CN110025574A - A kind of reduction response type amphipathic stem polymer prodrug and its preparation method and application - Google Patents
A kind of reduction response type amphipathic stem polymer prodrug and its preparation method and application Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
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- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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Abstract
The present invention relates to a kind of reduction response type amphipathic stem polymer prodrugs and its preparation method and application, have the molecular structural formula as shown in formula I:Wherein, X is NH or O；ROH is hydrophobic anticancer drug；N is 5~1000；M is 1 or 2.Prodrug provided by the invention can be realized target administration, not only remain the advantage of nano medicament carrying system, but also play disulfide bond the tumor locus selective degradation the characteristics of.Compared to linking arms such as 2,2 '-two conventional thiodiglycolic acids, 3,3 '-dithiodipropionic acids, without can be obtained by the anticancer drug of raw medicine molecular forms by further hydrolysis.
Description
Technical field
The present invention relates to a kind of polymer prodrugs and its preparation method and application more particularly to one kind can be applied to swell
The Pegylation amphiphilic polymer prodrug and its preparation method and application of tumor treatment.
Background technique
Chemotherapy is a kind of basic tumor therapeuticing method, mainly kills tumour cell using anticancer drug and reaches and control
Treat the purpose of tumour.Clinically common anticancer drug mainly includes camptothecin, taxanes, vincaleukoblastinum and Anthraquinones etc.,
But these anticancer drug physicochemical properties are poor (such as being insoluble in water, poor selectivity etc.), are woven with to normal cell and group serious
Toxic side effect causes chemotherapy of tumors effect poor, therefore clinical application is restricted.
Hydrophilic radical is introduced in the molecular structure of drug by chemical modification, water-soluble prodrug is prepared, it can
With the water solubility problems of effective solution hydrophobic drug.In water soluble polymer, polyethylene glycol has been obtained extensively
Concern.Polyethylene glycol is a kind of high molecular material that biocompatibility is excellent, has been approved by the FDA in the United States as can internal injection
One of medicinal high molecular polymer.After polyethyleneglycol modified, water-soluble and internal stability is mentioned hydrophobic drug
Height, and can significantly reduce kidney clearance rate, greatly prolong blood circulation time, moreover it is possible to which the product at tumour is enhanced by EPR effect
Poly-, these are of crucial importance raising oncotherapy effect, reduction toxic side effect.
In recent years, administration nano-drug administration system is had received widespread attention with its good characteristic, and administration nano-drug administration system has following
Feature: it largely improves the water solubility of drug, realized by improving permeability and reserve effects (EPR effect) to tumour
Passive target, extend circulation time in vivo, improve utilization ratio of drug and reduce toxic side effect etc..However, common nanometer
Preparation does not identify tumor locus and normal portions, can not distinguish intracellular and extracellular environment, therefore how to allow and receive
The selective raw medicine that releases is still a great problem in vivo for metric system agent.
The study found that intracellular glutathione concentrations (0.5~10mM) are extracellular glutathione concentrations (2~20 μM)
200 times or more, disulfide bond is gone back in the presence of the reducing agents such as a certain amount of glutathione (GSH) or dithiothreitol (DTT) (DTT)
It is primary at sulfydryl, but highly stable under the environment such as the normal body temperature in human body, pH and oxidation, i.e., extracellular glutathione
Concentration is not enough to Reduction of Disulfide, in addition, tumor tissue cell has more reproducibility environment than normal tissue cell anoxic.Cause
This, hydrophilic polymer and hydrophobic drug can be linked by disulfide bond, and be self-assembled into nanometre glue in a solvent
Beam is entered after target cell by endocytosis and is restored by GSH, i.e., disulfide bonds generate sulfydryl, thus fast and effeciently
Drug is discharged, and is diffused into the structures such as nucleus, to kill cancer cell.Most common disulfide bond linking arm is mainly 2,
2 '-two thiodiglycolic acids, 3,3 '-dithiodipropionic acids etc., but with these disulfide bond linking arms connect hydrophilic polymer with
After hydrophobic drug, under the reducing conditions such as GSH, DTT, disulfide bond is broken rapidly, but on the drug discharged after being broken
It is also connected with sulfydryl and ester bond is such a " tail ", and not raw molecule form, Chinese patent CN102775596 institute
Disclosed polymer prodrug belongs to above-mentioned situation when disulfide bonds discharge drug, to obtain raw material point
The step of drug of sub- form need to be using ester linkage hydrolyzing, and under the weak basic condition in human body cell, the hydrolysis of ester bond is slow
It is slow and incomplete, directly affect the antitumous effect of drug.
