CN103751148B - A kind of antineoplastic nanoparticle with targeting and slow releasing function by carrier of amphiphilic polyurethane and preparation method thereof - Google Patents
A kind of antineoplastic nanoparticle with targeting and slow releasing function by carrier of amphiphilic polyurethane and preparation method thereof Download PDFInfo
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- CN103751148B CN103751148B CN201410013388.9A CN201410013388A CN103751148B CN 103751148 B CN103751148 B CN 103751148B CN 201410013388 A CN201410013388 A CN 201410013388A CN 103751148 B CN103751148 B CN 103751148B
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Abstract
The invention discloses a kind of antineoplastic nanoparticle with targeting and slow releasing function by carrier of amphiphilic polyurethane and preparation method thereof, the nanoparticle has the core shell structure of double shells, the hydrophilic section of amphiphilic polyurethane is shell, hydrophobic section is core, medicine is wrapped in core, functional molecular is exposed to nanoparticle shell layer surface, and organosiloxane hydrolysis can form another layer of shell in hydrophilic and hydrophobic interlayer again；Wherein described medicine is capecitabine, adriamycin, taxol；The functional molecular is folic acid；The organosiloxane is tetramethoxy-silicane.It is characterized in：It is used for making drug controlled release preparation using biodegradated polymer materal, medicine can be made to produce therapeutic effect in specified patient part with minimum dosage, it is possible to improve therapeutic effect by optimizing drug release rate, and reduce toxic side effect.
Description
Technical field
The invention belongs to chemicals technical field, it is related to a kind of gentle with targeting by carrier of amphiphilic polyurethane
Release antineoplastic nanoparticle of effect and preparation method thereof.
Background technology
Colorectal cancer (CRC) is the third-largest reason that the mankind die from cancer, it is estimated that, in developed country, it can diagnose every year
Go out 1,000,000 new cases.Chemotherapy is one of essential means.
Fluorouracil is key agents of the approval for chemotherapy colorectal cancer.Capecitabine is that a kind of oral fluorine urine is phonetic
Pyridine, it is widely used in other drugs treatment colorectal cancer alone or in combination.It combines oxaliplatin and bevacizumab, to knot
Patients with bowel cancer has certain curative effect, but simultaneously, also produces certain side effect.Capecitabine combination irinotecan mCRC
In the presence of some toxic side effects, especially suffer from diarrhoea.The most common side effect related to capecitabine consumption of many document reports includes
Hyperbilirubinemia, diarrhoea and hand-foot syndrome, in fact, associated also has a series of toxicity to include angina pectoris, the heart
Restrain not normal and miocardial infarction etc..
One method for studying more is to reduce poisonous side effect of medicine using newtype drug transmission system.Nano-carrier
Induction system, be using biodegradable polymer prepare nano particle (NPs) packaging medicine.Medicine is because being isolated from the outside
And bio-toxicity is reduced, and the shielding action of pharmaceutical carrier adds slow release characteristic.Good biocompatibility and it can drop
The polymer of solution can also increase the security of drug therapy and reduce medicine disintegration, with the drop of polymer as carrier material
Solution, medicine slowly discharges, and reaches optimum therapeuticing effect.In addition, using the modifiability of polymer, the polymerization before microballoon is formed
Thing molecular chain-end either in strand or forms after microballoon and to connect target function group on its surface so that medicine reaches special
Determine position just to discharge.Reduce the loss of medicine and the infringement of normal tissue.
In recent years, domestic and foreign scholars have done many researchs for the clinic of Ka Peitabin other drugs alone or synergistically, but
It is that the research for using it for slow release formulation is also not affected by attention.
Polyurethane has good biocompatibility and excellent physical and mechanical properties, has good physiology can human body
Acceptance, the physical and chemical performance of polyurethane can be changed by the composition for changing soft and hard segments in strand.In addition, polyurethane is micro-
Ball has a micro phase separation structure, good biocompatibility, while the features such as there is high resiliency and high intensity again, therefore can be used as
The carrier and drug controlled release of protein, antibody, enzyme etc..
