CN103751148A - Targeting and slow-release antineoplastic medicine nanoparticle with amphiphilic polyurethane as carrier and preparation method thereof - Google Patents
Targeting and slow-release antineoplastic medicine nanoparticle with amphiphilic polyurethane as carrier and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a trgeting and slow-release antineoplastic medicine nanoparticle with amphiphilic polyurethane as a carrier and a preparation method thereof. The nanoparticle is of a nucleus-shell structure provided with two shell layers; a hydrophilic section of amphiphilic polyurethane serves as the shell layer, and a hydrophobic section serves as the nucleus; the nucleus covers the medicines; a functional molecule exposes from the surface of the shell layer of the nanoparticle; organo-siloxane can be hydrolyzed to form another shell layer between the hydrophilic section and the hydrophobic section; the medicines include capecitabine, adriamycin and paclitaxel; the functional molecule is folic acid; and organo-siloxane is tetramethoxysilane. The targeting and slow-release antineoplastic medicine nanoparticle with amphiphilic polyurethane as the carrier has the characteristics that degradable polymer materials are used as the medicine release-control preparations, which enables the medicine to act on a specified wound position with the minimum dosage; and the medicine release rate can be optimized to improve the treatment effect as well as reduce the toxic and side effects.
Description
Technical field
The invention belongs to chemicals technical field, relate to a kind of take that amphiphilic polyurethane is carrier there is antitumor drug Nano microsphere of targeting and slow releasing function and preparation method thereof.
Background technology
Colorectal cancer (CRC) is the third-largest reason that the mankind die from cancer, according to estimates, in developed country, can diagnose out every year 1000000 new cases.Chemotherapy one of the means that are absolutely necessary.
Fluorouracil is that approval is for the main medicine of chemotherapy colorectal cancer.Capecitabine is a kind of oral fluorouracil, and it is widely used in other drug treatment colorectal cancer alone or in combination.It has certain curative effect in conjunction with oxaliplatin and bevacizumab to colorectal cancer patients, but simultaneously, also produces certain side effect.Also there are some toxic and side effects in conjunction with irinotecan mCRC in capecitabine, especially diarrhoea.The modal side effect relevant to capecitabine consumption of many bibliographical informations comprises hyperbilirubinemia, diarrhoea and brothers' syndrome, and in fact, the associated a series of toxicity that also has comprises angina pectoris, arrhythmia and myocardial infarction etc.
A method of studying is morely to utilize newtype drug transmission system to reduce poisonous side effect of medicine.The induction system of nano-carrier is nano-particle (NPs) packaging medicine that utilizes biodegradable polymer to prepare.Medicine has reduced bio-toxicity because being isolated from the outside, and the shielding action of pharmaceutical carrier has increased slow release characteristic.Good biocompatibility and degradable polymer, as carrier material, also can increase the safety of Drug therapy and reduce medicine disintegrate, and along with the degraded of polymer, sustained release, reaches optimum therapeuticing effect.In addition, utilize the modifiability of polymer, in the polymer molecule end of the chain or strand before forming microsphere, or on its surface, connect target function group after forming microsphere, make medicine arrive specific part and just discharge.The loss of medicine and the infringement of normal tissue have been reduced.
In recent years, Chinese scholars for Ka Peitabin alone or synergistically other drug clinical done a lot of research, but the research of using it for slow release formulation does not also come into one's own.
Polyurethane has good biocompatibility and good physical and mechanical properties, human body is had to good physiology acceptable, can change the physical and chemical performance of polyurethane by changing the composition of soft or hard section in strand.In addition, polyaminoester microball has micro phase separation structure, and good biocompatibility has again the features such as high resiliency and high strength simultaneously, and the carrier and the medicine that therefore can be used as protein, antibody, enzyme etc. are controlled release.
Tetramethoxy-silicane, can be miscible with arbitrary proportion with organic solvent as the predecessor of silicon dioxide, but very easily hydrolysis, when when being dissolved with in the water-soluble solution of organic solvent of tetramethoxy-silicane, there is hydrolysis in TMOS, because of its hydrophobic property, reaction occurs between hydrophobic core and hydrophilic shell.Thereby formed the shell of layer of silicon dioxide.Meanwhile, because exposing oxygen atom after TMOS hydrolysis, in conjunction with the oxygen atom in hydrogen and PEG molecule, very easily form hydrogen bond, stablized this layer of silicon shell.Thus, this medicine-carrying polymer nano microsphere, because there have been these to discharge barrier, can make medicine discharge with slower and uniform speed.
Summary of the invention
One of object of the present invention provides a kind of antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier of take.
