CN110393806A - A kind of Temozolomide polymeric prodrugs and the preparation method and application thereof - Google Patents
A kind of Temozolomide polymeric prodrugs and the preparation method and application thereof Download PDFInfo
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Abstract
A kind of Temozolomide polymeric prodrugs and the preparation method and application thereof, comprising: synthesis end is the hydrophilic polymer of hydroxyl；Synthesize the Temozolomide derivative that end group is carboxyl；It is reacted by the hydroxyl of hydrophilic polymer end with the carboxyl of Temozolomide derivative, Temozolomide is bonded to hydrophilic polymer end, obtains the polymeric prodrugs of Temozolomide.Temozolomide polymeric prodrugs of the invention, Temozolomide and polymer by being covalently keyed, can recycle in vivo in keep stablizing；Temozolomide and polymer by that can form nano-micelle after being covalently keyed in water, this nano-micelle is not easy to dissociate in extracellular and blood, it solves and is easy to also overcome drug while degradation problem and be easily compromised in vivo under Temozolomide physiological condition, the deficiencies of circulation time is short.
Description
Technical field
The present invention relates to chemical synthesis and biological medicine, and in particular to a kind of Temozolomide polymeric prodrugs and preparation method thereof
With application.
Background technique
Traditional nano-medicament carrier can greatly enhance the water solubility of dewatering medicament, effectively weaken the secondary work of drug poison
With extending drug circulation time in vivo, but they also have disadvantages that: 1) it is low to contain medication amount than great for carrier itself；
2) pharmaceutical carrier enters in vivo since Macrodilution leads to bad stability, contains drug and is easy to reveal in advance, normal tissue
Generate toxic side effect；3) burst release is easy to happen in tumour cell.Polymeric prodrugs are steady due to that can effectively improve anticancer drug
Qualitative, drugloading rate and pharmacokinetics, now have developed into that scientists are widely recognized as can be effective for oncotherapy
Nano medication technology platform (Duncan, R.et al.Advanced Drug Delivery Reviews 2013,65,60；
Pasut,G.et al.Progress in Polymer Science 2007,32,933).Polymeric prodrugs and Conventional nano medicine
Object carrier is compared, and has following advantages: 1) drug is with polymer by being covalently keyed, and circulation is kept sufficiently stable in vivo,
It reduces a possibility that drug is revealed in advance: 2) drug delivery amount, and the constant release of energy can be greatly improved, be less prone to burst release.
Nano-micelle enters in vivo as pharmaceutical carrier, and human body reticuloendothelial system (RES) macrophage can be effectively reduced
The phagocytosis of cell can pass through space between cells, can be by the smallest capillary of human body and blood-brain barrier (BBB) and by cell tissue
It absorbs, releases anticancer drug and kill cancerous tumor cell.Meanwhile nano-micelle can be lost to avoid pharmaceutical activity, be conducive to drug
Storage and transport (Zhang, et al.Chemical Communications 2012,48,7542；Hossen,et
al.Journal of Advanced Research 2019,15,1)。
Poly- oxazoline (Pox) is a kind of polymer of discovery the 1960s, there is that toxicity is low, synthesis is simple, higher
Stability and the advantages that good biocompatibility (Bauer, M.et al.Macromol.Biosci, 2012,12,
986-998).So far, poly- (2- ethyl -2- oxazoline) (PEtOz) is by U.S.'s food and drug surveilance pipe
Reason office (FDA) approval as food additives (Rasolonjatovo B et al.Biomacromolecules, 2015,16
(3),748；Verbraeken,B et al.European Polymer Journal,2017,88,451).In recent years, poly- (2-
Ethyl -2- oxazoline) (PEtOz) attract extensive attention (Luxenhofer R et al.Macromol because of its good water solubility
Rapid Commun,2012,33(19),1613)。
Temozolomide (TMZ) is a kind of lipophilic small molecule chemotherapeutics, is current clinically widely used glioma
Chemotherapeutics.Temozolomide, which has lesser molecular weight and can easily pass through blood-brain barrier, reaches tumor locus with more preferable
Ground carries out oncotherapy.As a kind of small molecule prodrugs, spontaneous hydrolysis, released dna are alkylated methyl diazonium to TMZ at physiological ph
Cation, cause DNA methylation and realize antitumor action (Newlands, et al.Cancer Treatment Reviews,
1997,23,35；Zhang,J.et al.Current molecular pharmacology,2012,5,102).However, the Yishui River
Solution degradation and the property quickly removed in vivo limit tumor uptake and need frequent drug administration to maintain Antitumor Activity of Drugs,
This is very harmful to cancer patient.In order to overcome this disadvantage of TMZ, scientist takes many strategies to stablize TMZ.It leads
Include the cocrystallization with organic acid, the encapsulating of nano material, and and main polymer chain (Babu, the N.J.et such as combination
al.Chemistry-an Asian Journal,2012,7,2274；Appel,E.A.et al.A.Chemical
Communications,2012,48,9843；Fang,C.et al.ACS Applied Materials&Interfaces,
2015,7,6674).Work report of the Temozolomide in conjunction with polymer is fewer at present, therefore develops novel Temozolomide
The need of work of polymeric prodrugs obtains bigger concern.