Tetramethoxy-silicane, can be miscible with arbitrary proportion with organic solvent as the predecessor of silica, but easily water
Solution, when the organic solvent dissolved with tetramethoxy-silicane is dissolved in the aqueous solution, hydrolysis occurs for TMOS, because of its hydrophobic spy
Property, reaction occurs between hydrophobic core and hydrophilic shell.Thus form the shell of layer of silicon dioxide.Meanwhile, after TMOS hydrolysis
Oxygen atom is exposed, hydrogen bond is easily formed with reference to the oxygen atom in hydrogen and PEG molecules, this layer of silicon shell is stabilized.Thus, the load medicine
High molecular nanometer nanoparticle can be such that medicine is discharged with slower and uniform speed because there is these to discharge barrier
Come.
The content of the invention
An object of the present invention provides a kind of anti-with slow releasing function with targetting by carrier of amphiphilic polyurethane
Tumour medicine nanoparticle.
It is a further object of the present invention to provide realize the first purpose it is a kind of by carrier of amphiphilic polyurethane have target
To the preparation method with the antineoplastic nanoparticle of slow releasing function.
A kind of antineoplastic nanoparticle with targeting and slow releasing function by carrier of amphiphilic polyurethane, it is described
Nanoparticle has bivalve layer nucleocapsid structure, and its center is formed by the hydrophobic section of amphiphilic polyurethane, and antineoplastic is wrapped
In core, shell is formed by the hydrophilic section of amphiphilic polyurethane, and the targeted molecular connected on amphiphilic polyurethane strand is micro-
Ball is exposed to nanoparticle shell layer surface after being formed, and another shell of the nanoparticle is hydrolyzed to form by organosiloxane,
Between the shell and core formed by amphiphilic polyurethane；Wherein described antineoplastic be capecitabine, adriamycin or
Taxol；The targeted molecular is folic acid；The organosiloxane is tetramethoxy-silicane.
The present invention is to be realized by the following method：
A kind of system of the antineoplastic nanoparticle with targeting and slow releasing function by carrier of amphiphilic polyurethane
Preparation Method, the preparation method includes following three step：
（1）Using hydrophilic compounds and hydrophobic compound with good biocompatibility as raw material, polyisocyanates
Hydrophilic and hydrophobic compound group is synthesized by long-chain by pre-polymerization-chain extension with low molecule chain extender, amphiphilic carrier center is formed；
（2）Carrier center is connected into targeted molecular；
（3）Using microemulsion technology by the carrier center for being connected with targeted molecular wrap up antineoplastic prepare it is a kind of with
Amphiphilic polyurethane has targeting and the medicament nano microballoon of slow releasing function for carrier.
In the above method, the hydrophilic compounds are polyethylene glycol；The hydrophobic compound is poly-（Lactic acid-hydroxyl
Acetic acid）, PLA or polycaprolactone；The polyisocyanates is Toluene-2,4-diisocyanate, 4- diisocyanate, the isocyanide of 1B ethyl ester two
Acid esters or 4,4 '-dicyclohexyl methyl hydride diisocyanate；The low molecule chain extender is 2,2- dihydromethyl propionic acids.
In the above method, step（3）The microemulsion technology is emulsion-solvent evaporation method or nanoprecipitation-dialysis.
In the above method, step（1）Specific preparation process is as follows：By the acetone soln of hydrophilic compounds and excess
Polyisocyanates is mixed, and wherein the molar concentration of hydrophilic compounds in acetone is 0.01-0.3mol/L, polyisocyanates
The amount of material is 1-1.2 times of hydrophilic compounds, by reaction system warming while stirring to 70-80 DEG C, is dropped after reaction 1.5-2h
Temperature is to 25-40 DEG C, to its addition chain extender, and the ratio between amount of chain extender and hydrophilic compounds material is 1.0-1.1：1, stirring
60-80 DEG C is warming up under conditions of mixing, 0.5-1h is stirred, it is well mixed, then is cooled to 25-40 DEG C, adds dredge thereto
Aqueous compounds, the amount of the material of hydrophobic compound is 1.1-1.3 times of the amount of hydrophilic compounds material, i.e. 0.011-
0.39mol/L acetone soln, is warming up to 77-85 DEG C under conditions of mechanical agitation, stirs 1-2h, obtains polyurethane prepolymer
Acetone soln, is added dropwise to ice absolute ether, takes and is deposited in 60-70 DEG C of vacuum drying 12-24h, obtains amphiphilic polyurethane PCEC,
I.e. amphiphilic carrier center.