Another object of the present invention is to provide realize the first object a kind of and take the preparation method of the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier.
A kind ofly take the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier, described Nano microsphere has bivalve layer nucleocapsid structure, its center is formed by the hydrophobic section of amphiphilic polyurethane, antitumor drug is wrapped in core, shell is formed by the hydrophilic section of amphiphilic polyurethane, the targeted molecular connecting on amphiphilic polyurethane strand is exposed to Nano microsphere shell surface after microsphere forms, another shell of described Nano microsphere is formed by organosiloxane hydrolysis, by amphiphilic polyurethane between formed shell and core; Wherein said antitumor drug is capecitabine, amycin or paclitaxel; Described targeted molecular is folic acid; Described organosiloxane is tetramethoxy-silicane.
The present invention realizes by the following method:
A preparation method for the antitumor drug Nano microsphere with targeting and slow releasing function that the amphiphilic polyurethane of take is carrier, described preparation method comprises following three steps:
(1) take hydrophilic compounds and the hydrophobic compound with good biocompatibility is raw material, and polyisocyanates becomes long-chain by pre-polymerization-chain extension by hydrophilic and hydrophobic compound combination with low molecule chain extender, forms amphiphilic carrier center;
(2) carrier center is connected to targeted molecular;
(3) utilize microemulsion technology that the carrier center parcel antitumor drug that is connected with targeted molecular is prepared to a kind of medicament nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier of take.
In said method, described hydrophilic compounds is Polyethylene Glycol; Described hydrophobic compound is PLGA, polylactic acid or polycaprolactone; Described polyisocyanates is Toluene-2,4-diisocyanate, 4-vulcabond, 1B ethyl ester vulcabond or 4,4 '-dicyclohexyl methyl hydride diisocyanate; Described low molecule chain extender is 2,2-dihydromethyl propionic acid.
In said method, the described microemulsion technology of step (3) is emulsion-solvent evaporation method or nanometer precipitation-dialysis.
In said method, the concrete preparation process of step (1) is as follows: the acetone soln of hydrophilic compounds and excessive polyisocyanates are mixed, wherein the molar concentration of hydrophilic compounds in acetone is 0.01-0.3mol/L, the amount of substance of polyisocyanates is 1-1.2 times of hydrophilic compounds, by reaction system warming while stirring to 70-80 ℃, after reaction 1.5-2h, be cooled to 25-40 ℃, to it, add chain extender, chain extender is 1.0-1.1:1 with the ratio of hydrophilic compounds amount of substance, under the condition stirring, be warming up to 60-80 ℃, stir 0.5-1h, make its mix homogeneously, be cooled to again 25-40 ℃, add wherein hydrophobic compound, the amount of substance of hydrophobic compound is 1.1-1.3 times of hydrophilic compounds amount of substance, it is the acetone soln of 0.011-0.39mol/L, under churned mechanically condition, be warming up to 77-85 ℃, stir 1-2h, obtain polyurethane prepolymer acetone soln, drop to ice absolute ether, get and be deposited in 60-70 ℃ of vacuum drying 12-24h, obtain amphiphilic polyurethane PCEC, it is amphiphilic carrier center.
In said method, the described carrier center of step (2) connects targeted molecular, concrete grammar comprises the following steps: get step (1) product PCEC 2-5g and be dissolved in 20-30mL tetramethyl sulfoxide (DMSO), then the N-maloyl imines (NHS) that adds 0.02-0.08g 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and 0.01-0.1g, under room temperature, react 12-24h, add end AMT (FA-PEG-NH
2), wherein amount of substance compares PCEC:FA-PEG-NH
2for 1:1-1:1.2, continue reaction 12-24h, add 50-100 mL distilled water to stir, be cooled to after room temperature, under 3500-5000rpm rotating speed, centrifugal 5-10min, gets supernatant, and 36-48h is to dialyse in distilled water, every 2-4h, change water one time, postlyophilization, obtains FA-PCEC.
In said method, described emulsion-solvent evaporation method, specifically comprises the steps:
1) take FA-PCEC as solute, take dichloromethane or oxolane or acetone as solvent, being mixed with concentration is the oil phase substrate solution of 10-200mg/mL, antitumor drug is scattered in to above-mentioned matrix solution and forms oil phase; To adding tetramethoxy-silicane in described oil phase, under the rotating speed of 300-500rpm, stir 15-30min and make its mix homogeneously again, obtain solution A; The quality of wherein said medicine is the 5%-20% of FA-PCEC, and the 1.0-1.2 that the amount of substance of described tetramethoxy-silicane is FA-PCEC doubly;
2) take polyvinyl alcohol as solute, take water as solvent, make the aqueous phase solution that polyvinyl alcohol mass fraction is 0.5%-1.0%, ie in solution B;
3) again the solution A described in step 1) is added drop-wise to step 2) described solution B, the volume of water is 5-20 times of oil phase, stir 8-12 hour, then high speed centrifugation is collected the Nano microsphere of gained, get precipitation, adding distil water disperses, then repeated centrifugation is got the step of precipitation, until polyvinyl alcohol, by wash clean, finally obtains object product by precipitation lyophilization; Described stirring is 500-1000rpm, centrifugal speed 8000-10000rpm used.
