CN109438707A - A kind of poly- dithiothreitol (DTT) nanometer system and its preparation method and application for anti-tumor drug delivering - Google Patents
A kind of poly- dithiothreitol (DTT) nanometer system and its preparation method and application for anti-tumor drug delivering Download PDFInfo
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- CN109438707A CN109438707A CN201810997265.1A CN201810997265A CN109438707A CN 109438707 A CN109438707 A CN 109438707A CN 201810997265 A CN201810997265 A CN 201810997265A CN 109438707 A CN109438707 A CN 109438707A
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- dtt
- dithiothreitol
- drug
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
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Abstract
The medicament-carried nano system and its preparation method and application based on poly- dithiothreitol (DTT) that the invention discloses a kind of.The present invention prepares the controllable poly- dithiothreitol (DTT) of the novel polymer containing disulfide bond of the Nomenclature Composition and Structure of Complexes, successfully constructs the nano-carrier of anti-tumor drug targeted delivery；And different anti-tumor drugs is grafted on the hydroxyl on poly- dithiothreitol (DTT), then by nanoparticles preparation processes such as mon-galacta method, nanoprecipitation methods, form uniform particle diameter and stable nanoparticle solution.Property is stablized after the poly- dithiothreitol (DTT) grafting drug of novel polymer of the invention, there are good biocompatibility and degradability, and there is GSH quickly to restore responsiveness, improve the targeted delivery efficiency of nano-carrier, realize positioning controlled release of the drug in tumour cell, the bioavilability for improving dewatering medicament has a good application prospect and wide development space in field of medicaments.
Description
Technical field
The invention belongs to functional polymer materials and biomedicine technical field.More particularly, to one kind for anti-swollen
The poly- dithiothreitol (DTT) nanometer system and its preparation method and application of tumor medicine delivering.
Background technique
Malignant tumour has become one of the principal disease for threatening human life health.Although clinically having more than more than 90 kinds to resist
Tumour medicine, but most anti-tumor drugs are there are poorly water-soluble, controlled-release effect is poor, targeting is poor and it is strong to promote tumour to generate
The disadvantages of strong drug resistance.Meanwhile these drug normal tissues and organ can also bring serious toxic side effect, reduce human body and exempt from
Epidemic disease power.
Stimulating responsive polymer system because can be responded to external environments such as temperature, illumination, enzyme, pH, by
It is widely used in Nano medication field.Wherein reduction response controlled release method is reported by many researchers, is mainly used for target
Preparation to the controlled drug delivery systems of tumour cell.Reduction responsiveness generally refers to that will there is the group of reduction-sensitive to be introduced into
In high molecular polymer, using the reduction of high concentration glutathione in tumour cell, by drug system these are specific
Group such as disulfide bonds, to release medicine intracellular.Glutathione is free radical scavenger important in vivo and resists
Oxidant, studies have shown that concentration of the glutathione in body fluid and extracellular matrix is 2~20 μM, intracytoplasmic concentration is 2
~10mM, and the glutathione concentrations in tumour cell are at least 4 times of normal cell.The change of this special concentration gradient
Change, the delivery system containing disulfide bond is allowed to show broad application prospect in field of biomedicine in recent years.
Traditional chemotherapy and targeted therapy is the important and strong means of current clinical cancer therapy, but in therapeutic process
In, since the specificity of drug is lower, water-soluble low, toxicity is high, and causing also can be inevitable while killing cancer cell
Damaging action is generated to organism normal cell, to influence the function of body health organ.For example, camptothecine be 1966 by
The anticancer drug that M.E.Wall and M.C.Wani are screened is a kind of quinoline alkaloid.Since camptothecine water solubility is lower,
It is difficult to prepare comparatively ideal preparation.Currently, camptothecine for nanometer medicine-carried system method there are mainly two types of: physics carries medicine and change
It learns and carries medicine.The former is by liposome, and micella etc. contains camptothecine using physical absorption, and the latter is then by chemical bond by camplotheca acuminata
Alkali grafts on carrier.Many studies have shown that the stability of its lactonic ring can be increased by the grafting of position 20 of camptothecins hydroxyl, change
Become hydrophilicity and hydrophobicity.Most commonly camptothecine is grafted on the polyethylene glycol of 3kDa to 40kDa and forms polyethyleneglycol prodrug.
Camptothecine is connected to the both ends for the polyethylene glycol that molecular weight is 4000, at present by the Prothecan that Enzon company is developed
Through entering III clinical investigation phase.In addition to this, the macromolecular carrier for camptothecine grafting is there are also L-glutamic acid (PGA),
Polysaccharide and some synthesis macromolecules.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the defect of the above-mentioned prior art and deficiencies, provide a kind of for anti-swollen
The poly- dithiothreitol (DTT) nanometer system of tumor medicine delivering.The present invention quickly and is easily prepared into using dithiothreitol (DTT) as monomer
To the poly- dithiothreitol (DTT) with good biocompatibility；With poly- dithiothreitol (DTT) grafted hydrophobic anti-tumor drug to shape
At anti-tumor drug delivery system, realize the controllable load medicine of dewatering medicament, improve the dissolubility of drug, greatly improve
The utilizability of dewatering medicament, and there is GSH quickly to restore responsiveness, improve the targeting of anti-tumor drug.
