR780 iodide (chloro- three carbon of 1,1'- diη-propyl -3,3,3', the 3'- tetramethyl -10,12- trimethylene indoles flower of 11-
Green salt compounded of iodine) and one of DiR iodide or a variety of, but not limited to this.
Preferably, the contrast agent is selected from one of iohexol, Iopromide, B-15000, pantopaque and barium sulfate
Or it is a variety of, but not limited to this.
The placenta targeted nano particle that second aspect of the present invention provides, single layer lipid molecule during the preparation process, can be from group
Single layer lipid molecule layer is dressed up, and wraps up the hydrophobic cores, the hydrophobic side in the amphiphilic macromolecular compound passes through
Physical action is interspersed in the single layer lipid molecule layer in conjunction with the lipid molecule in the single layer lipid molecule layer, institute
The water-wet side for stating polypeptide and the amphiphilic macromolecular compound is covalently attached and extends in the outside of the targeted nano particle,
The polypeptide grafted amphiphilic macromolecular compound provides hydrophily outer layer and targeting placenta for the targeted nano particle
Receptor, therefore, the placenta targeted nano particle to placental trophoblasts have good targeting, can carry well
Target is delivered object and is entered in placental trophoblasts, helps to ensure that the enough administration concentrations of targeting moiety, improves miscarriage efficiency.
The third aspect, the present invention provides a kind of preparation methods of placenta targeted nano particle, comprising the following steps:
(1) hydrophobic polymer is dissolved in organic solvent, obtains hydrophobic polymer solution；
(2) single layer lipid molecule, amphiphilic macromolecular compound and target delivery object are dissolved in the first solvent, obtain first
Mixed solution, wherein it includes abortifacient that the target, which delivers object,；
(3) the hydrophobic polymer solution is added in first mixed solution, is ultrasonically treated 4-6min, obtains
Second mixed solution carries out centrifugal treating to second mixed solution, collects supernatant, obtain targeted nano particle precursor
Body；
(4) take the targeted nano particle precursor body, by it with the targeting polypeptide of placenta sample chondroitin sulfate A (CSA), catalyst,
Dehydrating agent carries out amide reaction in the second solvent, so that on the be grafted to amphiphilic macromolecular compound of the polypeptide；It collects
Liquid is answered, by the reaction solution after isolating and purifying, obtains the placenta targeted nano particle.Gained placenta targeted nano particle is such as
Described in first aspect present invention.
Preferably, in step (1), the organic solvent includes acetonitrile, acetone, ether, chloroform, methylene chloride and just
One of hexane is a variety of, but not limited to this.The organic solvent can preferably dissolve the volatile molten of hydrophobic polymer
Agent.
Wherein, first solvent includes that at least one hydrophilic solvent or water and at least one hydrophilic solvent are formed
Mixed solvent.Wherein, the hydrophilic solvent be selected from ethyl alcohol, methanol, 1- octanol, acetonitrile, acetone, dimethylformamide (DMF) and
Dimethyl sulfoxide (DMSO), but not limited to this.First solvent needs so that amphiphilic macromolecular compound, single layer lipid molecule
Delivering object with target can dissolve.
Preferably, first solvent is the mixed solvent that water and at least one hydrophilic solvent are formed, such as various concentration
Ethanol water, various concentration methanol aqueous solution.It is further preferred that in first solvent, the volume fraction of water is
3-8%.
In an embodiment of the present invention, first solvent is the ethanol water that volume fraction is 4% or volume point
The methanol aqueous solution that number is 4%.
Wherein, first solvent contains water, can when the organic solvent solution in later period and hydrophobic polymer mixes,
Making the solubility of hydrophobic polymer reduces, can be convenient for later period ultrasound, emulsification balling-up.
Preferably, in first mixed solution, the concentration of the single layer lipid molecule is 10-300 μ g/mL, described two
Parent's property macromolecular compound concentration is 30-600 μ g/mL.
Preferably, in first mixed solution, the concentration of the abortifacient is 33-750 μ g/mL.
Preferably, in first mixed solution, the quality of the abortifacient and the amphiphilic macromolecular compound
Than for (1-5): 1.Further preferably (1.9-3.5): 1 or (1-1.5): 1.More preferably (1-1.5): 1.