In said method, described nanometer precipitation-dialysis, specifically comprises the steps:
1) take FA-PCEC as solute, take dichloromethane, oxolane or acetone as solvent, being mixed with concentration is the oil phase substrate solution of 10-200mg/mL, and antitumor drug is scattered in to above-mentioned matrix solution, forms oil phase; And to adding tetramethoxy-silicane in described oil phase, stir, obtain solution A; The quality of wherein said antitumor drug is the 5%-20% of FA-PCEC, and the 1.0-1.2 that the amount of substance of described tetramethoxy-silicane is FA-PCEC doubly;
2) take polyvinyl alcohol as solute, take water as solvent, make the aqueous phase solution that polyvinyl alcohol mass fraction is 0.5%-1.0%, ie in solution B;
3) again by step 2) described aqueous phase B is dropwise added drop-wise to the oil-phase solution A described in step 1), the volume of water be oil phase 2-10 doubly; With 300-600rpm, continue to stir 2 hours; In distilled water medium, dialyse, every 2-4 hour changes water one time again, dialysis 36-48 hour; Product lyophilization obtains object product.
From realize the process of the object of the invention scheme, can find out, the present invention be take amphiphilic polyurethane as carrier, and because of close hydrophobic interaction, in solution, hydrophilic block and hydrophobic block are assembled respectively mutually, form hydrophobic block interior, hydrophilic block nucleocapsid structure outside.Adding while making it enter water from oil phase of tetramethoxy-silicane, hydrolysis is gradually hydrolyzed and formation one deck silicon shell between the main body of the close and distant water of Nano microsphere.The hydrolyzate of tetramethoxy-silicane and Polyethylene Glycol segment can also form hydrogen bond, have consolidated this layer of silicon shell.Thereby form the structure that medicine successively discharges.
Polyurethane has good biocompatibility, water-disintegrable and antioxidation, and the PEG end of the chain connects the compound of targeting preparation folic acid, because being connected to and being exposed to Nano microsphere surface on hydrophilic PEG chain when microsphere forms with hydrophilic carboxyl in folate molecule.Drug molecule is wrapped in the inside of Nano microsphere under hydrophobic interaction.
The present invention is by checking, and proof procedure carries out according to the step of the above-mentioned specific embodiment, with laser particle analyzer, measures particle diameter, with transmission electron microscope observing Nano microsphere structure and particle diameter, with ultraviolet spectrophotometer, measures drug loading and its release characteristics of research.Obtained good the result.Wherein Nano microsphere particle diameter is in about 200nm, smooth surface, and drug loading is 7.9%-13.3%, and envelop rate is 55.9-69.3%, and a more stable value range of product of the present invention is that drug loading is 10.2%-13.0%, and envelop rate is 63.4%-68.3%.Release, except initial several hours prominent releasing, can continue slowly to discharge more than 200 hours.
Compared with prior art, tool of the present invention has the following advantages:
(1) improved existing generally by the method synthesis of polyurethane Nano microsphere technology of pre-polymerization-chain extension-neutralization-emulsifying, only by the synthetic two block compounds of pre-polymerization-chain extension two steps, retained an active group, make its can be in modified connection of later stage functional group.
(2) the Nano microsphere form that adopts the present invention to prepare is smooth, and size evenly.Change the variation of each factor of preparation condition, can control the variation of Nano microsphere size.By controlling the molecular weight of amphiphilic carrier, can extend the action time of Ka Peitabin.In existing document, due to the difference of carrier, drug loading is not of uniform size.The drug loading that the PLGA of generally take is independent carrier packaging medicine is mostly at 5%-8%, the Nano microsphere drug loading that the PCEC of take is carrier is mostly 6%-12%, the present invention is in the situation that total molecular weight is the mixed carrier of 40,000 left and right, and drug loading is 10.2%-13.0%, and envelop rate is 63.4%-68.3%.