Summary of the invention
The first purpose of the invention is to provide a kind of preparation methods of novel Temozolomide polymeric prodrugs, comprising:
Synthesize the hydrophilic polymer that end is hydroxyl；Synthesize the Temozolomide derivative that end group is carboxyl；Pass through hydrophilic polymer
The hydroxyl of end is reacted with the carboxyl of Temozolomide derivative, and Temozolomide is bonded to hydrophilic polymer end, is obtained for not
The polymeric prodrugs of azoles amine.
Further, the molecular weight of the hydrophilic polymer is 1000~30000Da.
Further, the step S2 is specifically included: in concentrated sulfuric acid by Temozolomide dissolution, the yellow solution that will be obtained
It is cooled to 0 DEG C under a nitrogen, the aqueous solution of sodium nitrite is added dropwise；When mixture being warmed to room temperature, while being protected from light one section of stirring
Between after, mixture is cooled to 0 DEG C and is quenched with ice；Futher stirring at 0 DEG C makes it generate white solid precipitating, vacuum mistake
Precipitation and separation, cold water washing are filtered, vacuum drying obtains the Temozolomide derivative that end group is carboxyl.
Further, the step S3 is specifically included: the Temozolomide derivative that end group is carboxyl being suspended in DCM and is obtained
Hydrophilic polymer and 4-dimethylaminopyridine that end is hydroxyl are added in suspension, 1- (3- are then added by suspension
Dimethylamino-propyl) -3- ethyl carbodiimide, stirring a period of time obtains mixture, evaporation mixing in protective atmosphere at room temperature
Object obtains solid；Orange solids are dissolved in solvent and are dialysed, it is after dialysis, gained liquid freezing is dry for not
The polymeric prodrugs of azoles amine.
It is a further object to provide the Temozolomide polymeric prodrugs prepared by above-mentioned preparation method.
The present invention also provides a kind of polymeric prodrugs nano-micelle, the polymeric prodrugs nano-micelle is by aforementioned for not
Azoles amine polymer prodrug is self-assembly of in water, and the shell of nano-micelle is constituted by hydrophilic polymer is poly-, and kernel is by small point
Sub- Temozolomide is constituted, and is connected between shell and kernel by ester bond.
The present invention also provides aforementioned Temozolomide polymeric prodrugs application in preparations of anti-tumor drugs.
Compared with prior art, beneficial effects of the present invention:
Temozolomide and polymer by being covalently keyed, can recycle in vivo in keep sufficiently stable；Temozolomide with
Polymer by that can form nano-micelle after being covalently keyed in water, this nano-micelle not legibility in extracellular and blood
From, drug, which is also overcomed, while solving easy degradation problem under Temozolomide physiological condition is easily compromised in vivo, circulation
The deficiencies of time is short.
Detailed description of the invention
Fig. 1 is the conjunction of the Temozolomide derivative and poly- (2- ethyl -2- oxazoline)-Temozolomide in the embodiment of the present invention
At route；
Wherein, a is the synthetic route of the Temozolomide derivative in embodiment 3, and b is poly- (the 2- second in embodiment 4 and 5
Base -2- oxazoline)-Temozolomide (PEtOz-TMZ) synthetic route.
Specific embodiment:
A kind of polymeric prodrugs of Temozolomide, the polymer moieties of the polymeric prodrugs are the hydrophily that end is hydroxyl
Polymer, drug are Temozolomide.The polymeric prodrugs can be self-assembly of nano-micelle in water.Hydrophilic polymer choosing
From but be not limited to: the ends such as poly- oxazoline, polyethylene glycol, polyphosphate be hydroxyl hydrophilic polymer, hydrophilic polymer
Molecular weight be 1000~30000Da.
Temozolomide polymeric prodrugs can be self-assembly of polymeric prodrugs nano-micelle, polymeric prodrugs nanometer in water
Micella is made of hydrophilic polymer and Temozolomide, and the shell of nano-micelle is constituted by hydrophilic polymer is poly-, and kernel is by small point
Sub- drug Temozolomide is constituted, intermediate to be connected by ester bond, and the partial size of nano-micelle is 10~300nm, and particle diameter distribution PDI is
0.01~0.30.Above-mentioned polymeric prodrugs nano-micelle is not easy to dissociate in extracellular and blood, is solving Temozolomide physiology
Under the conditions of be easy to overcome drug while degradation problem and be easily compromised in vivo, the deficiencies of circulation time is short.
The present invention will be further described combined with specific embodiments below.According to following embodiments, can better understand
The present invention.However, specific material proportion, process conditions and its result described in embodiment are merely to illustrate the present invention, and
It should not will not limit the present invention described in detail in claims.