Preferably, in step (1), the concentration of the hydrophobic polymer solution is 1-4mg/ml.
Preferably, in step (3), the volume ratio of the hydrophobic polymer solution and first mixed solution is 1:3.
Preferably, in step (3), by hydrophobic polymer solution in a manner of being added dropwise with first mixed solution
It mixes, it is further preferred that the rate of addition of the hydrophobic polymer solution is 0.2-0.5mL/min.It can make in this way
Hydrophobic polymer is sufficiently complexed target and delivers object, and wraps up into shell, and cooperation ultrasound could form drug-loading nanoparticles.
Preferably, it is described ultrasound after, by second mixed solution at 40-80 DEG C gentle agitation.Gentle agitation,
Suitable solvent volatilization condition is provided, hydrophobic polymer, target is promoted to deliver object and single layer lipid molecule, amphipathic molecule phase
Interaction, the dispersibility of final resulting nano particle presoma is preferable, partial size is more uniform.The nano particle presoma is opposite
It for finally obtained placenta targeted nano particle, the difference is that only, surface is not decorated to placenta targeting
Polypeptide.
Preferably, in step (3), the centrifugal treating is centrifuged in the ultra-filtration centrifuge tube that molecular cut off is 5-10kDa
2-5 times, using water washing.
Preferably, in step (3), the centrifugal treating is to be centrifuged 3- every time at centrifugal rotational speed 3000-5000rpm
6min。
Preferably, in step (3), the ultrasound is the frequency 80-160W for using ultrasonic cell disruption instrument with 20kHz
Power carries out.
In step (3), the hydrophobic polymer, target deliver object, single layer lipid molecule and amphiphilic macromolecular chemical combination
Object forms the targeted nano particle precursor body (i.e. without the nano particle of targeting), not needing by self assembling process
Reaction is learned, preparation process is environment-protecting and non-poisonous, and method is simple to operation.
Preferably, in step (4), the amide reaction is to carry out at room temperature.Optionally, the time of the amide reaction
For 15-24h.
Second solvent can be water or other hydrophilic solvents.Preferably, in step (4), the second solvent packet
Include water, 2- (N- morpholine) ethanesulfonic acid buffer (referred to as " MES buffer solution "), the pH value 7.0- that pH value is 5.5-6.7
7.9 phosphate (PBS) buffer etc., but not limited to this.
In step (4), the method for the amidation process is well known to those skilled in the art.Catalyst can be described as again
Activator is often combined with condensing agent, is used for amidation process.
Preferably, in step (4), the condensing agent includes 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide hydrochloride
Salt (abbreviation EDC).
Preferably, in step (4), the catalyst includes n-hydroxysuccinimide (NHS), N- hydroxy succinyl
Any one in imines sodium salt (Sufo-NHS).
Preferably, in step (4), the condensing agent, catalyst and the amphiphilic macromolecular compound mass ratio be
(0.2-0.4): (0.05-0.3): 1.
It is highly preferred that the mass ratio of described EDC, NHS, DSPE-PEG-COOH are 1:0.4:5.
Preferably, in step (4), it is described isolate and purify for use molecular cut off for the ultra-filtration centrifuge tube of 5-10kDa into
Row ultrafiltration centrifugation collects gained supernatant after centrifugation, obtains placenta targeted nano particle.Preferably, the ultrafiltration centrifugation carries out
2-5 times.In addition to last time ultrafiltration centrifugation, water or PBS washing are all made of after centrifugation every time.
In another embodiment of the invention, can also first will it is described it is polypeptide grafted arrive amphiphilic macromolecular chemical combination
On object, hydrophobic polymer, target are then delivered into object, polypeptide grafted amphiphilic macromolecular compound, single layer lipid point again
The placenta targeted nano particle is made according to step (1)-(3) operation in son.
Preparation method is simple for placenta targeted nano particle provided by the invention, convenient for operation.Placenta target obtained
Strong to targeting of the nano particle to placental trophoblasts and enrichment degree is high, miscarriage success rate is high, and side effect is lower.
Fourth aspect, the present invention provides a kind of polypeptide for targeting placenta as described in the first aspect of the invention or
Application of the placenta targeted nano particle as described in respect of the second aspect of the invention in preparation mammal abortifacient.Preferably,
Application in preparation mammal abortion in first trimester drug.