Summary of the invention
The present invention provides one kind for deficiency existing for existing anti-tumor drug water solubility and Targeting delivery raw medicine aspect
Restore response type amphipathic stem polymer prodrug and its preparation method and application.
The technical scheme to solve the above technical problems is that
A kind of reduction response type amphipathic stem polymer prodrug has the structural formula as shown in formula I:
Wherein, X is NH or O；ROH is hydrophobic anticancer drug；N is 5~1000；M is 1 or 2.
Further, the polymer prodrug has the structural formula as shown in formula II:
Further, the anti-tumor drug refers to camptothecin, taxanes, any one in vinca drug.
Further, the camptothecine refers to camptothecine, Irinotecan, topotecan, 10-hydroxycamptothecine or 7-
One of ethyl-10-hydroxycamptothecin (SN-38), the taxone refers to taxol, Docetaxel, kappa
He matches or one of La Luotasai, and the vinca drug refers to one of vincaleukoblastinum, vincristine or vinorelbine.
The mechanism of polymer prodrug release raw medicine molecule provided by the invention are as follows:
Present invention employs the thinkings of tumor microenvironment target administration, by introducing type self-destroyed two sensitive to reducing environment
Sulfide linkage linking arm, under the reducing condition that tumour cell glutathion inside provides, the disulfide bond of polymer prodrug occurs disconnected
It splits, a free sulfydryl is generated after disulfide bonds, due to being influenced by stable structure factor, which can nucleophilic attack
Neighbouring ester bond to generate stable a five-membered ring or six-membered ring structure, while the raw medicine molecule of release anti-cancer medicine, with
For 7-Ethyl-10-hydroxycamptothecin, that is, SN-38, the mechanism of reduction response release raw medicine molecule is as shown in Figure 2.
Polymer prodrug provided by the invention has the beneficial effect that
1) prodrug provided by the invention can be realized target administration, both remain the advantage of nano medicament carrying system, together
When played disulfide bond again the tumor locus selective degradation the characteristics of.With 2,2 '-two conventional thiodiglycolic acids, 3,3 '-two
The linking arms such as thio-2 acid are compared, without can be obtained by the anticancer drug of raw medicine molecular forms by further hydrolysis.
2) the amphiphilic polymer prodrug that the present invention obtains, can be spontaneously assemble into nano-micelle in a solvent.
The polymer nano micelle being prepared by above-mentioned polymer prodrug is also claimed in the present invention, described poly-
Close object nano-micelle be by the following method made of, polymer prodrug above-mentioned and fatty acid triglycercide are placed in water
Dissolve the two mixed solution, after by solution ultrasound, filter membrane, thereto be added mannitol freeze-drying to get polymer nanocomposite
Micella, the partial size of gained micella are 10~400 nm, and drugloading rate is 1~50wt%.
The polymer that the present invention is also claimed prodrug above-mentioned and is prepared by prodrug of the invention
Application of the nano-micelle in field of antineoplastic medicaments.
Further, the tumour refers to colorectal cancer.
