CN106511297A - Adriamycin nanoparticle with particle size controllable and preparation method thereof - Google Patents
Adriamycin nanoparticle with particle size controllable and preparation method thereof Download PDFInfo
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Abstract
The invention provides an adriamycin nanoparticle with the particle size controllable. The adriamycin nanoparticle is formed by taking polyethylene glycol vitamin E succinate (TPGS) as a core and wrapping the core with polyethylene glycol-adriamycin and poly(isobutene-alt-maleic anhydride)-modified beta-cyclodextrin through self-assembly. The invention further provides a preparation method of the adriamycin nanoparticle. Compared with a traditional nanoparticle prepared through a chemical bond forming and rupturing method, the adriamycin nanoparticle is controllable in particle size, simple in preparation process, mild in reaction condition and capable of easily obtaining the raw materials and has the good biological safety and tissue compatibility.
Description
Technical field
The present invention relates to the preparation of nano particle and biologic applications field, and in particular to a kind of adriamycin of size tunable is received
Rice grain and preparation method thereof.
Background technology
For a long time, researcher be devoted to always study a kind of organic polymer nanometer that can prepare size tunable
The method of particle.In in the past few decades, numerous studies are made that in the application aspect of the biology and pharmaceutical field of nano particle,
And there are several different types of nano particles to obtain different field, different degrees of application.For example, modify corresponding tool
There are gold nano grain, the superparamagnetic nanoparticle of the molecule of targeting, can be used to show interior tumor cell；Drug molecule is repaiied
Adorn on nano-particle, antineoplastic can be made slowly to discharge in lesions position by certain transporting mechanism, this can be big
The big side effect for reducing cancer therapy drug, while extending drug treating time, improves drugs against tumor effect；Additionally, nano particle
Iconography is applied also for, for Real-time and Dynamic Detection such as MRI, PET etc..
However, the synthesis of nano particle with still face problems using upper, for example, the size and form of nano particle
Wayward, biological safety is low and immunogenicity is strong, and human recycle system stablizes bad, and then is difficult smoothly to reach focus,
The problems such as not degradable in vivo.
The content of the invention
For overcoming technological deficiency present in prior art, an object of the present invention be to provide a kind of size tunable Ah
Mycin nano particle.
It is a further object of the present invention to provide the preparation method of the adriamycin nano particle.
The present invention provide size tunable adriamycin nano particle with TPGS as kernel,
Wrapped up in described by self assembly by polyethylene glycol-adriamycin beta-schardinger dextrin modified with poly- (isobutene-alt- maleic anhydrides)
Karyomorphism into.
Specifically, the adriamycin nano particle of size tunable of the invention includes outer layer, intermediate layer and kernel, its
In, kernel is TPGS (TPGS), and intermediate layer is that poly- (isobutene-alt- maleic anhydrides) is modified
Beta-schardinger dextrin (p (IB-alt-MAnh)-CD), which plays function served as bridge in the assembling of nano particle, and adriamycin can be by super
Molecular action is embedded in the hydrophobic internal cavities of cyclodextrin, and the hydrophobic segment in poly- (isobutene-alt- maleic anhydrides) then can be with
Interior nuclear interaction, plays a part of to connect kernel and outer layer.Outer layer is then polyethylene glycol-adriamycin (mPEG-DOX), and which is tied
Structure is as follows：
During host-guest molecular self-assembling, using hydrophobicity and the benzene ring structure of adriamycin of cyclodextrin inner chamber
Interact, adriamycin end is embedded in the inner chamber of cyclodextrin, the polyethylene glycol end for connecting adriamycin forms hydrophilic outer layer.
In the adriamycin nano particle that the present invention is provided, polyethylene glycol tocopheryl succinate can be adjusted according to the requirement of particle diameter
The consumption of acid esters.In embodiments of the present invention, the quality of the TPGS kernel is described poly-
0.05～20 times of ethylene glycol-adriamycin beta-schardinger dextrin gross mass modified with poly- (isobutene-alt- maleic anhydrides)；Preferably
0.1～10 times；More preferably 0.2～5 times.