The first purpose of the invention is to provide a kind of polymer P DTT.
A second object of the present invention is to provide the preparation methods of above-mentioned polymer P DTT.
Third object of the present invention is to provide above-mentioned polymer P DTT as or in terms of preparing drug carrier system
Using.
Fourth object of the present invention is to provide a kind of poly- two sulphur threose for drug delivery with reduction responsiveness
Alcohol nanometer system.
Fifth object of the present invention is to provide the preparation methods of above-mentioned poly- dithiothreitol (DTT) nanometer system.
Sixth object of the present invention is to provide the poly- dithiothreitol (DTT) nanometer systems of above-mentioned polymer P DTT or above-mentioned to make
Application in standby anticancer drug.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of polymer P DTT, the polymer P DTT for drug delivery is by multiple duplicate dithiothreitol (DTT) structures
Unit composition, shown in structural formula such as following formula (I):
Wherein, n=5~10000.
Preferably, the molecular weight of the polymer P DTT is 1500~45000.
The present invention prepares the controllable poly- dithiothreitol (DTT) of the novel polymer containing disulfide bond (PDT T) of the Nomenclature Composition and Structure of Complexes, at
Function constructs the nano-carrier of anti-tumor drug targeted delivery；And different anti-tumor drugs is grafted to poly- dithiothreitol (DTT)
(PDTT) on the hydroxyl on (PDTT-CPT), then by nanoparticles preparation processes such as mon-galacta method, nanoprecipitation methods, partial size is formed
Uniform and stable nanoparticle solution, or orally available sustained-release preparation or injectable can also be prepared by other formulation methods
The pharmaceutical carriers such as type hydrogel.
Property is stablized after novel polymer of the invention poly- dithiothreitol (DTT) grafting drug, has good biocompatibility and can
Degradability, and there is GSH quickly to restore responsiveness, the targeted delivery efficiency of nano-carrier is improved, realizes drug in tumour
Intracellular positioning controlled release, improves the bioavilability of dewatering medicament, for disease it is effective treatment opened up it is a kind of newly
Approach.
The present invention also provides the preparation methods of polymer P DTT: after dithiothreitol (DTT) is dissolved with organic solvent A, true
Polymerization reaction is carried out under empty condition, the sulfydryl of dithiothreitol (DTT) end is made to be oxidized to disulfide bond, to obtain polymer P DTT.
Reaction equation is as follows:
Preferably, the temperature of the polymerization reaction is 40~180 DEG C, and the time of the polymerization reaction is 10min~48h.
It is highly preferred that the temperature of the polymerization reaction is 90~100 DEG C, the time of the polymerization reaction is 10~20h.
Preferably, the dithiothreitol (DTT) and the mass volume ratio of organic solvent A are 1~5g:2~20mL.Such as 1:2,1:
5,1:10,1:15,1:20,3:10,4:10,5:2,5:5,5:10,5:15,5:20g/mL etc..
It is highly preferred that the dithiothreitol (DTT) and the mass volume ratio of organic solvent A are 2~4g:5~11mL.As 2:5,
2:8,2:11,3:5,3:7,3:11,4:5,4:8,4:11g/mL etc..
Preferably, the organic solvent A be selected from dimethyl sulfoxide, n,N-Dimethylformamide, N, N- diethylformamide,
One of N, N- diethyl acetamide, acetone, tetrahydrofuran are a variety of.
The present invention also provides polymer P DTT as or application in terms of preparing drug carrier system.
Preferably, the transmitting carrier is the transmitting carrier with reduction responsiveness.
The present invention also provides it is a kind of with reduction responsiveness the poly- dithiothreitol (DTT) nanometer system for drug delivery,
It is using the polymer P DTT as nano-carrier carrying medicament.
The present invention also provides the preparation methods of the poly- dithiothreitol (DTT) nanometer system, comprising the following steps:
S1. drug and organic basic catalyst are added solid phosgene and be acylated instead after organic solvent B dissolution stirring
It answers, then the polymer P DTT of dissolution in a solvent is added dropwise and carries out graft reaction, be grafted the polymer of drug
PDTT；
S2. partial size is prepared by single emulsion method or nanoprecipitation method in the above-mentioned polymer P DTT for being grafted drug
Uniform, stable nanoparticle solution, the as described poly- dithiothreitol (DTT) nanometer system for being used for drug delivery.
Preferably, in step S1, the mass ratio of the drug and organic basic catalyst is 1~5:1~10.Such as 1:1,1:
2.5,1:5,1:8,1:10,1:1,1:2.5,1:5,1:8,1:10,3:5:3:9,4:1,4:9,5:1,5:8 etc..