In the above method, step（2）The carrier center connects targeted molecular, and specific method comprises the following steps：Take step
Suddenly（1）Reaction product PCEC 2-5g are dissolved in 20-30mL tetramethyl sulfoxides（DMSO）In, then add 0.02-0.08g 1- second
Base-(3- dimethylaminopropyls) carbodiimide（EDC）With 0.01-0.1g N- hydroxysuccinimides（NHS）, at room temperature instead
12-24h is answered, Amino End Group folic acid is added（FA-PEG-NH2）, the wherein amount of material compares PCEC: FA-PEG-NH2For 1:1-1:1.2,
Continue to react 12-24h, add 50-100 mL distilled water and stir, be cooled to after room temperature, under 3500-5000rpm rotating speeds
5-10min is centrifuged, supernatant is taken, is in distilled water the 36-48h that dialyses, a water is changed every 2-4h, rear freeze-drying is obtained
FA-PCEC。
In the above method, the emulsion-solvent evaporation method specifically includes following steps：
1）Using FA-PCEC as solute, using dichloromethane or tetrahydrofuran or acetone as solvent, concentration is configured to for 10-
200mg/mL oil phase substrate solution, above-mentioned matrix solution formation oil phase is scattered in by antineoplastic；Again to described oil phase
Tetramethoxy-silicane is added middlely, and 15-30min is stirred under 300-500rpm rotating speed is well mixed it, obtains solution A；
The quality of wherein described medicine is FA-PCEC 5%-20%, and the amount of the material of the tetramethoxy-silicane is FA-PCEC 1.0-
1.2 again；
2）Using polyvinyl alcohol as solute, using water as solvent, the aqueous phase that polyvinyl alcohol mass fraction is 0.5%-1.0% is made molten
Liquid, ie in solution B；
3）Again by step 1）Described solution A is added drop-wise to step 2）Described solution B, the volume of aqueous phase is the 5-20 of oil phase
Times, stir 8-12 hours, then the nanoparticle obtained by high speed centrifugation collection, takes precipitation, plus distilled water to disperse, repeat centrifugation
The step of taking precipitation, until polyvinyl alcohol is by wash clean, finally by pellet frozen drying to obtain purpose product；The stirring is
500-1000rpm, centrifugal speed 8000-10000rpm used.
In the above method, the nanoprecipitation-dialysis specifically includes following steps：
1）Using FA-PCEC as solute, using dichloromethane, tetrahydrofuran or acetone as solvent, concentration is configured to for 10-
200mg/mL oil phase substrate solution, above-mentioned matrix solution is scattered in by antineoplastic, forms oil phase；And to described oil phase
Tetramethoxy-silicane is added middlely, is stirred, and obtains solution A；The quality of wherein described antineoplastic is FA-PCEC's
5%-20%, the amount of the material of the tetramethoxy-silicane is 1.0-1.2 times of FA-PCEC；
2）Using polyvinyl alcohol as solute, using water as solvent, the aqueous phase that polyvinyl alcohol mass fraction is 0.5%-1.0% is made molten
Liquid, ie in solution B；
3）Again by step 2）Described aqueous phase B is added drop-wise to step 1 dropwise）Described oil-phase solution A, the volume of aqueous phase is oil
2-10 times of phase；Continue to stir 2 hours with 300-600rpm；Dialysed in distillation aqueous medium, it is every to change once within 2-4 hours
Water, dialyses 36-48 hours；Product freeze-drying obtains purpose product.
From can be seen that the present invention during realizing the object of the invention scheme using amphiphilic polyurethane as carrier, because of parent
Hydrophobic effect, in the solution, hydrophilic block and hydrophobic block mutual aggregation respectively are formed including hydrophobic block, hydrophilic block exists
Outer core shell structure.When the addition of tetramethoxy-silicane causes it from oil phase into aqueous phase, gradually hydrolyze, it is close and distant in nanoparticle
Hydrolyzed between the main body of water and form one layer of silicon shell.The hydrolysate of tetramethoxy-silicane can also form hydrogen with polyethylene glycol segment
Key, has consolidated this layer of silicon shell.So as to form the structure that medicine successively discharges.