5th aspect, the present invention provides a kind of pharmaceutical compositions, target including placenta described in second aspect of the present invention
Nano particle.Described pharmaceutical composition is miscarried for mammal.
Detailed description of the invention
Fig. 1 is the structural schematic diagram of placenta targeted nano particle prepared by the embodiment of the present invention 1；
Fig. 2 is the transmission electron microscope picture of placenta targeted nano particle prepared by the embodiment of the present invention 1；
Fig. 3 is that the placenta targeted nano particle prepared in the embodiment of the present invention 1 and other experimental groups are real to the miscarriage of pregnant mouse
The ultrasonic development result tested；
Fig. 4 is the shadow of the placenta targeted nano particle prepared in the embodiment of the present invention 1 and other experimental groups to embryo's weight
Ring result.
Specific embodiment
The following is a preferred embodiment of the present invention, it is noted that for those skilled in the art
For, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also considered as
Protection scope of the present invention.
In the present invention, the sequence such as SEQ ID NO:1- of the polypeptide for targeting placenta sample chondroitin sulfate A (CSA) (pl-CSA)
Shown in SEQ ID NO:3.Specifically, LKPSHEKKNDDNGKKLCKAC is as shown in SEQUENCE NO.1.
EDVKDINFDTKEKFLAGCLIVSFHEGKC is as shown in SEQUENCE NO.2.
GKKTQELKNIRTNSELLKEWIIAAFHEGKC is as shown in SEQUENCE NO.3.
The polypeptide is carried out according to conventional polypeptid synthesising process, wherein the left end of each sequence is N-terminal, right end
For the C-terminal of polypeptide, C-terminal or N-terminal can be covalently attached with the amphipathy macromolecule compound, this is according to amphiphilic used
Depending on the property of property high-molecular compound.Wherein, when amphipathy macromolecule compound has-COOH, using carboxylic thereon
Base is reacted with amino (that is, amino on cysteine C) Lai Jinhang amide in the C-terminal of the polypeptide.Work as amphipathy macromolecule
When compound has amino, it can be reacted using amino thereon with the carboxyl on the N-terminal of the polypeptide to carry out amide.
Embodiment 1
A kind of preparation method of placenta targeted nano particle, comprising the following steps:
(1) by poly lactide-glycolide acid, (PLGA, molecular weight 15000, monomer lactic acid and hydroxyacetic acid are total to
Poly- ratio is 50:50) it is dissolved in acetonitrile, obtain the acetonitrile solution of PLGA, concentration 2mg/mL；
(2) by the soybean lecithin of 90 μ g, DSPE-PEG-COOH (molecular weight of PEG is 2000), the 315 μ g of 210 μ g
Methotrexate (MTX) is dissolved in the ethanol water that the volume fraction of 3mL is 4%, obtains the first mixed solution；
(3) the PLGA acetonitrile solution of 1mL is added dropwise in the first mixed solution of 3mL with the speed of 0.3mL/min,
And ultrasonic cell disruption instrument is used to be ultrasonically treated with the power of the frequency of 20KHz and 130W, ultrasonic time 5min；
Solution after ultrasound is subjected to ultrafiltration centrifugation in the ultra-filtration centrifuge tube that molecular cut off is 10kDa, and is washed with water
It washs, is repeated 4 times, wherein centrifugal rotational speed 4000rpm, be centrifuged 4min every time, collect supernatant and obtain targeted nano particle precursor body；
(4) the targeted nano particle precursor body is soluble in water, it is living that 42 μ g EDC and 17 μ g NHS progress surface is added
Change 2h, the sequence that 0.5mg is added later is the polypeptide of LKPSHEKKNDDNGKKLCKAC (as shown in SEQUENCE NO.1),
Amidation process 16h is carried out at room temperature, obtains reaction solution；
With molecular cut off it is that 10kDa super filter tube carries out ultrafiltration centrifugation, and is washed with water by the reaction solution, is repeated 4 times,
Wherein under centrifugal rotational speed 3500rpm, it is centrifuged 4min every time, collects supernatant and obtains placenta targeted nano particle.