It is highly preferred that the mass ratio of the drug and organic basic catalyst is 1~2:1~5 in step S1.As 1:1,
1:5,1.5:1,1.5:4,2:1:2:3,2:5 etc..
Preferably, in step S1, the concentration of the polymer P DTT is 0.01~2.5g/mL.Such as 0.01,0.03,
0.045,0.1,0.15,0.2,0.25g/mL etc..
It is highly preferred that the concentration of the polymer P DTT is 0.01~1g/mL in step S1.
Preferably, in step S1, the time of the acylation reaction is 10~60min；The time of the graft reaction be 3~
48h。
Preferably, in step S1, the temperature of the graft reaction is room temperature.The room temperature refers to 15~25 DEG C.
Preferably, in step S1, the acylation reaction and graft reaction are to carry out under protection of argon gas.
Preferably, in step S1, the mixing time is 1min~1h.
Preferably, in step S1, the organic solvent B is selected from methylene chloride and/or tetrahydrofuran.
There is no particular/special requirement to the solvent for dissolving polymer P DTT, polymer P DTT can be dissolved.
Preferably, in step S1, the organic basic catalyst is selected from 4-dimethylaminopyridine (DMAP), 4- dimethylamino
Any one in pyridine-p- toluene fulfonate (DPTS) or n-hydroxysuccinimide (NHS).
Preferably, in step S2, method that nanoparticle solution is prepared by single emulsion method, comprising the following steps:
S21. it will be grafted the polymer P DTT of drug, ultrasonic dissolution is in organic solvent C immiscible and low boiling point with water
In, obtain emulsion oil phase；
S22. stabilizer is added into pure water and is used as water phase, by oil it is mutually mixed with water after, ultrasonic removing organic solvent C,
Uniform particle diameter, stable nanoparticle solution can be obtained.
It is described to refer to that solubility in water is less than the organic solvent of 0.01g with the immiscible organic solvent of water.
The organic solvent of the low boiling point refers to that boiling point is lower than 60 DEG C of organic solvent.
Preferably, in step S21, the organic solvent C immiscible with water and low boiling point, including but not limited to chloroform,
Methylene chloride, acetone or ethyl acetate etc..
Preferably, in step S2, method that nanoparticle solution is prepared by nanoprecipitation method, comprising the following steps:
S221. it will be grafted the polymer P DTT and stabilizer of drug, be dissolved in organic solvent D miscible with water, shape
At oily phase；
S222. under stirring condition, oil is mutually added drop-wise in water phase, uniform particle diameter, stable nanoparticle solution can be obtained.
Preferably, in step S221, oil is mutually slowly dropped in water phase, rate of addition is 0.01~1mL/ seconds.
Preferably, in step S221, by the polymer P DTT and the stabilizer that have been grafted drug with the mass ratio of 1~20:1,
It is completely dissolved in organic solvent D miscible with water.Such as 1:1,2:1,5:1,10:1,20:1.
It is highly preferred that in step S221, it is complete by the polymer P DTT and stabilizer that have been grafted drug with the mass ratio of 5:1
In fully dissolved organic solvent D miscible with water.
The organic solvent D miscible with water refers to that solubility in water is greater than the organic solvent of 100g.
Preferably, the organic solvent D miscible with water includes but is not limited to dimethyl sulfoxide, N, N- dimethyl formyl
Amine, tetrahydrofuran, dioxane, pyridine etc..
Preferably, in step S22 neutralization procedure S221, the stabilizer includes that distearoylphosphatidylethanolamine-is poly-
Ethylene glycol (DSPE-PEG) class stabilizer, polyvinyl alcohol (PVA), phospholipid molecule etc..
The drug includes hydrophobicity or hydrophilic drug.Polymer P DTT of the invention can load hydrophobicity medicine
Object improves the dissolubility of hydrophobic drug, improves its bioavilability, can also load hydrophilic medicament, has good biology
Compatibility.
Preferably, the drug includes containing-OH ,-NH2,-COOH or halogen functional group drug, protein medicaments or core
Acids drug.Experiment discovery, polymer P DTT of the present invention can be realized containing-OH ,-NH2,-COOH or halogen functional group
The high-efficient carrier of the drugs such as drug, protein medicaments, nucleic acid drug.
The protein medicaments include but is not limited to Herceptin, Lucentis, interferon, hematopoietin,
The protein medicaments such as streptokinase.
The nucleic acid drug includes but is not limited to the nucleic acid drugs such as Lamivudine, Aldoforwe ester, inosine, coacetylase.
The drug includes anti-tumor drug, antibiotics, antiviral class drug.
The anti-tumor drug is selected from camptothecine, ursolic acid, methotrexate (MTX), 9-aminocamptothecin, Herceptin, nitrogen
One of mustard, cis-platinum, cyclophosphamide, fluorouracil, podophyllotoxin etc. are a variety of.