In the adriamycin nano particle that the present invention is provided, kernel can also include other active components, especially can be with Ah mould
Element combination increases the antineoplastic of antitumor activity.In a preferred embodiment of the present invention, also contain in the kernel
There is paclitaxel nano crystal, taxol can produce synergistic function with adriamycin combination, thus can greatly improve nano particle
Antitumor activity, the size of paclitaxel nano crystal can be adjusted by adjusting the consumption of taxol, and then also be can adjust and received
Rice grain particle size；And, the structure of taxol also can preferably with poly- (isobutene-alt- maleic anhydrides) in ethylene linkage end
With reference to so as to form more stable nano particle.
In the adriamycin nano particle that the present invention is provided, poly- (isobutene-alt- maleic anhydrides) modified β-ring paste
Essence is poly- (isobutene-alt- maleic anhydrides) and hexamethylene diamine-beta-schardinger dextrin as obtained by coupling reaction.Its preparation process is in EDC/
Under NHS effects, can carry out in DMSO equal solvents, the pH value for adjusting reaction system is 8.0～9.0, is stirred at room temperature 48～72
Hour, reaction terminate after with phosphate buffer dialysis (pH8.0～9.0) 36～48 hours, obtain final product after freeze-drying, and in low
Temperature is preserved.
In the adriamycin nano particle that the present invention is provided, the mean molecule quantity of poly- (isobutene-alt- maleic anhydrides)
Can be 5000～10000.
In the adriamycin nano particle that the present invention is provided, in the polyethylene glycol-adriamycin, the polymerization degree n of polyethylene glycol can
Think 45～450, molecular weight can be 2000～20000.
The preparation of polyethylene glycol-adriamycin can be using existing method, also can be such as procedure below：By mPEG- hydrazides and Ah mould
Element is dissolved in anhydrous polar solvent, adds excess of triethylamine, and room temperature, lucifuge, 48～72h of stirring make which react complete, pure
Change.MPEG- hydrazides can be 1 with the mol ratio of adriamycin:0.2～5, preferably 1:1.5～2.0.Can use in course of reaction
NaOH solution etc. adjusts the pH value of reaction system so as to be maintained at 8.0～10.0, preferably 8.5～9.0.
In the adriamycin nano particle that the present invention is provided, can also include the one kind or many in surfactant, emulsifying agent
Kind, kernel can be partly or entirely substituted for TPGS (TPGS).For example, can be surfactant
IGEPAL CO-520, emulsifying agent PluronicF 127 etc..
The preparation method of the adriamycin nano particle that the present invention is provided, comprises the following steps：
S1：Will be polyethylene glycol-adriamycin modified with poly- (isobutene-alt- maleic anhydrides) beta-schardinger dextrin soluble in water super
Self assembly is carried out under the conditions of sound, and freeze-drying obtains supramolecular complex；
S2：TPGS and optional paclitaxel nano crystal are dissolved in absolute ethyl alcohol and are made
Obtain emulsion；
S3：Will be the supramolecular complex obtained by step S1 soluble in water, then emulsion obtained by step S2 is added thereto,
Absolute ethyl alcohol is volatilized, centrifugation after 0.45 μm of membrane filtration obtains final product the adriamycin nano particle.
In above-mentioned preparation method, in the emulsion obtained by step S2, TPGS and optional
Paclitaxel nano Crystallization nano-micelle form.
In above-mentioned preparation method, the polyethylene glycol-adriamycin is modified with poly- (isobutene-alt- maleic anhydrides)
The mass ratio of beta-schardinger dextrin is 1:50～60.
In above-mentioned preparation method, in step S1, by polyethylene glycol-adriamycin and poly- (isobutene-alt- maleic acids
Acid anhydride) modified beta-schardinger dextrin is soluble in water, and it is 8.0～9.0 to adjust pH value, carries out self assembly.
The adriamycin nano particle that the present invention is provided make use of host-guests of the p (IB-alt-MAnh) and between mPEG-DOX certainly
Assembling reaction forms nano particle, and in mPEG-DOX molecules, hydrazone key has acid-sensitive, and under sour environment, mPEG-DOX is discharged
Doxorubicin molecules, and under organism physiological environment (pH7.35～7.45), mPEG-DOX will not occur hydrolysis, will not discharge Ah
Mycin molecule.On the other hand, the adriamycin nano particle that the present invention is provided adds the molecule TPGS with surface-active, together
When wrap up hydrophobic antitumor drug paclitaxel (PTX), adjust the adjustable nano particle size of taxol consumption.TPGS with
PTX constitutes hydrophobic inner core, contributes to transport of the hydrophobic drug taxol in body, and the less nano particle of size is more easy to
Into inside tumor tissues.After the adriamycin nano particle that the present invention is provided is reached in tumor tissues, mPEG-DOX generations point
Solution, DOX, PTX are released, and the two drug combination, with synergy, can significantly improve antitumor activity, the targeting of medicine
Property is higher, and therapeutic effect is greatly enhanced.