Fig. 1 is the structural schematic diagram of placenta targeted nano particle made from the embodiment of the present invention 1.The placenta targeted nano
Particle includes the hydrophily shell of hydrophobic cores 1, the single layer lipid molecule layer 2 of the package hydrophobic cores and targeting placenta
3, the ingredient of single layer lipid molecule layer 2 is soybean lecithin, and the ingredient of the hydrophily shell 3 is the DSPE- that polypeptide 32 is grafted
PEG31 11 is methotrexate (MTX), 12 is hydrophobic polymer PLGA, 1 for 11 and 12 compositions hydrophobic cores；Polypeptide grafted
In DSPE-PEG, the rouge end DSPE of DSPE-PEG31 is inserted in the soybean lecithin layer 22, and water-wet side PEG and the polypeptide are logical
Superamide key connection, the polypeptide are exposed to outside the single layer lipid molecule layer.
Fig. 2 is the transmission electron microscope picture of the targeted nano particle, figure it is seen that prepared placenta targeted nano
Particle is spherical in shape, and dispersibility is preferably.The average grain diameter that the placenta targeted nano particle is measured with Particle Size Analyzer is 90-
120nm。
The encapsulation rate of methotrexate (MTX): EN%=(1-Cf/Ct) × 100%, wherein Cf is calculated separately out using following formula
For the amount of free drug, Ct is the total amount of drug, and obtain the targeted nano particle is to the encapsulation rate EN% of methotrexate (MTX)
52.3 ± 4.4%.In addition, measuring the bonding ratio of polypeptide using BCA method are as follows: 53.4 ± 3.5%.
Embodiment 2
A kind of preparation method of placenta targeted nano particle, comprising the following steps:
(1) polycaprolactone (molecular weight 10000) is dissolved in acetone, obtains polycaprolactone solution, concentration 1mg/mL；
(2) by the egg yolk lecithin of 40 μ g, the DSPE-PEG-NH of 100 μ g2The rice of (molecular weight of PEG is 3000), 50 μ g
The Misoprostol of mifepristone and 50 μ g are dissolved in the methanol aqueous solution that 3mL volume fraction is 4%, obtain the first mixed solution；
(3) the polycaprolactone solution of 1mL is added dropwise in the first mixed solution of 3mL with the speed of 0.2mL/min,
And ultrasonic cell disruption instrument is used to be ultrasonically treated with the power of the frequency of 20KHz and 80W, ultrasonic time 6min；
Solution after ultrasound is subjected to ultrafiltration centrifugation in the ultra-filtration centrifuge tube that molecular cut off is 5kDa, and is washed with water
It washs, is repeated 4 times, wherein under centrifugal rotational speed 3000rpm, be centrifuged 6min every time, collect supernatant and obtain targeted nano particle precursor
Body；
(4) the targeted nano particle precursor body is soluble in water, 20 μ g EDC and 5 μ g NHS are added and carry out surface active
2h, the sequence that 0.4mg is added later is the polypeptide of LKPSHEKKNDDNGKKLCKAC (as shown in SEQUENCE NO.1), in room
Temperature is lower to carry out amidation process 15h, obtains reaction solution；
With molecular cut off it is that 5kDa super filter tube carries out ultrafiltration centrifugation, and is washed with water by the reaction solution, is repeated 4 times,
Wherein under centrifugal rotational speed 3000rpm, it is centrifuged 6min every time, collects supernatant and obtains placenta targeted nano particle.
Embodiment 3
A kind of preparation method of placenta targeted nano particle, comprising the following steps:
(1) polylactic acid (molecular weight 21800) is dissolved in DMF, obtains the PLA solution that concentration is 4mg/mL；
(2) cephalin of 800 μ g, the DSPE-PEG-NH2 (molecular weight of PEG be 2000) of 1600 μ g, 2250 μ g are come
Bent azoles is dissolved in the acetone of 3mL, obtains the first mixed solution；
(3) PLA solution of 1mL is added dropwise in the first mixed solution of 3mL with the speed of 0.4mL/min, and
Ultrasonic cell disruption instrument is used to be ultrasonically treated with the power of the frequency of 20KHz and 160W, ultrasonic time 4min；
Solution after ultrasound is subjected to ultrafiltration centrifugation in the ultra-filtration centrifuge tube that molecular cut off is 10kDa, and is washed with water
It washs, is repeated 4 times, wherein under centrifugal rotational speed 5000rpm, be centrifuged 3min every time, collect supernatant and obtain targeted nano particle precursor
Body；
(4) the targeted nano particle precursor body is soluble in water, it is living that 640 μ g EDC and 80 μ g NHS progress surface is added
Change 4h, the sequence that 1.6mg is added later is EDVKDINFDTKEKFLAGCLIVSFHEGKC (as shown in SEQUENCE NO.2)
Polypeptide carries out amidation process 18h at room temperature, obtains reaction solution；
With molecular cut off it is that 10kDa super filter tube carries out ultrafiltration centrifugation, and is washed with water by the reaction solution, is repeated 4 times,
Wherein under centrifugal rotational speed 5000rpm, it is centrifuged 3min every time, collects supernatant and obtains placenta targeted nano particle.