Polyurethane has good biocompatibility, water-disintegrable and antioxidation, PEG end of the chains connection targeting preparation
The compound of folic acid, receives because being connected on hydrophilic PEG chains to be exposed to when microballoon is formed with hydrophilic carboxyl in folate molecule
Rice microsphere surface.Drug molecule is wrapped in the inside of nanoparticle under hydrophobic effect.
The present invention is carried out according to the step of above-mentioned embodiment, surveyed with laser particle analyzer by checking, verification process
Determine particle diameter, with transmission electron microscope observing nanoparticle structure and particle diameter, drugloading rate is determined with ultraviolet specrophotometer and it is studied and released
Put characteristic.Obtain preferable the result.Wherein nanoparticle particle diameter is in 200nm or so, and surface is smooth, and drugloading rate is
7.9%-13.3%, envelop rate is 55.9-69.3%, and a value range relatively stablized of product of the invention is that drugloading rate is
10.2%-13.0%, envelop rate is 63.4%-68.3%.Drug release releases outer except initial a few houres are prominent, can continue slowly to discharge 200 hours
More than.
Compared with prior art, the invention has the advantages that：
（1）Improve existing generally by the method synthesis of polyurethane nanoparticle skill of pre-polymerization-chain extension-neutralization-emulsification
Art, i.e., only synthesize double block compounds by the step of pre-polymerization-chain extension two, remain an active group, allow it in the later stage
Through the upper functional group of modification connection.
（2）The nanoparticle form prepared using the present invention is smooth, uniform in size.Change the change of each factor of preparation condition
Change, the change of nanoparticle size can be controlled.By controlling the molecular weight of amphiphilic carrier, Ka Peitabin work can be extended
Use the time.In existing literature, due to the difference of carrier, drugloading rate is not of uniform size.Typically using PLGA as independent carrier packaging medicine
Drugloading rate mostly in 5%-8%, the nanoparticle drugloading rate by carrier of PCEC is mostly 6%-12%, the present invention in total molecular weight
For 40,000 or so mixed carrier in the case of, drugloading rate is 10.2%-13.0%, and envelop rate is 63.4%-68.3%.
（3）The present invention is also added into organosiloxane reagent during preparation.With methyl in its hydrolytic process
Leave away, expose oxygen atom, so as to the strand of carrier water-wet side formation hydrogen bond, the product deposition of hydrolysis, hydrophobic
Chain and hydrophilic interchain formation layer of silicon dioxide shell, silicon shell can play shielding action for insoluble drug release, can greatly extend
The deenergized period of medicine.Nanoparticle energy sustained release in PBS cushioning liquid, in addition to initial 17h burst drug release,
During 190h, Cumulative release amount is 49% or so, and the drug release rate is significantly lower than the medicament-carrying nano-microsphere body without this layer of shielding action
The drug release rate of system.
Brief description of the drawings
Fig. 1 is compound synthesis schematic diagram in embodiment 1；
Fig. 2 is the infrared spectrogram of Polyurethane carrier connection targeted molecular in embodiment 1;
Fig. 3 is TMOS hydrolysis and the intermolecular schematic diagrames for forming hydrogen bond of PEG in embodiment 1；
Fig. 4 is the Polyurethane carrier connection targeted molecular chain schematic diagram that embodiment 1 is prepared into；
Fig. 5 is the structural representation for the medicament-carrying nano-microsphere that embodiment 1 is prepared into；
Fig. 6 is nanoparticle transmission electron microscope picture in embodiment 1；
Fig. 7 is the grain size distribution of nanoparticle in embodiment 1；
Fig. 8 is nanoparticle transmission electron microscope picture in embodiment 2；
Fig. 9 is PCEC/TMOS NPs prepared by embodiment 2 and PCEC NPs, PEG-PCL NPs drugs compared release song
Line.
Embodiment
The embodiment to the present invention is described further below in conjunction with the accompanying drawings, but embodiments of the present invention are not limited
In this.