Different from traditional nano particle prepared with the method for rupturing by the formation of chemical bond, the nanometer of the present invention
Grain preparation process is simple, and reaction condition is gentle, and raw material is easily obtained, using the nano particle of the final gained of ultrasonic power assembling,
Also granular size is can adjust by changing ultrasound condition.The nano particle of the present invention has good biological safety and tissue phase
Capacitive, prepares nano particle using the host-guest self-assembling reaction between supermolecule, can modify the anti-of adriamycin even multiple combination
Cancer drug, to play the synergy of antineoplastic, greatly enhances curative effect of medication.Additionally, nano particle prepared by the present invention
With acid-sensitive, the release of medicine is more conducive in the sour environment of tumor tissues.On the other hand, by the use of regulation TPGS
Amount, can make the nano particle to be formed in organism with the particle diameter of conveniently regulating and controlling nano particle while a nanometer bridge effect can also be played
There is under physiological environment good stability.
Description of the drawings
Fig. 1 is p (IB-alt-MAnh)-CD obtained in the embodiment of the present invention1H-NMR schemes.
Fig. 2 is p (IB-alt-MAnh)-CD to breast cancer cell MCF-7 cell lines and adriamycin breast carcinoma cell strain
The Toxic test results chart of MCF-7/ADR cells.
Fig. 3 is mPEG-DOX obtained in the embodiment of the present invention1H-NMR schemes.
The nano particle diameter point that Fig. 4 A-4C are measured for DLS under the conditions of paclitaxel concentrations different in the embodiment of the present invention
Butut and transmission electron microscope results；Wherein, Fig. 4 A represent PTX concentration be 0.5mg/ml when obtained by nano particle diameter distribution map and its
Transmission electron microscope, nano particle diameter distribution map and its transmission electron microscope obtained by when Fig. 4 B represent that PTX concentration is 1mg/ml, Fig. 4 C are represented
Nano particle diameter distribution map and its transmission electron microscope obtained by when PTX concentration is 2mg/ml.
FT-IR collection of illustrative plates of the Fig. 5 for nano particle obtained in the embodiment of the present invention.
Specific embodiment
Below by embodiment, the present invention is described in detail, so that the features and advantages of the present invention become apparent from.But should
This points out that embodiment is used for understanding the design of the present invention that the scope of the present invention to be not limited only to reality listed herein
Apply example.
Such as it is not particularly illustrated, the raw material used by embodiment is commercially available prod, the operation that used is this area
Routine operation.
The preparation of the adriamycin nano particle of embodiment size tunable
The preparation of the 1st, poly- (isobutene-alt- maleic anhydrides) modified beta-schardinger dextrin (p (IB-alt-MAnh)-CD)
(1) by poly- (isobutene-alt- maleic anhydrides), (p (IB-alt-MAnh), Mn (0.5K-1K) are dissolved in DMSO, dense
Spend for 5-15mg/ml；
(2) add 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride mol ratio 2-3 times maleic anhydride
Repeat chain number；
(3) adjust the pH to 8.0-9.0 of resulting solution；
(4) N- hydroxysuccinimides (NHS) (EDC is added in 10-20min:NHS mol ratio=1:1)；
(5) hexamethylene diamine-beta-schardinger dextrin is dissolved in DMSO (concentration is 0.01-0.1mg/ml), magnetic agitation, obtains oneself two
Amine-beta-schardinger dextrin solution；
(6) 15-20min after step (4) adds NHS, by the solution containing p (IB-alt-MAnh) of gained with 60-80
The speed of drop/minute is added in the hexamethylene diamine-beta-schardinger dextrin solution of step (5), while being stirred vigorously, 48-72 is stirred at room temperature
Hour；
(7) solution obtained by step (6) is carried out into phosphate buffer dialysis (pH 8.0-9.0) 36-48 hours,
(8) freeze-drying obtains white powder solid, is placed in -20 DEG C of preservations.