The TEM partial size of the placenta targeted nano particle made from the present embodiment is 100-120nm；It is measured using BCA method
The bonding ratio of polypeptide are as follows: 55.4 ± 2.5%.
Embodiment 4
A kind of preparation method of placenta targeted nano particle, comprising the following steps:
(1) by poly lactide-glycolide acid, (PLGA, molecular weight 10000, monomer lactic acid and hydroxyacetic acid are total to
Poly- ratio is 50:50) it is dissolved in acetonitrile, obtain the acetonitrile solution of PLGA, concentration 2mg/mL；
(2) by the phosphatidyl choline of 120 μ g, the DSPE-PEG-NH of 250 μ g2(molecular weight of PEG is 3000), 300 μ g
Gemeprost is dissolved in the methanol of 3mL, obtains the first mixed solution；
(3) acetonitrile solution of the PLGA of 1mL is added dropwise to the first mixed solution of 3mL with the speed of 0.5mL/min
In, and ultrasonic cell disruption instrument is used to be ultrasonically treated with the power of the frequency of 20KHz and 120W, ultrasonic time is
5min；
Solution after ultrasound is subjected to ultrafiltration centrifugation in the ultra-filtration centrifuge tube that molecular cut off is 5kDa, and is washed with water
It washs, is repeated 4 times, wherein under centrifugal rotational speed 3500rpm, be centrifuged 4min every time, collect supernatant and obtain targeted nano particle precursor
Body；
(4) the targeted nano particle precursor body is soluble in water, it is living that 75 μ g EDC and 50 μ g NHS progress surface is added
Change 3h, the sequence that 0.75mg is added later is GKKTQELKNIRTNSELLKEWIIAAFHEGKC (such as SEQUENCE NO.3 institute
Show) polypeptide, at room temperature carry out amidation process 17h, obtain reaction solution；
With molecular cut off it is that 5kDa super filter tube carries out ultrafiltration centrifugation, and is washed with water by the reaction solution, is repeated 4 times,
Wherein under centrifugal rotational speed 3000rpm, it is centrifuged 3min every time, collects supernatant and obtains placenta targeted nano particle.
The TEM partial size of the placenta targeted nano particle made from the present embodiment is 90-130nm；It is measured using BCA method more
The bonding ratio of peptide is 54%.
Application Example
To made from the embodiment of the present invention 1 be coated with methotrexate (MTX) placenta targeted nano particle (being abbreviated as CSA-MNPs) into
The effect test of the pregnant mouse miscarriage of row, and opposed with PBS group, free methotrexate (MTX) group, common nanoparticle group, out-of-order polypeptide group
According to, wherein the sequence for the polypeptide that out-of-order polypeptide group SCR-MNPs is modified are as follows: PNNKCESDKLAKHKKLGDKC is (such as
Shown in SEQUENCE NO.4), the polypeptide is to placenta without targeting.Concrete operations are as follows:
Using 6 week old, the female CD-1 mouse that weight is 15-20g is as experimental animal, by female mice and male mouse with 1:2 ratio
It mates, next day checks negative bolt to female mice, sees the day of negative bolt for gestation 0.5 day.It is every other day, right since pregnant mouse gestation 5.5 days
Pregnant mouse is divided into following each group by the different pharmaceutical of tail vein injection (equivalent of methotrexate (MTX) is 1 μ g/g weight): PBS group,
Free methotrexate (MTX) group (Free DOX), common nanoparticle group (MNPs, the polypeptide of unmodified placenta targeting, i.e., in the present invention
Nano particle presoma), out-of-order polypeptide group (SCR-MNPs), the placenta targeted nano particle (CSA- for containing methotrexate (MTX)
MNPs).Using vevo2100 ultrahigh resolution toy ultrasound, molecule image system observes and records embryo in real time daily simultaneously
The test result of size and growing state, ultrasonic development is as shown in Figure 3.Meanwhile embryo is taken out daily and weighs fetal weight and remembers
Record, experimental result are as shown in Figure 4.