The present invention is further illustrated in conjunction with the embodiments, wherein degradable hydrophilic compounds are polyethylene glycol（PEG）, its
Molecular weight is 4000g/mol；Degradable hydrophobic compound is polycaprolactone（PCL）, its molecular weight is 4000g/mol；It is many
Isocyanates is 4,4 '-dicyclohexyl methyl hydride diisocyanate（HMDI）, its relative molecular mass is 262 g/mol；Low molecule
Chain extender is 2,2- dihydromethyl propionic acids (DMPA)；Targeted molecular is folic acid（FA）；Antineoplastic is Ka Peitabin（CAP）；
Organosiloxane is tetramethoxy-silicane（TMOS）.
Embodiment 1
A kind of antineoplastic nanoparticle with targeting and slow releasing function by carrier of amphiphilic polyurethane, it is special
Levy and be that scheme is specially：
Microemulsion technology is emulsion-solvent evaporation method.
Step one：Amphiphilic polyurethane is prepared, is comprised the following steps：
（1）Equipped with agitator, 5gPEG and 20mL acetone, stirring are being added in the there-necked flask of reflux condensing tube and thermometer
0.36gHMDI is added after uniform thereto 80 DEG C are to slowly warm up in the case of mechanical agitation, stir 1h, make its mixing equal
It is even；
（2）By reaction system warming while stirring to 75 DEG C, 30 DEG C are cooled to after reaction 1.5h, is added to it
0.20gDMPA.70 DEG C are warming up in the case of mechanical agitation, 1h is stirred, is well mixed it, then be cooled to 30 DEG C.
（3）It is warming up to 70 DEG C in the case of mechanical agitation, stirs 0.5h, be well mixed it, then is cooled to 30 DEG C, to
5.5gPCL is wherein added, 80 DEG C are warming up in the case of mechanical agitation, 2h is stirred, obtains polyurethane prepolymer acetone molten
Liquid, is added dropwise to ice absolute ether, takes and is deposited in 60 DEG C of vacuum drying 12h, obtains amphiphilic polyurethane PCEC, i.e., amphiphilic carrier
Center.
Step 2：Amphiphilic polyurethane connects targeted molecular, comprises the following steps：
Take first step reaction product (PCEC) 3g to be dissolved in 20mL tetramethyl sulfoxides, then add 0.036gEDC and
0.02gNHS, reacts 24h, then the addition 1.01g Amino End Group folic acid into the reaction system at room temperature（FA-PEG-NH2）, continue anti-
Answer 20 hours, add 50mL distilled water and stir, be cooled to after 25 DEG C, in centrifuging 10min under 3500 r/min, take supernatant
Liquid, dialyse 40h in distilled water, changes a water to remove the small molecules such as DMSO and NHS within every three hours.Then it is freeze-dried, obtains
To FA-PCEC.
The compound course of reaction of step one and step 2 such as schematic diagram 1, the infrared test result of its reaction result is as schemed
2。
In Fig. 2, in 3490 cm-1For molecule segment-OH vibration peak, 2905 cm-1、1469 cm-1With 842 cm-1Place is equal
There is the characteristic absorption peak of C-H stretching vibration, flexural vibrations and rocking vibration.In 1780 cm-1Have a strong vibration peak for C=
O stretching vibration absworption peak.1186 cm-1With 1089.6 cm-1For aliphatic ether C-O characteristic peaks.FA-PCEC and PCEC spectrum
Figure feature is roughly the same, simply in 1573 cm-1Appearance phenyl ring skeletal vibration, the phenyl ring be folate molecule on, show PCEC connect
FA-PEG-NH is connected2.From FA-PCEC spectrograms, it can also be seen that absworption peak such as 2140 cm-1And the peak of lower wave number section
It there occurs similar to FA-PEG-NH2Change.Also indicate that FA-PEG-NH2Successfully it has been connected on PCEC.