Shown in the following schema of the course of reaction：
Product p (IB-alt-MAnh)-CD is dissolved in deuterium oxide to be done1H-NMR, as a result as shown in Figure 1.
For further exploring the biocompatibility of the material, it is human breast carcinoma cell lines MCF-7 and MCF- from cell
7ADR cells tested (with reference to [1] R.Namgung, Y.Mi Lee, J.Kim, Y.Jang, B.Lee, I.Kim, P.Sokkar,
Y.M.Rhee,A.S.Hoffman,W.J.Kim,Poly-cyclodextrin and poly-paclitaxel nano-
assembly for anticancer therapy.Nature Communications 5(2014).[2]X.Xu,X.Chen,
Z.Wang,X.Jing,Ultrafine PEG–PLA fibers loaded with both paclitaxel and
doxorubicin hydrochloride and their in vitro cytotoxicity.Eur J Pharm
72 (1) (2009) 18-25. of Biopharm), as a result as shown in Fig. 2 abscissa represents that p (IB-alt-MAnh)-CD's is dense in figure
Degree, ordinate represent the cytoactive to clone.
2nd, the preparation of compound mPEG-DOX
(1) ADMh is dissolved in in dimethyl sulfoxide (DMSO) (concentration is 1-100mg/ml), magnetic agitation；
(2) appropriate triethylamine is added, is 1.5 times of equivalents of ADMh；
(3) NaOH solution is added to adjust pH value of solution to alkaline (pH=8.5-9.0)；
(4) mPEG-HZ (Mw=2000-20000), room temperature, lucifuge, magnetic agitation 72h are added；
(5) a large amount of ether are added to be precipitated (10-15 times of liquor capacity)；
(6) it is vacuum dried, obtains mPEG-DOX red powders, be placed in -20 DEG C of preservations.
The course of reaction shows following schema：
Product mPEG-DOX with deuterated dimethyl sulfoxide as solvent,1H-NMR results are as shown in Figure 3.
3rd, the preparation of p (IB-alt-MAnh)-CD/mPEG-DOX nano particles
(1) by p (IB-alt-MAnh) (10mg), mPEG-DOX (0.2mg) is dissolved in deionized water 2ml；
(2) pH to 8.0-9.0, room temperature, lucifuge, ultrasound, 60～100W, 20K HZ are adjusted；
(3) freeze-drying, obtains powder-like solid；
(4) pressed powder after will be lyophilized, is dissolved in deionized water, and concentration is 3mg/ml；
(5) ultrasound, 60～100W, 20K HZ, 10-20min are labeled as A；
(6) by Paclitaxel (PTX) (respectively 1mg/ml, 2mg/ml, 5mg/ml), vitamin E polyethylene glycol amber
Acid esters (TPGS) (mass ratio TPGS:PTX=2：1) absolute ethyl alcohol is dissolved in, is sufficiently stirred for, be labeled as B；
(7) B is added dropwise in A (1.0-1.5ml/min) by micro-injection pump, while being stirred vigorously, is surpassed after being added completely into
Sound 60-100W, 20K HZ 10-20min；
(8) room temperature, lucifuge, magnetic agitation 24h make absolute ethyl alcohol volatilize completely；
(9) 0.45 μm of membrane filtrations；
(10) 14000rpm, 10-15min are centrifuged；
(11) supernatant is removed, precipitates resuspended, ultrasonic (100W, 15min).
Survey dynamic light scattering (Malvern ZS90), as a result as shown in figs. 4 a-4 c, represent respectively PTX concentration be 1mg/ml,
Under the conditions of 2mg/ml, 5mg/ml, dynamic light scattering measures nano particle diameter size, receives obtained by when PTX concentration is 0.5mg/ml
Rice grain average grain diameter be 88.7 ± 4.5nm, PTX concentration be 1mg/ml when obtained by nano particle average grain diameter be 136.5 ±
The average grain of nano particle obtained by when 6.1nm, PTX concentration is 2mg/ml is 214.5 ± 7.4nm；Phosphotungstic acid is dyeed, transmission electron microscope inspection
Survey nano particle form.Additionally, the FT-IR results of Fig. 5 contain p (IB-alt-MAnh)-CD, mPEG- in showing nano particle
HZ、TPGS、PTX。
From embodiment, the nano particle of the present invention can control the particle diameter of nano particle by the amount of kernel taxol,
Thus its size tunable is made, so as to be conducive to strengthening the stability of nano particle.