The present invention also provides the preparation methods of above-mentioned amphiphilic polymer prodrug, include the following steps:
1) by mercaptoalcohol or mercapto-amine and 2 containing 2-3 carbon atom, pyridyl group two is made in the reaction of 2 '-two sulphur, two pyridine
Sulfenyl alcohol or pyridyidithio amine；
2) using the pyridyidithio alcohol or pyridyidithio amine that nitro phenyl chloroformate and step 1) are obtained into
Carbonic ester or amino carbonic ester is made in row coupling reaction；
3) the resulting carbonic ester of step 2) or amino carbonic ester and the hydrophobic anticancer drug of hydroxyl group are passed through
Ester exchange reaction generates conjugate；
4) the resulting conjugate of step 3) and double sulfydryl polyethylene glycols (HS-PEG-SH) are handed over by thiol disulfide
Reaction is changed, the polyethylene glycol polymer prodrug containing disulfide bond is made；
Reaction route is as follows:
Further, the specific reaction process of each step is as follows in above-mentioned preparation method:
Step 1): by mercaptoalcohol or mercapto-amine and 2 containing 2-3 carbon atom, 2 '-two sulphur, two pyridine is according to molar ratio 1:
(1~3) it is added in solvent, reaction is stirred at room temperature 12~48 hours, end of reaction is concentration, silica gel post separation, concentration, dry
Pyridyidithio alcohol or pyridyidithio amine；
Step 2): under alkaline condition, the resulting pyridyidithio alcohol of step 1) or pyridyidithio amine are dissolved in
In solvent, nitro phenyl chloroformate will be added dropwise in solution, be stirred to react 1~10 hour under being stirred at room temperature, and control pyridyl group
Disulfide group alcohol or pyridyidithio amine are 1:(1~3 with the molar ratio to nitro phenyl chloroformate), concentration, silica gel post separation,
Concentration, dry carbonic ester or amino carbonic ester；
Step 3): under alkaline condition, by the resulting carbonic ester of step 2) or amino carbonic ester and contain hydroxyl group
Hydrophobic anticancer drug 1:(1~3 in molar ratio) it is dissolved in solvent, back flow reaction 1~10 hour, it is down to room temperature, reaction solution
Through pickling, liquid separation, drying, concentration, silica gel column purification, concentration, be dried in vacuo the two conjugate；
Step 4): under nitrogen protection, double sulfydryl polyethylene glycols (HS-PEG-SH) are added to step 3) under stirring condition
In the solution of gained conjugate, the molar ratio of HS-PEG-SH and conjugate is 1:(2~6), it is stirred to react 12~48 at room temperature
Hour, concentration, silica gel column purification, concentration, dissolution, filtering, freeze-drying obtain the polyethylene glycol anticancer prodrugs containing disulfide bond.
The beneficial effect of the preparation method of amphiphilic polymer prodrug provided by the invention is: raw material is easy to get, reacts
The advantages that mild condition, high yield and product purity, is conducive to batch production.
Detailed description of the invention
Fig. 1 is that 1 resulting polymers prodrug of embodiment restores response drug release result figure under the conditions of DTT；
Fig. 2 is the mechanism schematic diagram of Inventive polymers prodrug reduction response release raw medicine；
Fig. 3 is the grain size distribution of 2 gained micella of embodiment；
Fig. 4 is 2 gained micella of embodiment compared with SN-38 is to the proliferation inhibition activity of colon cancer cell HT29；
Fig. 5 is 2 gained micella of embodiment compared with SN-38 is to the proliferation inhibition activity of colon cancer cell HCT116；
Specific embodiment
Principles and features of the present invention are described below in conjunction with example, the given examples are served only to explain the present invention, and
It is non-to be used to limit the scope of the invention.
Embodiment 1:
A kind of reduction response type amphipathic stem polymer prodrug, has the following structure formula:
Wherein 5 < n < 100.