In Fig. 3, wherein the 10th day, in the 12nd day ultrasonic development result, inverse 2 figures of every row are CSA-MNPs
Experimental result shows two different states of pregnant mouse embryo after medication, the pregnant mouse embryo development that second-to-last figure embodies
It is slow, the close death of the pregnant mouse embryo that the 1st figure reciprocal is embodied with.From figure 3, it can be seen that CSA-MNPs group is it can be seen that embryo
Occurred a large amount of miscarriages (abortion ratio 80%) at gestation the 14th day, and can see embryonic development feelings between gestation-the 12 day the 9th day
Condition ratio PBS group slowly, illustrates that placenta targeted nano drug granule generates obstruction to embryo growth, and further prevent pregnant
It is pregnent, Free DOX group is it can also be seen that there is abortion situation, but it is few to end pregnant 14th day miscarriage quantity, and MNPs group, SCR-
MNPs group has no that abortion situation, upgrowth situation of fetus are preferable.
From fig. 4, it can be seen that CSA group fetal weight increases there is no the increase with pregnancy time compared with other groups
Add, i.e., fetus is dead.
Above test result explanation, placenta targeted nano particle provided in the present invention can significantly inhibit gestation, can be with
Play good abortion effect.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention
Protect range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
SEQUENCE LISTING
<110>Shenzhen Institutes of Advanced Technology, Chinese Academy of Science
<120>it is used for the placenta targeted nano particle and its preparation method and application of drug abortion
<130> 2017
<160> 4
<170> PatentIn version 3.3
<210> 1
<211> 20
<212> PRT
<213>artificial sequence
<400> 1
Leu Lys Pro Ser His Glu Lys Lys Asn Asp Asp Asn Gly Lys Lys Leu
1 5 10 15
Cys Lys Ala Cys
20
<210> 2
<211> 28
<212> PRT
<213>artificial sequence
<400> 2
Glu Asp Val Lys Asp Ile Asn Phe Asp Thr Lys Glu Lys Phe Leu Ala
1 5 10 15
Gly Cys Leu Ile Val Ser Phe His Glu Gly Lys Cys
20 25
<210> 3
<211> 30
<212> PRT
<213>artificial sequence
<400> 3
Gly Lys Lys Thr Gln Glu Leu Lys Asn Ile Arg Thr Asn Ser Glu Leu
1 5 10 15
Leu Lys Glu Trp Ile Ile Ala Ala Phe His Glu Gly Lys Cys
20 25 30
<210> 4
<211> 20
<212> PRT
<213>artificial sequence
<400> 4
Pro Asn Asn Lys Cys Glu Ser Asp Lys Leu Ala Lys His Lys Lys Leu
1 5 10 15
Gly Asp Lys Cys
20
Claims (10)
1. a kind of placenta targeted nano particle, which is characterized in that the placenta targeted nano particle is used for drug abortion, the tire
Disk targeted nano particle includes the parent of hydrophobic cores, the single layer lipid molecule layer of the package hydrophobic cores and targeting placenta
Aqueous shell, the hydrophobic cores include the target delivery object of the hydrophobic polymer and its load, and the target is delivered
Object includes abortifacient；The ingredient of the hydrophily shell is target placenta sample chondroitin sulfate A (CSA) polypeptide grafted amphipathic
Macromolecular compound, the hydrophobic side of the amphiphilic macromolecular compound are interspersed in the single layer lipid molecule layer, and described two
The water-wet side of parent's property macromolecular compound and the polypeptide are keyed by amide, and the polypeptide is exposed to the single layer lipid point
Outside sublayer, wherein the amino acid sequence of the polypeptide is in the amino acid sequence shown in the SEQ ID NO:1-SEQ ID NO:3
It is one or more.