Unless limited otherwise, term used herein is the implication that those skilled in the art are generally understood that.
Embodiment described in the invention is merely for exemplary purpose, and is not used to limit the scope of the invention,
Those skilled in the art can be made within the scope of the invention various other replacements, changes and improvements, thus, the invention is not restricted to
Above-mentioned embodiment, and be only defined by the claims.
Claims (10)
1. the adriamycin nano particle of a kind of size tunable, it is characterised in that with TPGS as interior
Core, it is described by self assembly parcel by polyethylene glycol-adriamycin beta-schardinger dextrin modified with poly- (isobutene-alt- maleic anhydrides)
Kernel is formed.
2. adriamycin nano particle according to claim 1, it is characterised in that the polyethylene glycol VE succinic acid
The quality of ester kernel is the polyethylene glycol-adriamycin beta-schardinger dextrin total matter modified with poly- (isobutene-alt- maleic anhydrides)
0.05～20 times of amount；Preferably 0.1～10 times；More preferably 0.2～5 times.
3. adriamycin nano particle according to claim 1, it is characterised in that also include antineoplastic in the kernel
Thing, preferably paclitaxel nano crystal.
4. adriamycin nano particle according to claim 1, it is characterised in that the poly- (isobutene-alt- maleic acids
Acid anhydride) modified beta-schardinger dextrin be poly- (isobutene-alt- maleic anhydrides) with hexamethylene diamine-beta-schardinger dextrin as obtained by coupling reaction.
5. adriamycin nano particle according to claim 4, it is characterised in that the poly- (isobutene-alt- maleic acids
Acid anhydride) mean molecule quantity 5000～10000.
6. adriamycin nano particle according to claim 1, it is characterised in that poly- second in the polyethylene glycol-adriamycin
The degree of polymerization of glycol is 45～450.
7. the adriamycin nano particle according to any one of claim 1-6, it is characterised in that the adriamycin nano particle
Also include one or more in surfactant, emulsifying agent.
8. the preparation method of adriamycin nano particle described in any one of claim 1-7, it is characterised in that comprise the following steps：
S1：By it is polyethylene glycol-adriamycin modified with poly- (isobutene-alt- maleic anhydrides) beta-schardinger dextrin soluble in water carry out from
Assembling, freeze-drying obtain supramolecular complex；
S2：TPGS and optional paclitaxel crystal are dissolved in absolute ethyl alcohol emulsion is obtained；
S3：Will be the supramolecular complex obtained by step S1 soluble in water, then emulsion obtained by step S2 is added thereto, surpass
Sound, volatilizes absolute ethyl alcohol, and centrifugation after 0.45 μm of membrane filtration obtains final product the adriamycin nano particle.
9. preparation method according to claim 8, it is characterised in that the polyethylene glycol-adriamycin and the poly- (isobutyl
Alkene-alt- maleic anhydrides) mass ratio of modified beta-schardinger dextrin is 1:50～60.
10. preparation method according to claim 8, it is characterised in that in step S1, by polyethylene glycol-adriamycin
The beta-schardinger dextrin modified with poly- (isobutene-alt- maleic anhydrides) is soluble in water, and it is 8.0～9.0 to adjust pH value, is carried out from group
Dress.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107551276A (en) * | 2017-10-23 | 2018-01-09 | 锡山区东港全宝机械经营部 | Antineoplastic carries adriamycin α cyclodextrin pressurization vibrations parcel preparation technology |
| CN115960834A (en) * | 2023-03-07 | 2023-04-14 | 浙江省肿瘤医院 | Method for establishing PD-1/PTX combined PD-1 drug resistance model |
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| CN103976950A (en) * | 2014-05-21 | 2014-08-13 | 华中科技大学 | Adriamycin nano drug delivery system as well as preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107551276A (en) * | 2017-10-23 | 2018-01-09 | 锡山区东港全宝机械经营部 | Antineoplastic carries adriamycin α cyclodextrin pressurization vibrations parcel preparation technology |
| CN115960834A (en) * | 2023-03-07 | 2023-04-14 | 浙江省肿瘤医院 | Method for establishing PD-1/PTX combined PD-1 drug resistance model |
| CN115960834B (en) * | 2023-03-07 | 2023-06-09 | 浙江省肿瘤医院 | PD-1/PTX combined PD-1 drug resistance model establishment method |
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