Above-mentioned amphiphilic polymer prodrug the preparation method is as follows:
1) preparation of 2- (2- pyridyidithio) ethyl alcohol:
By 2 mercapto ethanol (0.87g, 11.1mmol) and 2,2 '-two sulphur, two pyridine (Py-SS-Py, 2.44g,
It 11.1mmol) is added in 100mL methanol, reaction 12 hours is stirred at room temperature.Decompression boils off methanol, crosses silica gel column purification, is concentrated, very
Empty dry the faint yellow oil product of 1.6g, yield 77.1%.Through detection product1H NMR shows to obtain 2- shown in formula a
(2- pyridyidithio) ethyl alcohol.
2) preparation of 4- nitrobenzophenone -2- (2- pyridyidithio) ethyl carbonate ester:
2- (2- pyridyidithio) ethyl alcohol (1.6g, 8.56mmol) and triethylamine (1.73g, 17.1 mmol) are dissolved in
In 100mL methylene chloride, nitro phenyl chloroformate (2.57g, 12.8mmol) will be slowly added dropwise to solution under being stirred at room temperature
In, drop finishes, and is stirred to react 1 hour.Concentration, silica gel post separation, concentration are dried in vacuo to obtain white solid product 2.21g, yield
73.3%.Through detection product1H NMR shows to obtain 4- nitrobenzophenone -2- (2- pyridyidithio) ethyl shown in formula b
Carbonic ester；
3) preparation of 2- (2- pyridyidithio) ethyl carbonate ester and SN-38 conjugate:
By 4- nitrobenzophenone -2- (2- pyridyidithio) ethyl carbonate ester (2.21g, 6.28mmol) and SN-38
(3.69g, 9.41mmol) is dissolved in 200mL methylene chloride, and 2ml triethylamine is added, then heats to back flow reaction 5 hours.Instead
Should finish, be down to room temperature, with dilute hydrochloric acid washing organic phase, liquid separation, drying, concentration, through silica gel column purification, concentration, vacuum drying
Obtain 2.8g faint yellow solid, yield 73.7%.Through detection product1H NMR shows 2- (the 2- pyrrole for obtaining structure shown in formula c
Piperidinyl disulfide group) ethyl carbonate ester and SN-38 conjugate (Py-SS (O)-SN38).
4) preparation of polyethylene glycol-disulfide bond (O)-SN38:
By HS-PEG2000- SH (3.0g, 1.5mmol) is dissolved in 100mL DMF, and under nitrogen protection, stirring, Py-SS is added dropwise
(O) DMF (100mL) solution of-SN38 (2.0g, 3.3mmol), is stirred to react 48 hours at room temperature.Decompression boils off DMF, through silicon
Rubber column gel column purifying, concentration obtain 3.1g faint yellow solid, yield 69.1%.Through detection product1H NMR shows to obtain formula d
Polyethylene glycol-disulfide bond (O)-SN38 of shown structure.
Synthetic route is as follows:
In order to verify whether the resulting amphiphilic polymer prodrug of embodiment 1 discharges raw medicine point under the reducing conditions
Son, the product of different time after 1 resulting polymers prodrug of embodiment is placed in the reducing agent DTT solution of 10mM by we
HPLC test is carried out, as a result as shown in Figure 1, by Fig. 1 it will be seen that 1 resulting polymers prodrug of embodiment exists
After placing 10min in DTT solution, raw medicine molecule SN-38 has been had already appeared in product, shows some polymer medicine
The decomposition of object precursor has released raw medicine, and with the gradually extension of standing time, the amount of raw medicine molecule SN-38 gradually increases, because
And polymer prodrug provided by the present application can decompose rapidly release raw medicine under the reducing conditions.
Embodiment 2:
A kind of nano-micelle containing 1 gained amphiphilic polymer prodrug of embodiment, is made with the following method: will
20mg polymer prodrug and 10 μ L MCT Oils are placed in water, then ultrasound 1min, filter membrane, thereto
Mannitol freeze-drying is added to get reduction response type polymer nano-micelle freeze-dried powder.Utilize dynamic light scattering (Dynamic
Light Scattering, DLS) measurement obtain partial size and the distribution of nano-micelle, as shown in Figure 3.