(3) the present invention, in the process of preparation, has also added organosiloxane reagent.Leaving away along with methyl in its hydrolytic process, expose oxygen atom, thereby can form hydrogen bond with the strand of carrier water-wet side, the product deposition of hydrolysis, between hydrophobic chain and hydrophilic chain, form layer of silicon dioxide shell, silicon shell can play shielding action for drug release, greatly the deenergized period of prolong drug.This Nano microsphere is energy sustained release in PBS buffer solution, and except the burst drug release of initial 17h, when 190h, Cumulative release amount is in 49% left and right, and this drug release rate is starkly lower than the drug release rate that there is no the medicament-carrying nano-microsphere of this layer of shielding action system.
Accompanying drawing explanation
Fig. 1 is compou nd synthesis schematic diagram in embodiment 1;
Fig. 2 is the infrared spectrogram that in embodiment 1, polyurethane carrier connects targeted molecular;
Fig. 3 is the schematic diagram of TMOS hydrolysis and the intermolecular formation hydrogen bond of PEG in embodiment 1;
Fig. 4 is that the polyurethane carrier that embodiment 1 is prepared into connects targeted molecular chain schematic diagram;
Fig. 5 is the structural representation of the medicament-carrying nano-microsphere that is prepared into of embodiment 1;
Fig. 6 is Nano microsphere transmission electron microscope picture in embodiment 1;
Fig. 7 is the particle size distribution figure of Nano microsphere in embodiment 1;
Fig. 8 is Nano microsphere transmission electron microscope picture in embodiment 2;
Fig. 9 is the drugs compared release profiles of the prepared PCEC/TMOS NPs of embodiment 2 and PCEC NPs, PEG-PCL NPs.
The specific embodiment
below in conjunction with accompanying drawing, the specific embodiment of the present invention is described further, but embodiments of the present invention are not limited to this.
The present invention further illustrates in conjunction with the embodiments, and wherein degradable hydrophilic compounds is Polyethylene Glycol (PEG), and its molecular weight is 4000g/mol; Degradable hydrophobic compound is polycaprolactone (PCL), and its molecular weight is 4000g/mol; Polyisocyanates is 4,4 '-dicyclohexyl methyl hydride diisocyanate (HMDI), and its relative molecular mass is 262 g/mol; Low molecule chain extender is 2,2-dihydromethyl propionic acid (DMPA); Targeted molecular is folic acid (FA); Antitumor drug is Ka Peitabin (CAP); Organosiloxane is tetramethoxy-silicane (TMOS).
embodiment 1
The antitumor drug Nano microsphere with targeting and slow releasing function that the amphiphilic polyurethane of take is carrier, is characterized in that scheme is specially:
Microemulsion technology is emulsion-solvent evaporation method.
Step 1: prepare amphiphilic polyurethane, comprise the steps:
(1) agitator is being housed, in the there-necked flask of reflux condensing tube and thermometer, is adding 5gPEG and 20mL acetone, after stirring, adding wherein 0.36gHMDI in churned mechanically situation, to be slowly warming up to 80 ℃, stirring 1h, making its mix homogeneously;
(2) by reaction system warming while stirring to 75 ℃, after reaction 1.5h, be cooled to 30 ℃, to it, add 0.20gDMPA.In churned mechanically situation, be warming up to 70 ℃, stir 1h, make its mix homogeneously, then be cooled to 30 ℃.
(3) in churned mechanically situation, be warming up to 70 ℃, stir 0.5h, make its mix homogeneously, then be cooled to 30 ℃, add wherein 5.5gPCL, in churned mechanically situation, be warming up to 80 ℃, stir 2h, obtain polyurethane prepolymer acetone soln, drop to ice absolute ether, get and be deposited in 60 ℃ of vacuum drying 12h, obtain amphiphilic polyurethane PCEC, be i.e. amphiphilic carrier center.
Step 2: amphiphilic polyurethane connects targeted molecular, comprises the following steps:
Get first step product (PCEC) 3g and be dissolved in 20mL tetramethyl sulfoxide, then add 0.036gEDC and 0.02gNHS, under room temperature, react 24h, then add 1.01g end AMT (FA-PEG-NH in this reaction system
2), continue reaction 20 hours, add 50mL distilled water to stir, be cooled to after 25 ℃, under 3500 r/min, centrifugal 10min, gets supernatant, and the 40h that dialyses in distilled water changes a water for every three hours to remove the micromolecule such as DMSO and NHS.Then lyophilization, obtains FA-PCEC.
The compound course of reaction of step 1 and step 2 is as schematic diagram 1, and the infrared test result of its reaction result is as Fig. 2.