The antibiotics includes polymyxins, ampicillin, cefalexin, amikacin etc..
The antiviral class drug includes Lamivudine, Ganciclovir, Entecavir, Aldoforwe ester etc..
Shown in the structural formula such as following formula (II) of the poly- dithiothreitol (DTT) grafting camptothecine:
Shown in the structural formula such as following formula (III) of the poly- dithiothreitol (DTT) grafting ursolic acid:
Shown in the poly- dithiothreitol (DTT) grafting structure of methotrexate formula such as following formula (IV):
Shown in the structural formula such as following formula (V) of the poly- dithiothreitol (DTT) grafting 9-aminocamptothecin:
The drug of the functional group Han-COOH includes that methotrexate (MTX), amino acids (polymyxins) drug, protide are (dry
Disturb element) drug etc..
The poly- dithiothreitol (DTT) and drug (R-COOH) with carboxyl react, and generate the drug with ester bond.
Shown in the structural formula such as following formula (VI) of poly- dithiothreitol (DTT) grafting drug containing carboxyl:
The halogen-containing drug R-X (X=F, Cl, Br, I) includes mustargen, cis-platinum, cyclophosphamide, fluorouracil etc..
The poly- dithiothreitol (DTT) and the drug with halogen react, and generate the drug with ehter bond.
Shown in the structural formula such as following formula (VII) of poly- dithiothreitol (DTT) grafting drug containing halogen:
The nanoparticle solution prepared by above method by DLS measurement, the size controlling of the nanoparticle 10~
500nm。
It is highly preferred that the partial size of the nanoparticle is 10~150nm.
Nanoparticle after the polymer poly dithiothreitol (DTT) grafting drug has quick GSH responsiveness.When according to 37 DEG C
In the PBS solution of different GSH concentration, nanometer system release free drug testing result show: be not present GSH phase
Than in the presence of GSH, free drug release increased significantly the nanoparticle, and with the raising of GSH concentration, nanometer
The speed that system discharges free drug is faster.This is because the cystine linkage in the sulfydryl attack system of GSH, so that cystine linkage restores
At sulfydryl, sulfydryl increases the degradation for accelerating degradable chemical key (such as ester bond) in environment.It is above to act on while carrying out, add
The speed degradation of nanometer system, drug are able to quick release.
Shown in the structure such as following formula (VIII) of reduced glutathione (GSH):
Poly- dithiothreitol (DTT) of the invention has good pharmaceutical carrier application prospect, is also embodied in: by poly- two sulphur
Threitol new material and monomer dithiothreitol (DTT) carry out the detection of MCF-7/A549/HpeG-2/CT-26/4T1 cytotoxicity and send out
Existing, in sufficiently large concentration range, poly- dithiothreitol (DTT) does not obviously inhibit cell growth, and with two sulphur threose of monomer
Alcohol is compared, and shows better biocompatibility.After being grafted drug formation nanometer system, compared with single medicine drug, poly- two sulphur Soviet Union
The antitumous effect of sugar alcohol is suitable, still shows excellent anti-tumor activity.
Therefore, the poly- dithiothreitol (DTT) nanometer system for drug delivery with reduction responsiveness is in preparation anticancer
Application in drug, also within protection scope of the present invention.
Compared with prior art, the invention has the following advantages:
(1) present invention is by sulfydryl by polymerization reaction, and what is be simple and efficient has synthesized polymer poly dithiothreitol (DTT), the polymerization
Object stable structure, its biocompatibility are good, can contain hydrophobic anti-tumor drug, and a large amount of existing two in polymer
Sulfide linkage makes system that there is GSH quickly to restore responsiveness.
(2) drug is grafted on poly- dithiothreitol (DTT) side group by the present invention, is realized such as camptothecine and is contained-OH or-NH2Equal officials
The controllable load medicine for the dewatering medicament that can be rolled into a ball, improves the dissolubility of drug, greatly improves the utilizability of dewatering medicament.
(3) present invention can obtain the nanoparticle of controllable grain size, partial size using poly- dithiothreitol (DTT) as carrier loaded drug
Distribution is small, is accumulated in tumor tissues by the high-permeability and high retention (EPR effect) of tumor tissues, from
And realize the effect of passive target, poly- dithiothreitol (DTT) nanometer system can reduce release of the drug under normal physiological conditions with
Reduce burst drug release bring toxic side effect；And after being absorbed by tumour cell, under the effect of tumour cell glutathion inside, nanometer
Disulfide bonds in system, are reduced into sulfydryl, and the monomer energy promotion system with sulfydryl is disintegrated, and promote drug release；Meanwhile
The small molecule of separate out acts on carbonic acid ester bond, accelerates the release of drug, enhances the therapeutic effect of cancer, has high face
Bed application value.
(4) present invention has reaction process simple, and reaction step is few, and reaction time is short, the advantages such as reproducible, in medicine
Field has a good application prospect and wide development space.