Embodiment 3:
A kind of reduction response type amphipathic stem polymer prodrug, has the following structure formula:
Wherein 100 < n < 300.
Above-mentioned amphiphilic polymer prodrug the preparation method is as follows:
1) preparation of 3- (2- pyridyidithio) propyl alcohol:
By 3- mercaprol (0.5g, 5.43mmol) and 2,2 '-two sulphur, two pyridine (Py-SS-Py, 2.4 g, 10.9mmol)
It is added in 60mL methanol, reaction 24 hours is stirred at room temperature.Decompression boils off methanol, crosses silica gel column purification, concentration, be dried in vacuo as
0.87g pale yellow oily liquid product shown in formula e, yield 79.7%.
2) preparation of 4- nitrobenzophenone -3- (2- pyridyidithio) propyl carbonate:
3- (2- pyridyidithio) propyl alcohol (0.87g, 4.33mmol) and triethylamine (0.52g, 5.15mmol) are dissolved in
In 50mL methylene chloride, nitro phenyl chloroformate (0.87 g, 4.33mmol) will be slowly added dropwise into solution under being stirred at room temperature,
Drop finishes, and is stirred to react 10 hours.Concentration, silica gel post separation, concentration are dried in vacuo to obtain pale yellow oily liquid shown in formula f
1.32g, yield 83.3%.
3) preparation of 3- (2- pyridyidithio) propyl carbonate and Cabazitaxel conjugate:
By 4- nitrobenzophenone -3- (2- pyridyidithio) propyl carbonate (1.32g, 3.61mmol) and Cabazitaxel
(3.05g, 3.65mmol) is dissolved in 100mL methylene chloride, and 1ml triethylamine is added, then heats to back flow reaction 10 hours.Instead
Should finish, be down to room temperature, with dilute hydrochloric acid washing organic phase, liquid separation, drying, concentration, through silica gel column purification, concentration, vacuum drying
Obtain 2.52g faint yellow solid 3- (2- pyridyidithio) propyl carbonate as shown in formula g and Cabazitaxel conjugate (Py-
SS (O)-Cabazitaxel), yield 65.7%.
4) polyethylene glycol-disulfide bond (O)-Cabazitaxel preparation:
By HS-PEG5000- SH (5.75g, 1.15mmol) is dissolved in 100mL DMF, and under nitrogen protection, stirring, Py- is added dropwise
SS (O)-Cabazitaxel (7.33g, 6.9mmol) DMF (100mL) solution, is stirred to react 12 hours at room temperature.Decompression boils off
DMF, through silica gel column purification, concentration obtains 5.25g faint yellow solid shown in formula h, yield 66.1%.
Synthetic route is as follows:
Embodiment 4:
A kind of amphiphilic polymer prodrug of reduction response release raw medicine, has the following structure formula:
Wherein 300 < n < 1000.
Above-mentioned amphiphilic polymer prodrug the preparation method is as follows:
1) preparation of 3- (2- pyridyidithio) propylamin hydrochloride:
By 3- mercaptopropylamine hydrochloride (1.0g, 7.87mmol) and 2,2 '-two sulphur, two pyridine (Py-SS-Py, 5.2g,
It 23.6mmol) is added in 30mL methanol, reaction 48 hours is stirred at room temperature.Decompression boils off methanol, crosses silica gel column purification, is concentrated, very
Empty dry the 1.4g faint yellow solid product with the structure as shown in i, yield 75.4%.
2) preparation of the third carbamic acid of 3- (2- pyridyidithio) -4- nitrobenzene base ester:
By 3- (2- pyridyidithio) propylamin hydrochloride (1.4g, 5.93mmol) and triethylamine (1.2g, 11.8mmol)
Be dissolved in 100mL methylene chloride, nitro phenyl chloroformate (3.57g, 17.76mmol) will be slowly added dropwise under being stirred at room temperature to
In solution, drop finishes, and is stirred to react 3 hours.Concentration, silica gel post separation, concentration, be dried in vacuo the structure as shown in j white it is solid
Body product 1.5g, yield 69.3%.