In Fig. 2, at 3490 cm
-1for the vibration peak of molecule segment-OH, 2905 cm
-1, 1469 cm
-1with 842 cm
-1all there is the characteristic absorption peak of stretching vibration, bending vibration and the rocking vibration of C-H in place.At 1780 cm
-1there is the stretching vibration absworption peak that a strong vibration peak is C=O.1186 cm
-1with 1089.6 cm
-1for aliphatic ether C-O characteristic peak.The chromatogram characteristic of FA-PCEC and PCEC is roughly the same, just at 1573 cm
-1appearance phenyl ring skeletal vibration, this phenyl ring is on folate molecule, has shown in PCEC connection FA-PEG-NH
2.From FA-PCEC spectrogram, the absworption peak that also can see is as 2140 cm
-1and there is to be similar to FA-PEG-NH in the peak of lower wave number section
2change.Also show FA-PEG-NH
2successfully be connected on PCEC.
Step 3: emulsion-solvent evaporation method is prepared Nano microsphere, comprises the steps:
(1) getting 2g FA-PCEC is solute, is dissolved in 20mL dichloromethane, and being mixed with concentration is the oil phase substrate solution of 100mg/mL, and 0.2g antitumor drug CAP is scattered in to above-mentioned matrix solution, forms oil phase; And be added dropwise to 0.019g tetramethoxy-silicane in described oil phase, stir;
(2) take polyvinyl alcohol as solute, take water as solvent, make the aqueous phase solution that 100mL polyvinyl alcohol mass fraction is 1.0%;
(3) again the oil phase described in (1) step is added drop-wise to the described aqueous phase solution of step (2), this mixed liquor is stirred 12 hours, organic solvent is fully volatilized, then high speed centrifugation is collected the Nano microsphere of gained, get precipitation, adding distil water disperses repeated centrifugation to get the step of precipitation again, until polyvinyl alcohol, by wash clean, finally obtains object product by precipitation lyophilization.Described stirring is 600rpm, and centrifugal speed used is 8000rpm;
In microsphere preparation process, the H bond structure of TMOS hydrolysis and the intermolecular formation of PEG is as accompanying drawing 3.Because of after TMOS hydrolysis, expose oxygen atom, in conjunction with the oxygen atom in hydrogen and PEG molecule, form hydrogen bond, this also stablized in microsphere preparation process, form 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 of preparation;
With laser particle analyzer and transmission electron microscope, resulting Nano microsphere is tested to sign, transmission electron microscope results is referring to Fig. 6, and particle diameter and particle size distribution result are as Fig. 7.From Fig. 6, can clearly observe sample is that regular circle and surface are relatively smooth.But also can see obvious nucleocapsid structure.From Fig. 7, also can see that microspherulite diameter presents normal distribution, and distribution is narrow, shows that the microsphere size of preparation is more consistent, in 200nm left and right, consistent with the result of transmission electron microscope.
embodiment 2
The difference of the present embodiment and embodiment 1 is:
Step 3 is prepared Nano microsphere and by nanometer precipitation-dialysis, is prepared the method for Nano microsphere, comprises the steps:
(1) getting 2g FA-PCEC is solute, is dissolved in 20mL dichloromethane, and being mixed with concentration is the oil phase substrate solution of 100mg/mL, and 0.2g antitumor drug CAP is scattered in to above-mentioned matrix solution, forms oil phase; And be added dropwise to 0.019g tetramethoxy-silicane (TMOS) in described oil phase, stir;
(2) take polyvinyl alcohol as solute, take water as solvent, make the aqueous phase solution that 100mL polyvinyl alcohol mass fraction is 1.0%;
(3) again water step (2) Suo Shu is slowly dropwise added drop-wise to the described oil-phase solution of step (1), with 600rpm, continues to stir 2 hours; In distilled water medium, dialyse again, within every 2 hours, change one time water, dialyse 48 hours; Product lyophilization obtains object product.
(4) whether basis adds TMOS, the present embodiment is prepared two kinds of medicament-carrying nano-microspheres, and a kind of TMOS group that adds is wherein the Nano microsphere of preparation of the present invention, be denoted as PCEC/TMOS NPs, the another kind of Nano microsphere that does not add TMOS and prepare is that contrast groups is denoted as PCEC NPs.The difference of preparation PCEC NPs and PCEC/TMOS NPs is only to prepare in Nano microsphere process and saves and add this step of TMOS.
With laser particle analyzer and transmission electron microscope, resulting Nano microsphere is tested to sign, transmission electron microscope results is shown in that accompanying drawing 8. finds that from figure the particle diameter of the present embodiment Nano microsphere is medium and small compared with embodiment 1, average out to 190nm.