Step 3：Emulsion-solvent evaporation method prepares nanoparticle, comprises the following steps：
（1）It is solute to take 2g FA-PCEC, is dissolved in 20mL dichloromethane, is configured to the oil phase that concentration is 100mg/mL
Matrix solution, above-mentioned matrix solution is scattered in by 0.2g antineoplastics CAP, forms oil phase；And be added dropwise into described oil phase
Enter 0.019g tetramethoxy-silicanes, stir；
（2）Using polyvinyl alcohol as solute, using water as solvent, the aqueous phase that 100mL polyvinyl alcohol mass fraction is 1.0% is made
Solution；
（3）Again by（1）The described oil phase of step is added drop-wise to step（2）Described aqueous phase solution, 12 are stirred by the mixed liquor
Hour, organic solvent is fully volatilized, then the nanoparticle obtained by high speed centrifugation collection, take precipitation, plus distilled water to disperse again
The step of repeated centrifugation takes precipitation, until polyvinyl alcohol is by wash clean, finally by pellet frozen drying to obtain purpose product.Institute
It is 600rpm to state stirring, and centrifugal speed used is 8000rpm；
The H bond structures such as accompanying drawing 3 of TMOS hydrolysis and the intermolecular formation of PEG in microballoon preparation process.Because sudden and violent after TMOS hydrolysis
Expose oxygen atom, with reference to the oxygen atom formation hydrogen bond in hydrogen and PEG molecules, this also stabilizes what is formed in microballoon preparation process
Silicon shell.Fig. 4 is that Polyurethane carrier connects targeted molecular chain schematic diagram, and Fig. 5 is the structural representation of the medicament-carrying nano-microsphere prepared;
Carry out test sign to resulting nanoparticle with laser particle analyzer and transmission electron microscope, transmission electron microscope results referring to
Fig. 6, particle diameter and particle diameter distribution result such as Fig. 7.Sample can be clearly observable for regular circle shapes and surface relative smooth from Fig. 6.
And can also be seen that obvious nucleocapsid structure.From Fig. 7 it can also be seen that normal distribution, and distribution is presented in microspherulite diameter
It is narrow, show the microballoon size prepared than more consistent, it is consistent with the result of transmission electron microscope in 200nm or so.
Embodiment 2
The present embodiment and the difference of embodiment 1 are：
Step 3 prepares the method that nanoparticle prepares nanoparticle with nanoprecipitation-dialysis, comprises the following steps：
（1）It is solute to take 2g FA-PCEC, is dissolved in 20mL dichloromethane, is configured to the oil phase that concentration is 100mg/mL
Matrix solution, above-mentioned matrix solution is scattered in by 0.2g antineoplastics CAP, forms oil phase；And be added dropwise into described oil phase
Enter 0.019g tetramethoxy-silicanes（TMOS）, stir；
（2）Using polyvinyl alcohol as solute, using water as solvent, the aqueous phase that 100mL polyvinyl alcohol mass fraction is 1.0% is made
Solution；
（3）Again by step（2）Described aqueous phase is slowly added drop-wise to step dropwise（1）Described oil-phase solution, with 600rpm
Continue to stir 2 hours；Dialysed in distillation aqueous medium, change within every 2 hours a water, dialysed 48 hours；Product freezing is dry
It is dry to obtain purpose product.
（4）According to whether addition TMOS, the present embodiment prepares two kinds of medicament-carrying nano-microspheres, one of which adds TMOS groups,
The nanoparticle of preparation as of the present invention, is denoted as PCEC/TMOS NPs, another nanoparticle for being not added with TMOS and preparing
PCEC NPs are denoted as contrast groups.Prepare PCEC NPs and prepare nanoparticle with the difference is that only for PCEC/TMOS NPs
During save addition TMOS the step for.
Test sign is carried out to resulting nanoparticle with laser particle analyzer and transmission electron microscope, transmission electron microscope results are shown in attached
Fig. 8 have found that the particle diameter of the present embodiment nanoparticle is small compared with embodiment 1 from figure, average out to 190nm.