3) preparation of 3- (2- pyridyidithio) third carbamic acid and vinorelbine conjugate:
By the third carbamic acid -4- nitrobenzene base ester (1.5g, 4.11mmol) of 3- (2- pyridyidithio) and vinorelbine
(9.6g, 12.33mmol) is dissolved in 200mL methylene chloride, and 2ml triethylamine is added, then heats to back flow reaction 1 hour.Instead
Should finish, be down to room temperature, with dilute hydrochloric acid washing organic phase, liquid separation, drying, concentration, through silica gel column purification, concentration, vacuum drying
Obtain faint yellow solid 3- (2- pyridyidithio) the third carbamic acid and vinorelbine conjugate (Py-SS of the structure as shown in k
(N)-vinorelbine) 2.75g, yield 67.6%.
4) polyethylene glycol-disulfide bond (N)-vinorelbine preparation:
By HS-PEG10000- SH (11.1g, 1.11mmol) is dissolved in 100mL DMF, and under nitrogen protection, stirring, Py- is added dropwise
SS (N)-vinorelbine (3.34g, 3.33mmol) DMF (150 mL) solution, is stirred to react 24 hours at room temperature.Decompression boils off
DMF, through silica gel column purification, concentration obtains faint yellow solid 11.3g shown in formula I, yield 86.3%.
Synthetic route is as follows:
In order to verify resulting polymers prodrug of the present invention to the proliferation inhibiting effect of tumour cell, our Examples
2 resulting polymer micelles and SN-38 have carried out the Contrast on effect experiment of extracorporeal anti-tumor cell, we are with colorectal cancer
The resulting polymer micelle of example 2 and SN-38 are carried out for HT29 and colorectal cancer HCT116 respectively to tumour cell
Proliferation inhibiting effect experiment, specific operation process are as follows:
The cell of logarithmic growth phase adjusts cell density appropriate, is inoculated in 96 orifice plates, 100 μ l/well, culture
In 37 DEG C, 5%CO2Incubator in.It is administered after overnight incubation, dosing acts on 48h respectively.Set up blank group, administration group separately, often
Group sets 4 multiple holes.Tuberculosis in vitro carcinoma of the rectum effect is as shown in Fig. 4 and Fig. 5.As can be seen, polyethylene glycol-from Fig. 4 and Fig. 5
Disulfide bond (O)-SN38 polymer micelle and SN-38 have approximate cytotoxicity, polyethylene glycol-disulfide bond (O)-SN38 polymerization
Median lethal dose IC of the object micella to colorectal cancer HT2950It is 7.65 μM, to the median lethal dose IC50 of colorectal cancer HCT116
It is 0.391 μM, there is stronger anti-tumor activity.
In conclusion amphiphilic polymer prodrug provided by the invention not only good water solubility, and can be in tumour
Raw medicine is released in 1h under intracellular reducing condition, realizes Targeting delivery, and it was proved that have with raw medicine basic
Identical anti-tumor activity, can be in playing its inhibiting effect to tumour cell in 48h.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of reduction response type amphipathic stem polymer prodrug, which is characterized in that have the structural formula as shown in formula I:
Wherein, X is NH or O；ROH is hydrophobic anticancer drug；N is 5~1000；M is 1 or 2.
2. polymer prodrug according to claim 1, which is characterized in that have the structural formula as shown in formula II:
3. polymer prodrug according to claim 1 or 2, which is characterized in that the anti-tumor drug refers to camplotheca acuminata
Bases, taxanes, any one in vinca drug.