Drug release situation for contrast polyaminoester microball and the autonomous microsphere filling of general amphiphilic compound.By the method for embodiment 2, prepared and take PEG-PCL(molecular weight as 8056g/mol) microsphere prepared of two block compounds.Its concrete steps are:
Getting 2g PEG-PCL is solute, is dissolved in 20mL dichloromethane, and being mixed with concentration is the oil phase substrate solution of 100mg/mL, and 0.2g antitumor drug CAP is scattered in to above-mentioned matrix solution, forms oil phase; And be added dropwise to 0.019g tetramethoxy-silicane in described oil phase, stir; Take polyvinyl alcohol as solute, take water as solvent, make the aqueous phase solution that 100mL polyvinyl alcohol mass fraction is 1.0%; Again water is slowly dropwise added drop-wise to oil-phase solution, with 600rpm, continues to stir 2 hours; In distilled water medium, dialyse again, within every 2 hours, change one time water, dialyse 48 hours; Product lyophilization obtains object product.
Fig. 9 for by the embodiment of the present invention 2, prepare Nano microsphere PCEC/TMOS NPs and Nano microsphere PCEC NPs, and the vitro drug release comparison diagram of common PE G-PCL NPs, therefrom find that PCEC/TMOS medicament-carrying nano-microsphere prepared by the present invention has good sustained drug release effect, without obvious initial stage burst drug release, more than slow-release time reaches 190h.Capecitabine is from PEG-PCL NPs, PCEC NPs, rate of release in PCEC/TMOS NPs is successively decreased successively, capecitabine bag is loaded in NPs hydrophobic core, its release in vitro from NPs is by the structures shape of NPs to a great extent, the polyurethane structural of PCEC is more stable than PEG-PCL, and PCEC/TMOS NPs is than PCEC NPs, many one decks discharge barrier, capecitabine is had to good controlled release ability, therefore its rate of release is minimum, and three kinds of NPs are reaching stable drug release rate through initial stage 10h after prominent releasing.
embodiment 3
The difference of the present embodiment and embodiment 1 is:
The PVA aqueous solution volume of (2) step of the step 3 in embodiment 1 is adjusted into 400mL, and the volume of the surfactant solution of emulsifying is for the second time 20 times of organic solvent volumes.With laser particle analyzer and scanning electron microscope, resulting Nano microsphere is tested to sign, the particle diameter of finding the present embodiment Nano microsphere is medium and small compared with embodiment 1, reason is the increase of water volume, reduced the viscosity of oil phase, be conducive to the dispersion of oil phase in water and form emulsion droplet, the final microspherulite diameter forming is reduced.
embodiment 4
The present embodiment difference from Example 2 is:
The mixing speed of (3) step of the step 3 in embodiment 2 is adjusted into 300rpm.
With laser particle analyzer and ultraviolet spectrophotometer, resulting Nano microsphere is tested to sign, find particle diameter and the particle size distribution of the present embodiment Nano microsphere, drug loading and envelop rate are as shown in table 1.
The present embodiment difference from Example 2 is:
The mixing speed of (3) step of the step 3 in embodiment 2 is adjusted into 400rpm.
With laser particle analyzer and ultraviolet spectrophotometer, resulting Nano microsphere is tested to sign, find particle diameter and the particle size distribution of the present embodiment Nano microsphere, drug loading and envelop rate are as shown in table 1.
embodiment 6
The difference of the present embodiment and embodiment 2 is:
The mixing speed of (3) step of the step 3 in embodiment 2 is adjusted into 500rpm.
With laser particle analyzer and ultraviolet spectrophotometer, resulting Nano microsphere is tested to sign, find particle diameter and the particle size distribution of the present embodiment Nano microsphere, drug loading and envelop rate are as shown in table 1.
As seen from the results in Table 1, along with the increase of mixing speed, the particle diameter of Nano microsphere reduces gradually, and particle size distribution also narrows down to a certain extent simultaneously.And the envelop rate of microsphere and drug loading also decline.Reason is the increase along with mixing speed, and shearing force also increases, and the degree of scatter that causes oil phase liquid to drop in water improves, and makes NPs more easily be separated into less emulsion droplet, but because stir acutely, has caused the leakage of medicine, therefore envelop rate and drug loading significantly reduce.
The targeting research of relevant nanometer formulation that had a large amount of bibliographical informations, wherein confirmed particle diameter 250nm with interior nanometer formulation due to the EPR effect of tumor tissues can passive target in tumor tissues, and reduced the lethal effect of normal tissue.As polymer medicament carrying micelle, elaioplast nanometer particle etc. can pass in and out very smoothly tumor tissue cell in the internal recycle of human body, and then must be controlled at small diameter in tumor tissues accumulation.And envelop rate and drug loading are the important indicators of evaluating nanometer formulation quality, envelop rate is larger, and drug loss is fewer, and drug loading is larger, more easily meets the demand of clinical application, and comprehensive the above results can be found out, selects mixing speed 500rpm relatively suitable.