Detailed description of the invention
Fig. 1 is the nanoparticle and its releasing in tumour cell that the present invention has been grafted that the poly- dithiothreitol (DTT) of camptothecine is formed
Put schematic diagram.
Fig. 2 is the nucleus magnetic hydrogen spectrum figure of poly- dithiothreitol (DTT) in the present invention.
Fig. 3 is the nucleus magnetic hydrogen spectrum figure that the poly- dithiothreitol (DTT) of camptothecine has been grafted in the present invention.
Fig. 4 is transmission electron microscope (TEM) result figure for being grafted the nanoparticle of poly- dithiothreitol (DTT) formation of camptothecine.
Fig. 5 is dynamic light scattering (DLS) result figure for being grafted the nanoparticle of poly- dithiothreitol (DTT) formation of camptothecine.
Fig. 6 is drug of the nanoparticle for the poly- dithiothreitol (DTT) formation for being grafted camptothecine at 37 DEG C of various concentration GSH
Release figure.
Fig. 7 is poly- dithiothreitol (DTT) (PDTT), dithiothreitol (DTT) monomer (DTT) to the cell of MCF-7 breast tumor cell
Toxicity figure.
Fig. 8 is to be grafted nanoparticle (PDTT-CPT), the camptothecine list medicine (CPT) that the poly- dithiothreitol (DTT) of camptothecine is formed
To the cytotoxicity figure of MCF-7 breast tumor cell.
Specific embodiment
The present invention is further illustrated below in conjunction with Figure of description and specific embodiment, but embodiment is not to the present invention
It limits in any form.Unless stated otherwise, the present invention uses reagent, method and apparatus routinely try for the art
Agent, method and apparatus.
Unless stated otherwise, following embodiment agents useful for same and material are commercially available.
The synthesis of the poly- dithiothreitol (DTT) of embodiment 1
1, the polymer poly dithiothreitol (DTT) (PDTT) as pharmaceutical carrier, including following step are prepared by the following method
It is rapid:
(1) 4.62g dithiothreitol (DTT) is weighed, with dmso solution of the 11mL after dry, is frozen by liquid nitrogen is cooling
Pumping method makes reaction vessel interior keep high vacuum；
(2) after room temperature to be restored, 90 DEG C is warming up to, is kept stirring simultaneously, after reacting 10h, pump remaining dimethyl sulfoxide
With product water；
(3) ethyl acetate is added, it is cooling at room temperature that solid is precipitated after heating dissolves solid crude product, it is repeated several times
Afterwards, white solid is obtained, as poly- dithiothreitol (DTT).
2, result
The nucleus magnetic hydrogen spectrum figure of polymer P DTT is as shown in Fig. 2, the signal at as shown in Figure 2~5.17ppm is solvent heavy water
Absorption peak, the signal at~3.34ppm corresponds to the proton uptake peak on the connected-CH- of two hydroxyls of dithiothreitol (DTT) ,~
Signal at 3.02ppm ,~2.72ppm corresponds to two connected methylene-CH of two sulfydryls of dithiothreitol (DTT)2On proton
Absorption peak successfully synthesizes polymer P DTT as the result is shown, shown in specific general structure such as formula (I):
Wherein, n=5~10000.
The synthesis of the poly- dithiothreitol (DTT) of embodiment 2
1, the polymer poly dithiothreitol (DTT) (PDTT) as pharmaceutical carrier, including following step are prepared by the following method
It is rapid:
(1) 2.31g dithiothreitol (DTT) is weighed, with dmso solution of the 5.5mL after dry, is frozen by liquid nitrogen is cooling
Pumping method makes reaction vessel interior keep high vacuum；
(2) after room temperature to be restored, 100 DEG C is warming up to, is kept stirring simultaneously, after reacting 20h, pump remaining dimethyl sulfoxide
With product water；
(3) ethyl acetate is added, it is cooling at room temperature that solid is precipitated after heating dissolves solid crude product, it is repeated several times
Afterwards, white solid is obtained, as poly- dithiothreitol (DTT).
2, result
The poly- dithiothreitol (DTT) stable structure that is prepared, its biocompatibility are good, can contain hydrophobic antitumor
Drug, and a large amount of existing disulfide bond make system that there is GSH quickly to restore responsiveness in polymer, as drug delivery
There is applications well prospect in terms of carrier.
Embodiment 3 is grafted the preparation of drug (poly- dithiothreitol (DTT) grafting camptothecine)
1, it is prepared by the following method grafting drug, comprising the following steps:
(1) it is molten to weigh camptothecine 2g, 4-dimethylaminopyridine (DMAP) 2.11g for the 250mL round-bottomed flask for taking clean dried
Solution under argon gas protection, is placed on magnetic stirring apparatus in the methylene chloride of 100mL and stirs 10min；
(2) phosgene 0.57g is weighed, is quickly adding into round-bottomed flask, system continues to stir 30min, carries out acylation reaction；
(3) poly- dithiothreitol (DTT) 0.9g is dissolved in 30mL tetrahydrofuran, is placed in constant pressure funnel, under protection of argon gas
It instills in round-bottomed flask, carries out graft reaction for 24 hours at room temperature；
(4) it with concentrated by rotary evaporation solvent to 30mL, then instills in ethyl acetate, is statically placed in 20 DEG C of refrigerator overnights, filter,
It is rinsed solid 3 times with glacial acetic acid ethyl ester, drying has been grafted the poly- dithiothreitol (DTT) of camptothecine.