The insoluble drug release situation of the microballoon independently filled with general amphiphilic compound for contrast polyaminoester microball.By embodiment
2 method is prepared for PEG-PCL（Molecular weight is 8056g/mol）Microballoon prepared by double block compounds.It is concretely comprised the following steps：
It is solute to take 2g PEG-PCL, is dissolved in 20mL dichloromethane, is configured to the oil phase base that concentration is 100mg/mL
Matter solution, above-mentioned matrix solution is scattered in by 0.2g antineoplastics CAP, forms oil phase；And be added dropwise into described oil phase
0.019g tetramethoxy-silicanes, stir；Using polyvinyl alcohol as solute, using water as solvent, 100mL polyvinyl alcohol quality is made
Fraction is 1.0% aqueous phase solution；Aqueous phase is slowly added drop-wise to oil-phase solution dropwise again, continues to stir 2 hours with 600rpm；Again
Dialysed in distillation aqueous medium, change within every 2 hours a water, dialysed 48 hours；Product freeze-drying obtains purpose product.
Fig. 9 is the nanoparticle PCEC/TMOS NPs and nanoparticle PCEC prepared by the embodiment of the present invention 2
NPs, and common PE G-PCL NPs vitro drug release comparison diagram, therefrom find that the PCEC/TMOS for preparing of the present invention is carried
Medicine nanoparticle has good sustained drug release effect, dashes forward and releases without obvious primary drugs, slow-release time is up to more than 190h.Card training
He successively decreases shore successively from the rate of release in PEG-PCL NPs, PCEC NPs, PCEC/TMOS NPs, capecitabine contain in
In NPs hydrophobic cores, it is from the structures shape that the release in vitro in NPs is largely by NPs, PCEC polyurethane structural
More more stable than PEG-PCL, and PCEC/TMOS NPs are than PCEC NPs, many one layer of release barriers have very to capecitabine
Good controlled release ability, therefore its rate of release is minimum, and three kinds of NPs by initial stage 10h it is prominent release after reach that stable medicine is released
Put speed.
Embodiment 3
The present embodiment and the difference of embodiment 1 are：
By of the step three in embodiment 1（2）The PVA aqueous solution volumes of step are adjusted to 400mL, i.e., second emulsification
The volume of surfactant solution is 20 times of organic solvent volume.It is micro- to resulting nanometer with laser particle analyzer and ESEM
Ball carries out test sign, it is found that the particle diameter of the present embodiment nanoparticle is small compared with embodiment 1, reason is the increase of aqueous phase volume,
The viscosity of oil phase is reduced, is conducive to scattered in aqueous phase of oil phase to form emulsion droplet so that the microspherulite diameter ultimately formed subtracts
It is small.
Embodiment 4
The present embodiment difference from Example 2 is：
By of the step three in embodiment 2（3）The mixing speed of step is adjusted to 300rpm.
Test sign is carried out to resulting nanoparticle with laser particle analyzer and ultraviolet specrophotometer, this implementation is found
The particle diameter and particle diameter distribution of example nanoparticle, drugloading rate and envelop rate are as shown in table 1.
Embodiment 5
The present embodiment difference from Example 2 is：
By of the step three in embodiment 2（3）The mixing speed of step is adjusted to 400rpm.
Test sign is carried out to resulting nanoparticle with laser particle analyzer and ultraviolet specrophotometer, this implementation is found
The particle diameter and particle diameter distribution of example nanoparticle, drugloading rate and envelop rate are as shown in table 1.
Embodiment 6
The present embodiment and the difference of embodiment 2 are：
By of the step three in embodiment 2（3）The mixing speed of step is adjusted to 500rpm.
Test sign is carried out to resulting nanoparticle with laser particle analyzer and ultraviolet specrophotometer, this implementation is found
The particle diameter and particle diameter distribution of example nanoparticle, drugloading rate and envelop rate are as shown in table 1.
As seen from the results in Table 1, with the increase of mixing speed, the particle diameter of nanoparticle is gradually reduced, while particle diameter distribution
Also narrow to a certain extent.And the envelop rate and drugloading rate of microballoon also decline.Reason is the increase with mixing speed, is cut
Shear force also increases, and causes degree of scatter of the oil phase drop in aqueous phase to improve so that NPs is more easy to be separated into less emulsion droplet, but
Because stirring is violent, the leakage of medicine is result in, therefore envelop rate and drugloading rate are substantially reduced.