Table 1
| Rotating speed (rpm) | Particle diameter (nm) | Particle size distribution index | Drug loading (%) | 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 (8)
1. take the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier for one kind, it is characterized in that, described Nano microsphere has bivalve layer nucleocapsid structure, its center is formed by the hydrophobic section of amphiphilic polyurethane, antitumor drug is wrapped in core, shell is formed by the hydrophilic section of amphiphilic polyurethane, the targeted molecular connecting on amphiphilic polyurethane strand is exposed to Nano microsphere shell surface after microsphere forms, another shell of described Nano microsphere is formed by organosiloxane hydrolysis, by amphiphilic polyurethane between formed shell and core, wherein said antitumor drug is capecitabine, amycin or paclitaxel, described targeted molecular is folic acid, described organosiloxane is tetramethoxy-silicane.
2. a kind of preparation method of take the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier claimed in claim 1, is characterized in that, described preparation method comprises following three steps:
(1) take hydrophilic compounds and the hydrophobic compound with good biocompatibility is raw material, and polyisocyanates becomes long-chain by pre-polymerization-chain extension by hydrophilic and hydrophobic compound combination with low molecule chain extender, forms amphiphilic carrier center;
(2) carrier center is connected to targeted molecular;
(3) utilize microemulsion technology that the carrier center parcel antitumor drug that is connected with targeted molecular is prepared to a kind of medicament nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier of take.
3. a kind of preparation method of take the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier according to claim 2, is characterized in that, described hydrophilic compounds is Polyethylene Glycol; Described hydrophobic compound is PLGA, polylactic acid or polycaprolactone; Described polyisocyanates is Toluene-2,4-diisocyanate, 4-vulcabond, 1B ethyl ester vulcabond or 4,4 '-dicyclohexyl methyl hydride diisocyanate; Described low molecule chain extender is 2,2-dihydromethyl propionic acid.
4. a kind of preparation method of take the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier according to claim 2, it is characterized in that, the described microemulsion technology of step (3) is emulsion-solvent evaporation method or nanometer precipitation-dialysis.
5. a kind of preparation method of take the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier according to claim 2, it is characterized in that, the concrete preparation process of step (1) is as follows: the acetone soln of hydrophilic compounds and excessive polyisocyanates are mixed, wherein the molar concentration of hydrophilic compounds in acetone is 0.01-0.3mol/L, the amount of substance of polyisocyanates is 1-1.2 times of hydrophilic compounds, by reaction system warming while stirring to 70-80 ℃, after reaction 1.5-2h, be cooled to 25-40 ℃, to it, add chain extender, chain extender is 1.0-1.1:1 with the ratio of hydrophilic compounds amount of substance, under the condition stirring, be warming up to 60-80 ℃, stir 0.5-1h, make its mix homogeneously, be cooled to again 25-40 ℃, add wherein hydrophobic compound, the amount of substance of hydrophobic compound is 1.1-1.3 times of hydrophilic compounds amount of substance, it is the acetone soln of 0.011-0.39mol/L, under churned mechanically condition, be warming up to 77-85 ℃, stir 1-2h, obtain polyurethane prepolymer acetone soln, drop to ice absolute ether, get and be deposited in 60-70 ℃ of vacuum drying 12-24h, obtain amphiphilic polyurethane PCEC, it is amphiphilic carrier center.
6. a kind of preparation method of take the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier according to claim 2, it is characterized in that, the described carrier center of step (2) connects targeted molecular, concrete grammar comprises the following steps: get step (1) product PCEC 2-5g and be dissolved in 20-30mL tetramethyl sulfoxide (DMSO), then the N-maloyl imines (NHS) that adds 0.02-0.08g 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and 0.01-0.1g, under room temperature, react 12-24h, add end AMT (FA-PEG-NH
2), wherein amount of substance compares PCEC:FA-PEG-NH
2for 1:1-1:1.2, continue reaction 12-24h, add 50-100 mL distilled water to stir, be cooled to after room temperature, under 3500-5000rpm rotating speed, centrifugal 5-10min, gets supernatant, and 36-48h is to dialyse in distilled water, every 2-4h, change water one time, postlyophilization, obtains FA-PCEC.