Be grafted the nucleus magnetic hydrogen spectrum figure of the poly- dithiothreitol (DTT) of camptothecine as shown in figure 3, from the figure 3, it may be seen that~8.69ppm,
~8.17ppm ,~8.11ppm ,~7.86ppm ,~7.72ppm ,~7.45ppm ,~5.51ppm, the signal at~5.43ppm
Proton uptake peak on corresponding camptothecine aromatic rings ,~1.74ppm ,~0.89ppm are represented on camptothecine on methylene and ethyl
Absorption peak ,~3.34ppm ,~3.05ppm ,~5.27ppm respectively represent methine on poly- dithiothreitol (DTT), methylene and hydroxyl
On proton uptake peak.These results suggest that camptothecin drug is successfully grafted on poly- dithiothreitol (DTT).
Embodiment 4 is grafted the preparation of drug (poly- dithiothreitol (DTT) grafting camptothecine)
1, it is prepared by the following method grafting drug, comprising the following steps:
(1) it is molten to weigh camptothecine 1g, 4-dimethylaminopyridine (DMAP) 1.05g for the 100mL round-bottomed flask for taking clean dried
Solution under argon gas protection, is placed on magnetic stirring apparatus in the tetrahydrofuran of 50mL and stirs 10min；
(2) phosgene 0.57g is weighed, is quickly adding into round-bottomed flask, system continues to stir 30min, carries out acylation reaction；
(3) poly- dithiothreitol (DTT) 0.45g is dissolved in 10mL tetrahydrofuran, is placed in constant pressure funnel, protected in argon gas
In lower instillation round-bottomed flask, graft reaction is carried out for 24 hours at room temperature；
(4) it with concentrated by rotary evaporation solvent to 30mL, then instills in ethyl acetate, is statically placed in 20 DEG C of refrigerator overnights, filter,
It is rinsed solid 3 times with glacial acetic acid ethyl ester, drying has been grafted the poly- dithiothreitol (DTT) of camptothecine.Through nucleus magnetic hydrogen spectrum analytical table
Bright, camptothecin drug is successfully grafted on poly- dithiothreitol (DTT).
A kind of poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering with reduction responsiveness of embodiment 5
1, poly- dithiothreitol (DTT) nanometer system is prepared by single emulsion method, comprising the following steps:
(1) the poly- dithiothreitol (DTT) ultrasonic dissolution that embodiment 3 has been grafted camptothecine obtains emulsion in methylene chloride
Oily phase, the concentration of oily phase are 30mg/mL；
(2) 3000 2mg of stabilizer DSPE-PEG is added in 10mL pure water as water phase；Oily phase 0.2mL is taken to instill water
Xiang Zhong, the ultrasound 5min under ice bath obtain white mixed emulsion；
(3) white mixed emulsion is transferred to room temperature, after stirring one day night, vapors away low-boiling methylene chloride, obtain
There must be the nanoparticle solution of Tyndall effect, remove large granular impurity through 0.8 μm of membrane filtration, the nanoparticle for obtaining carrying medicine is molten
Liquid, the as described poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering with reduction responsiveness.
2, result
(1) DLS detection is carried out, the partial size of the present embodiment nanoparticle is statically placed in 4 DEG C of refrigerators and produces without precipitating in 150nm
It is raw.Its transmission electron microscope (TEM) result figure and dynamic light scattering (DLS) result figure difference are as shown in Figure 4 and Figure 5.The result shows that carrying
The PDTT nanoparticle of camptothecine is spherical in shape, and size is more uniform, and particle diameter distribution is relatively narrow.
(2) nanoparticle made from the present embodiment is under the conditions of 37 DEG C, in various concentration glutathione (0mM, 2mM, 10mM,
Drug release experiment is carried out in PBS solution 20mM), detects the free camplotheca acuminata that nanometer system discharges in 72 hours in PBS solution
Alkali concentration.Experimental result as shown in fig. 6, thus prove heretofore described nanometer medicine-carried system have GSH restore responsiveness,
And as GSH concentration increases, reduction responsiveness is reinforced.