There is targeting Journal of Sex Research of the substantial amounts of document report about nanometer formulation, wherein confirming particle diameter within 250nm
Nanometer formulation due to tumor tissues EPR effects can passive target in tumor tissues, and reduce the killing of normal tissue
Effect.Such as polymer medicament carrying micelle, elaioplast nanometer particle etc. can smoothly pass in and out tumor group very much in the interior circulation of human body
Cell is knitted, and then must be controlled in small diameter in tumor tissues accumulation.And envelop rate and drugloading rate are to evaluate nanometer formulation matter
The important indicator of amount, envelop rate is bigger, and drug loss is fewer, and drugloading rate is bigger, more readily satisfies the demand of clinical application,
Summary result can be seen that selection mixing speed 500rpm is relatively appropriate.
Table 1
| Rotating speed（rpm） | Particle diameter (nm) | Particle diameter distribution index | Drugloading rate（%） | Envelop rate（%） | Embodiment |
| 300 | 232±0.12 | 0.659 | 13.3 | 69.3 | 4 |
| 400 | 220±0.25 | 0.543 | 12.2 | 63.8 | 5 |
| 500 | 212±0.37 | 0.433 | 8.8 | 58.3 | 6 |
| 600 | 198±0.33 | 0.391 | 7.9 | 55.9 | 2 |
Claims (1)
1. a kind of antineoplastic nanoparticle with targeting and slow releasing function by carrier of amphiphilic polyurethane, its feature
It is：
Step one：Amphiphilic polyurethane is prepared, is comprised the following steps：
（1）Equipped with agitator, 5gPEG and 20mL acetone is added in the there-necked flask of reflux condensing tube and thermometer, is stirred
Add 0.36gHMDI thereto afterwards and 80 DEG C are to slowly warm up in the case of mechanical agitation, stir 1h, be well mixed it；
（2）By reaction system warming while stirring to 75 DEG C, 30 DEG C are cooled to after reaction 1.5h, 0.20gDMPA is added to it；
70 DEG C are warming up in the case of mechanical agitation, 1h is stirred, is well mixed it, then be cooled to 30 DEG C；
（3）70 DEG C are warming up in the case of mechanical agitation, 0.5h is stirred, it is well mixed, then is cooled to 30 DEG C, thereto
5.5gPCL is added, 80 DEG C are warming up in the case of mechanical agitation, 2h is stirred, obtains polyurethane prepolymer acetone soln, is dripped
Ice absolute ether is added to, takes and is deposited in 60 DEG C of vacuum drying 12h, obtain amphiphilic polyurethane PCEC, i.e., amphiphilic carrier center；
Step 2：Amphiphilic polyurethane connects targeted molecular, comprises the following steps：
Take first step reaction product PCEC 3g to be dissolved in 20mL dimethyl sulfoxide (DMSO)s, then add 0.036gEDC and 0.02gNHS,
24h, then the addition 1.01g Amino End Group folic acid FA-PEG-NH into the reaction system are reacted at room temperature2, continue to react 20 hours, plus
Enter 50mL distilled water to stir, be cooled to after 25 DEG C, in centrifuging 10min under 3500 r/min, supernatant is taken, in distilled water
Dialyse 40h, changes a water to remove the small molecules such as DMSO and NHS within every three hours；Then it is freeze-dried, obtains FA-PCEC；
Step 3：Emulsion-solvent evaporation method prepares nanoparticle, comprises the following steps：
（1）It is solute to take 2g FA-PCEC, is dissolved in 20mL dichloromethane, is configured to the oil phase substrate that concentration is 100mg/mL
Solution, above-mentioned matrix solution is scattered in by 0.2g antineoplastics CAP, forms oil phase；And be added dropwise into described oil phase
0.019g tetramethoxy-silicanes, stir；
（2）Using polyvinyl alcohol as solute, using water as solvent, the aqueous phase solution that 100mL polyvinyl alcohol mass fraction is 1.0% is made；
（3）Again by（1）The described oil phase of step is added drop-wise to step（2）Described aqueous phase solution, the mixed liquor is stirred 12 hours,
Organic solvent is fully volatilized, then high speed centrifugation collect obtained by nanoparticle, take precipitation, plus distilled water disperse to repeat from
The step of heart takes precipitation, until polyvinyl alcohol is by wash clean, finally by pellet frozen drying to obtain purpose product；The stirring
For 600rpm, centrifugal speed used is 8000rpm.
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