7. a kind of preparation method of take the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier according to claim 4, is characterized in that, described emulsion-solvent evaporation method, specifically comprises the steps:
1) take FA-PCEC as solute, take dichloromethane or oxolane or acetone as solvent, being mixed with concentration is the oil phase substrate solution of 10-200mg/mL, antitumor drug is scattered in to above-mentioned matrix solution and forms oil phase; To adding tetramethoxy-silicane in described oil phase, under the rotating speed of 300-500rpm, stir 15-30min and make its mix homogeneously again, obtain solution A; The quality of wherein said medicine is the 5%-20% of FA-PCEC, and the 1.0-1.2 that the amount of substance of described tetramethoxy-silicane is FA-PCEC doubly;
2) take polyvinyl alcohol as solute, take water as solvent, make the aqueous phase solution that polyvinyl alcohol mass fraction is 0.5%-1.0%, ie in solution B;
3) again the solution A described in step 1) is added drop-wise to step 2) described solution B, the volume of water is 5-20 times of oil phase, stir 8-12 hour, then high speed centrifugation is collected the Nano microsphere of gained, get precipitation, adding distil water disperses, then repeated centrifugation is got the step of precipitation, until polyvinyl alcohol, by wash clean, finally obtains object product by precipitation lyophilization; Described stirring is 500-1000rpm, centrifugal speed 8000-10000rpm used.
8. a kind of preparation method of take the antitumor drug Nano microsphere with targeting and slow releasing function that amphiphilic polyurethane is carrier according to claim 4, is characterized in that, described nanometer precipitation-dialysis, specifically comprises the steps:
1) take FA-PCEC as solute, take dichloromethane, oxolane or acetone as solvent, being mixed with concentration is the oil phase substrate solution of 10-200mg/mL, and antitumor drug is scattered in to above-mentioned matrix solution, forms oil phase; And to adding tetramethoxy-silicane in described oil phase, stir, obtain solution A; The quality of wherein said antitumor drug is the 5%-20% of FA-PCEC, and the 1.0-1.2 that the amount of substance of described tetramethoxy-silicane is FA-PCEC doubly;
2) take polyvinyl alcohol as solute, take water as solvent, make the aqueous phase solution that polyvinyl alcohol mass fraction is 0.5%-1.0%, ie in solution B;
3) again by step 2) described aqueous phase B is dropwise added drop-wise to the oil-phase solution A described in step 1), the volume of water be oil phase 2-10 doubly; With 300-600rpm, continue to stir 2 hours; In distilled water medium, dialyse, every 2-4 hour changes water one time again, dialysis 36-48 hour; Product lyophilization obtains object product.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106667911A (en) * | 2017-01-25 | 2017-05-17 | 东华大学 | Amphiphilic polyurethane self-assembly nanoparticles and preparation and application thereof |
| CN106860429A (en) * | 2017-02-27 | 2017-06-20 | 上海宁竹新材料科技有限公司 | A kind of nano drug-carrying transhipment material based on polyurethane and containing amino active material and preparation method thereof |
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| CN108472120A (en) * | 2015-11-30 | 2018-08-31 | 阿莱奥Bme公司 | Polymer material for biomedical applications |
| CN109999009A (en) * | 2019-03-14 | 2019-07-12 | 重庆医药高等专科学校 | A kind of anti-tumor drug oral slow-releasing preparation and preparation method thereof |
| CN110023407A (en) * | 2016-09-20 | 2019-07-16 | 康奈尔大学 | Poly- (the esteramides carbamate) of label, the nanoparticle formed by it and its purposes |
| CN113230037A (en) * | 2021-04-15 | 2021-08-10 | 杭州千岛湖天鑫有限公司 | Camellia oil slow-release diaper |
| CN113230036A (en) * | 2021-04-15 | 2021-08-10 | 杭州千岛湖天鑫有限公司 | Sea-buckthorn oil slow-release diaper |
| WO2022081795A3 (en) * | 2020-10-14 | 2022-06-02 | University Of Maryland, Baltimore County | On demand and long-term drug delivery from degradable nanocapsules |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103055322A (en) * | 2012-12-20 | 2013-04-24 | 华南理工大学 | Targeted sustained release medicine carrying nanoparticle and preparation method thereof |
-
2014
- 2014-01-10 CN CN201410013388.9A patent/CN103751148B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103055322A (en) * | 2012-12-20 | 2013-04-24 | 华南理工大学 | Targeted sustained release medicine carrying nanoparticle and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 徐静: "聚氨酯的合成及其与壳聚糖的复合研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 石淑先: "《生物材料制备与加工》", 31 August 2009, article "聚氨酯弹性体的一般制备方法", pages: 110 * |
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