(3) poly- dithiothreitol (DTT) (PDTT), dithiothreitol (DTT) monomer (DTT), the present embodiment the poly- of camptothecine has been grafted
Nanoparticle (PDTT-CPT), the camptothecine list medicine (CPT) of dithiothreitol (DTT) formation carry out external anti-MCF-7 tumor cytotoxicity respectively
Property experiment, effect is as shown in Figure 7 and Figure 8.As can be seen that poly- dithiothreitol (DTT) biocompatibility is fine, the life to MCF-7 cell
It grows and inhibits without obvious in the range of a larger activity.The PDTT nanoparticle for carrying camptothecine, with simple camptothecine
It compares, maintains the excellent anticancer activity of camptothecine.
A kind of poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering with reduction responsiveness of embodiment 6
1, poly- dithiothreitol (DTT) nanometer system is prepared by nanoprecipitation method, comprising the following steps:
(1) the poly- dithiothreitol (DTT) and stabilizer DSPE-PEG 3000 for embodiment 4 being grafted camptothecine are with the matter of 2:1
Ratio is measured, is dissolved completely in dimethyl sulfoxide, the oily phase that polymer concentration is 20mg/mL is obtained；
(2) pure water of 10mL is taken to be placed on magnetic agitation platform, speed of agitator 1500r/min mutually slowly drips 0.2mL oil
Enter in water phase, rate of addition is 0.05mL/ seconds, obtains the milky emulsion with Tyndall effect, removes diformazan after ultrafiltration 3 times
Base sulfoxide filters out big molecular impurity with 0.8 μm of organic phase filter membrane, obtains the nanoparticle solution for carrying medicine, as described to have also
The poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering of former responsiveness.
2, result
(1) DLS detection is carried out, the partial size of the present embodiment nanoparticle is statically placed in 4 DEG C of refrigerators in 100nm or so without heavy
It forms sediment and generates.Its transmission electron microscope (TEM) result figure and dynamic light scattering (DLS) result figure difference are as shown in Figure 4 and Figure 5.As a result table
Bright, the PDTT nanoparticle for carrying camptothecine is spherical in shape, and size is more uniform, and particle diameter distribution is relatively narrow.
(2) nanoparticle made from the present embodiment is under the conditions of 37 DEG C, in various concentration glutathione (0mM, 2mM, 10mM,
Drug release experiment is carried out in PBS solution 20mM), detects the free camplotheca acuminata that nanometer system discharges in 72 hours in PBS solution
Alkali concentration.Experimental result as shown in fig. 6, thus prove heretofore described nanometer medicine-carried system have GSH restore responsiveness,
And as GSH concentration increases, reduction responsiveness is reinforced.
(3) poly- dithiothreitol (DTT) (PDTT), dithiothreitol (DTT) monomer (DTT), the present embodiment the poly- of camptothecine has been grafted
Nanoparticle (PDTT-CPT), the camptothecine list medicine (CPT) of dithiothreitol (DTT) formation carry out external anti-MCF-7 tumor cytotoxicity respectively
Property experiment, effect is as shown in Figure 7 and Figure 8.As can be seen that poly- dithiothreitol (DTT) biocompatibility is fine, the life to MCF-7 cell
It grows and inhibits without obvious in the range of a larger activity.The PDTT nanoparticle for carrying camptothecine, with simple camptothecine
It compares, maintains the excellent anticancer activity of camptothecine, there is significant tumor killing effect, there is certain application in field of cancer treatment
Potentiality.
The preparation of 7 polymer P DTT of embodiment
Other conditions are same as Example 1, only difference is that, the temperature of polymerization reaction is 40 DEG C, polymerization reaction
Time be 48h, solid white polymer PDTT is prepared.
The preparation of 8 polymer P DTT of embodiment
Other conditions are same as Example 2, only difference is that, the temperature of polymerization reaction is 180 DEG C, polymerization reaction
Time be 10min, solid white polymer PDTT is prepared.
Embodiment 9 is grafted the preparation of drug (poly- dithiothreitol (DTT) grafting camptothecine)
Other conditions are same as Example 3, only difference is that, the time of acylation reaction is 10min, graft reaction
Time be 48h, be prepared the poly- dithiothreitol (DTT) for being grafted camptothecine, finally obtained anti-tumor drug delivery system,
The controllable load medicine for realizing dewatering medicament, improves the dissolubility of drug, greatly improves the utilizability of dewatering medicament, and
And there is GSH quickly to restore responsiveness, improve the targeting of anti-tumor drug.
Embodiment 10 is grafted the preparation of drug (poly- dithiothreitol (DTT) grafting camptothecine)
Other conditions are same as Example 4, only difference is that, the time of acylation reaction is 60min, graft reaction
Time be 3h, be prepared the poly- dithiothreitol (DTT) for being grafted camptothecine, finally obtained anti-tumor drug delivery system is real
The controllable load medicine for having showed dewatering medicament, improves the dissolubility of drug, greatly improves the utilizability of dewatering medicament, and
Responsiveness is quickly restored with GSH, improves the targeting of anti-tumor drug.