4. polymer prodrug according to claim 3, which is characterized in that the camptothecine refers to camplotheca acuminata
One of alkali, Irinotecan, topotecan, 10-hydroxycamptothecine or 7-Ethyl-10-hydroxycamptothecin, the taxanes
Drug refers to that one of taxol, Docetaxel, Cabazitaxel or La Luotasai, the vinca drug refer to Changchun
One of alkali, vincristine or vinorelbine.
5. a kind of polymer nano micelle, which is characterized in that the polymer nano micelle be by the following method made of, will weigh
Benefit require polymer prodrug described in any one of 1-4 and fatty acid triglycercide be placed in water dissolve the two mixing
Solution, after by solution ultrasound, filter membrane, thereto be added mannitol freeze-drying to get polymer nano micelle.
6. polymer nano micelle according to claim 5, which is characterized in that the partial size of the polymer nano micelle is
10~400nm, drugloading rate are 1~50wt%.
7. polymer prodrug of any of claims 1-4 and claim 5,6 described in any item polymer
Application of the nano-micelle in field of antineoplastic medicaments.
8. application according to claim 7, which is characterized in that the tumour refers to colorectal cancer.
9. a kind of preparation method of polymer prodrug of any of claims 1-4, which is characterized in that including such as
Lower step:
1) by mercaptoalcohol or mercapto-amine and 2 containing 2-3 carbon atom, pyridyidithio is made in the reaction of 2 '-two sulphur, two pyridine
Alcohol or pyridyidithio amine；
2) it is carried out using the pyridyidithio alcohol or pyridyidithio amine that are obtained to nitro phenyl chloroformate and step 1) even
Connection, which reacts, is made carbonic ester or amino carbonic ester；
3) the resulting carbonic ester of step 2) or amino carbonic ester and the hydrophobic anticancer drug of hydroxyl group are handed over by ester
It changes reaction and generates conjugate；
4) the resulting conjugate of step 3) is exchanged instead with double sulfydryl polyethylene glycols (HS-PEG-SH) by thiol disulfide
It answers, the polyethylene glycol polymer prodrug containing disulfide bond is made；
Reaction route is as follows:
10. the preparation method of polymer prodrug according to claim 9, which is characterized in that each step it is specific
Reaction process is as follows:
Step 1): by mercaptoalcohol or mercapto-amine and 2 containing 2-3 carbon atom, 2 '-two sulphur, two pyridine according to molar ratio 1:(1~
3) it is added in solvent, reaction is stirred at room temperature 12~48 hours, end of reaction, concentration, silica gel post separation, concentration, dry pyridine
Base disulfide group alcohol or pyridyidithio amine；
Step 2): under alkaline condition, the resulting pyridyidithio alcohol of step 1) or pyridyidithio amine are dissolved in solvent
In, nitro phenyl chloroformate will be added dropwise in solution, be stirred to react 1~10 hour under being stirred at room temperature, and control two sulphur of pyridyl group
Base alcohol or pyridyidithio amine are 1:(1~3 with the molar ratio to nitro phenyl chloroformate), it is concentration, silica gel post separation, dense
Contracting, dry carbonic ester or amino carbonic ester；
Step 3): under alkaline condition, by the resulting carbonic ester of step 2) or amino carbonic ester and contain the hydrophobic of hydroxyl group
Property anti-tumor drug 1:(1~3 in molar ratio) it is dissolved in solvent, back flow reaction 1~10 hour, it is down to room temperature, reaction solution is through acid
Wash, liquid separation, drying, concentration, silica gel column purification, concentration, be dried in vacuo the two conjugate；
Step 4): under nitrogen protection, double sulfydryl polyethylene glycols (HS-PEG-SH) are added drop-wise to obtained by step 3) under stirring condition
In the solution of conjugate, the molar ratio for controlling HS-PEG-SH and conjugate is 1:(2~6), it is small that it is stirred to react 12~48 at room temperature
When, concentration, silica gel column purification, concentration, dissolution, filtering, freeze-drying obtain the polyethylene glycol polymer prodrug containing disulfide bond.
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