2. placenta targeted nano particle as described in claim 1, which is characterized in that the abortifacient be selected from mifepristone,
One of Misoprostol, Gemeprost, sulprostone, tamoxifen, Letrozole and methotrexate (MTX) are a variety of.
3. placenta targeted nano particle as described in claim 1, which is characterized in that the abortifacient and described amphipathic big
The mass ratio of molecular compound is (1-5): 1.
4. placenta targeted nano particle as described in claim 1, which is characterized in that it further includes contrast agent that the target, which delivers object,
With one of fluorescence tracer or a variety of；The target is delivered in object, the abortifacient and the fluorescence tracer and/or
The mass ratio of contrast agent is 1:(0.1-0.8).
5. placenta targeted nano particle according to any one of claims 1-4, which is characterized in that the hydrophobic polymer with
The mass ratio that the target delivers object is 1:(0.1-0.6).
6. placenta targeted nano particle as described in claim 1, which is characterized in that the hydrophobic polymer, single layer lipid
The mass ratio of molecule and the amphiphilic macromolecular compound is 1:(0.04-0.2): (0.1-0.4)；The amphiphilic macromolecular
The mass ratio of compound and the polypeptide is 1:(1-4).
7. a kind of preparation method of placenta targeted nano particle, which comprises the following steps:
(1) hydrophobic polymer is dissolved in organic solvent, obtains hydrophobic polymer solution；
(2) single layer lipid molecule, amphiphilic macromolecular compound and target delivery object are dissolved in the first solvent, obtain the first mixing
Solution, wherein it includes abortifacient that the target, which delivers object,；
(3) the hydrophobic polymer solution is added in first mixed solution, is ultrasonically treated 4-6min, obtains second
Mixed solution carries out centrifugal treating to second mixed solution, collects supernatant, obtain targeted nano particle precursor body；
(4) the targeted nano particle precursor body is taken, by polypeptide, the catalyst, dehydration of itself and targeting placenta sample chondroitin sulfate A (CSA)
Agent carries out amide reaction in the second solvent, so that on the be grafted to amphiphilic macromolecular compound of the polypeptide；Collect reaction
Liquid obtains the placenta targeted nano particle by the reaction solution after isolating and purifying；
The placenta targeted nano particle includes the single layer lipid molecule layer and target of hydrophobic cores, the package hydrophobic cores
To the hydrophily shell of placenta, the hydrophobic cores include the target delivery object of the hydrophobic polymer and its load, institute
Stating target and delivering object includes abortifacient, and the ingredient of the hydrophily shell is the polypeptide grafted of placenta sample chondroitin sulfate A (CSA)
Amphiphilic macromolecular compound, the hydrophobic side of the amphiphilic macromolecular compound are interspersed in the single layer lipid molecule layer,
The water-wet side and the polypeptide of the amphiphilic macromolecular compound are keyed by amide, and the polypeptide is exposed to the single layer
Outside lipid molecule layer, wherein the amino acid sequence of the polypeptide is selected from amino acid shown in SEQ ID NO:1-SEQ ID NO:3
One of sequence is a variety of.
8. preparation method as claimed in claim 7, which is characterized in that in first mixed solution, the abortifacient with
The mass ratio of the amphiphilic macromolecular compound is (1-5): 1.
9. placenta targeted nano particle as claimed in any one of claims 1 to 6 or the preparation method as described in claim 7-8
Application of the placenta targeted nano particle obtained in preparation mammal abortifacient.
10. a kind of pharmaceutical composition, including placenta targeted nano particle as claimed in any one of claims 1 to 6.
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| CN201710905200.5A CN109568598B (en) | 2017-09-28 | 2017-09-28 | Placenta-targeted nanoparticles for drug abortion and preparation method and application thereof |
| PCT/CN2017/108646 WO2019061648A1 (en) | 2017-09-28 | 2017-10-31 | Polypeptide targeting placental chondroitin sulfate a, targeted delivery system, and preparation method and application thereof |
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| CN117159736A (en) * | 2023-08-25 | 2023-12-05 | 香港大学深圳医院 | Lipid nanoparticle for targeted delivery of nucleic acid and preparation method and application thereof |
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