A kind of poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering with reduction responsiveness of embodiment 11
Other conditions are same as Example 6, only difference is that, it has been grafted the poly- dithiothreitol (DTT) of camptothecine and steady
The mass ratio for determining agent DSPE-PEG 3000 is 5:1.Finally obtained anti-tumor drug delivery system, realize camptothecine can
Control carries medicine, improves the dissolubility of camptothecine, greatly improves the utilizability of camptothecine, and there is GSH quickly to restore
Responsiveness improves the targeting of camptothecin drug.
In addition, poly- dithiothreitol (DTT) nanometer system of the invention is applied also for such as ursolic acid, methotrexate (MTX), 9- amino camplotheca acuminata
The anti-tumor drugs such as alkali, Herceptin, mustargen, cis-platinum, cyclophosphamide, fluorouracil, podophyllotoxin, as Herceptin,
Lucentis, interferon, hematopoietin, streptokinase protein medicaments, such as Lamivudine, Aldoforwe ester, inosine, auxiliary
The delivering of the nucleic acid drugs such as enzyme A, property is stablized after the poly- dithiothreitol (DTT) of novel polymer of the invention is grafted said medicine, has good
Good biocompatibility and degradability, and there is GSH quickly to restore responsiveness, improve the targeted delivery effect of nano-carrier
Rate realizes positioning controlled release of the drug in tumour cell, improves the bioavilability of dewatering medicament, is the effective of disease
It treats and has opened up a kind of new approach.
The preferred embodiment that the above specific embodiment is of the invention for ease of understanding and illustrates, but the invention is not limited to
Above-described embodiment does not mean that the present invention must rely on above-described embodiment and could implement.Person of ordinary skill in the field
It is the addition of equivalence replacement and auxiliary element to raw material selected by the present invention, specific it will be clearly understood that any improvement in the present invention
The selection etc. of mode, all of which fall within the scope of protection and disclosure of the present invention.
Claims (10)
1. a kind of polymer P DTT for drug delivery, which is characterized in that the polymer P DTT is by multiple duplicate two sulphur
Threitol structural unit composition, shown in the following formula (I) of structural formula:
,
Wherein, n=5~10000.
2. the preparation method of polymer P DTT described in claim 1, which is characterized in that dithiothreitol (DTT) organic solvent A is molten
Xie Hou carries out polymerization reaction under vacuum conditions, and the sulfydryl of dithiothreitol (DTT) end is made to be oxidized to disulfide bond, to be gathered
Close object PDTT.
3. preparation method according to claim 2, which is characterized in that the temperature of the polymerization reaction is 40~180 DEG C, institute
The time for stating polymerization reaction is the h of 10 min~48.
4. polymer P DTT described in claim 1 as or application in terms of preparing drug carrier system.
5. a kind of poly- dithiothreitol (DTT) nanometer system for drug delivery with reduction responsiveness, which is characterized in that with power
Benefit requires the 1 polymer P DTT as nano-carrier carrying medicament.
6. poly- dithiothreitol (DTT) nanometer system according to claim 5, which is characterized in that by method comprising the following steps
It is prepared:
S1. drug and organic basic catalyst are added solid phosgene and carry out acylation reaction after organic solvent B dissolution stirring,
The polymer P DTT of dissolution in a solvent is added dropwise again and carries out graft reaction, has been grafted the polymer of drug
PDTT；
S2. it is equal that partial size is prepared by single emulsion method or nanoprecipitation method in the above-mentioned polymer P DTT for being grafted drug
One, stable nanoparticle solution, the as described poly- dithiothreitol (DTT) nanometer system.
7. poly- dithiothreitol (DTT) nanometer system according to claim 6, which is characterized in that in step S1, the acylation is anti-
The time answered is 10~60 min；The time of the graft reaction is 3~48 h.
8. poly- dithiothreitol (DTT) nanometer system according to claim 6, which is characterized in that in step S2, pass through single emulsion
The method that method prepares nanoparticle solution, comprising the following steps:
S21. the polymer P DTT of drug will be grafted, ultrasonic dissolution in organic solvent C immiscible and low boiling point with water,
Obtain emulsion oil phase；
S22. stabilizer is added into pure water and is used as water phase, by oil it is mutually mixed with water after, ultrasonic removing organic solvent C
Obtain uniform particle diameter, stable nanoparticle solution；
In step S2, method that nanoparticle solution is prepared by nanoprecipitation method, comprising the following steps:
S221. it will be grafted the polymer P DTT and stabilizer of drug, be dissolved in organic solvent D miscible with water, oil is formed
Phase；
S222. under stirring condition, oil is mutually added drop-wise in water phase, uniform particle diameter, stable nanoparticle solution can be obtained.
9. poly- dithiothreitol (DTT) nanometer system according to claim 5, which is characterized in that the drug include containing-OH ,-
NH2,-COOH or halogen functional group drug, protein drug or nucleic acid drug.
10. polymer P DTT described in claim 1 or any poly- dithiothreitol (DTT) nanometer system of claim 5~9
Preparing the application in anticancer drug.
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