Embodiment 1 synthesizes poly- (2- ethyl -2- oxazoline) (PEtOz-OH) that target molecular weight is 5000Da
It is monomer in methyl tosylate that the synthesis of poly- (2- ethyl -2- oxazoline) (PEtOz-OH), which is using EtOz,
(MeOTs) ring-opening polymerisation obtains under initiation.First under nitrogen protection successively by EtOz (10.0g, 0.101mol), acetonitrile
(33.3ml) and methyl tosylate (0.34g, 1.83 × 10-3Mol reaction flask) is added.It is reacted for 24 hours at 100 DEG C later.
Then cool to room temperature and be added the methanol solution 18ml of 0.1M potassium hydroxide, stir and terminate reaction after 4h, then with ice ether into
Solid is collected in row sedimentation, and vacuum drying is for 24 hours.Measuring actual molecular weight is 4700Da.
Embodiment 2 synthesizes poly- (2- ethyl -2- oxazoline) (PEtOz-OH) that target molecular weight is 7500Da
First under nitrogen protection successively by EtOz (10.0g, 0.101mol), acetonitrile (33.3ml) and p-methyl benzenesulfonic acid first
Ester (0.24g, 1.32 × 10-3Mol reaction flask) is added.It is reacted for 24 hours at 100 DEG C later.It then cools to room temperature and hydrogen is added
The methanol solution (0.1M, 33ml) of potassium oxide terminates reaction after stirring 4h, then is settled with ice ether, collects solid, vacuum
Drying is for 24 hours.Measuring actual molecular weight is 8800Da.
The Temozolomide derivative (TMZ-COOH) of the synthesis carboxyl terminal of embodiment 3
As shown in Figure 1a, 5mg TMZ is dissolved in the 47ml concentrated sulfuric acid, obtained yellow solution is cooled under a nitrogen
0 DEG C, the aqueous solution of 47ml sodium nitrite (4.02g, 72.8mmol) is added dropwise.Mixture is warmed to room temperature, while being protected from light stirring
After for 24 hours, mixture is cooled to 0 DEG C and is quenched with 122g ice.It is futher stirred at 0 DEG C and generates white solid precipitating, vacuum
It is separated by filtration.It is washed with cold water, and is dried under vacuum to obtain TMZ-COOH.
Embodiment 4 synthesizes poly- (2- ethyl -2- oxazoline)-Temozolomide (PEtOz-TMZ, Mn PEtOz=4700Da)
P-methyl benzenesulfonic acid methyl esters ring-opening polymerisation monomer 2- ethyl 2- oxazoline is used first, and obtaining end is the poly- of hydroxyl
The molecular weight of (2- ethyl -2- oxazoline) (PEtOz-OH), poly- (2- ethyl -2- oxazoline) can be added by control to methyl
The amount of methyl benzene sulfonate adjusts the molecular weight of poly- oxazoline.
39mg TMZ-COOH is suspended in 20ml DCM, by 0.5g PEtOz and 2.5mg 4-dimethylaminopyridine
(DMAP) it is added in suspension, 45mg 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide (EDC) is then added；In nitrogen
Under gas shielded, after being stirred at room temperature 20 hours, mixture is obtained into solid by rotary evaporation.2ml H is added2O is dissolved, thoroughly
Analysis 24 hours.After dialysis, PEtOz-TMZ will can be obtained after the drying of gained liquid freezing.Obtained Temozolomide gathers
Object prodrug is closed with poly- (2- ethyl -2- oxazoline) as hydrophilic section (Mn PEtOz=4700Da), Temozolomide is hydrophobic section.
Embodiment 5 synthesizes poly- (2- ethyl -2- oxazoline)-Temozolomide (PEtOz-TMZ, Mn PEtOz=8800Da)
The synthesis step of the present embodiment is substantially the same manner as Example 4, and 21mg TMZ-COOH is specifically suspended in 20ml
In DCM, 0.5g PEtOz and 1.5mg 4-dimethylaminopyridine (DMAP) are added in suspension, 25mg1- is then added
(3- dimethylamino-propyl) -3- ethyl carbodiimide (EDC).Under nitrogen protection, after being stirred at room temperature 20 hours, mixture is led to
It crosses rotary evaporation and obtains solid.2ml H is added2O is dissolved, and is dialysed 24 hours.After dialysis, gained liquid freezing is done
PEtOz-TMZ (M can be obtained after dryn PEtOz=8800Da).
6 synthesizing polyethylene glycols of embodiment-Temozolomide (PEG-TMZ, Mn PEG=5000Da)
29mg TMZ-COOH is suspended in 20ml DCM, by 0.5g PEG and 2.5mg 4-dimethylaminopyridine
(DMAP) it is added in suspension, 45mg 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide (EDC) is then added.In nitrogen
Under gas shielded, after being stirred at room temperature 20 hours, mixture is obtained into solid by rotary evaporation.2ml H is added2O is dissolved, thoroughly
Analysis 24 hours.After dialysis, PEG-TMZ (M will can be obtained after the drying of gained liquid freezingn PEG=5000Da).
Poly- (2- ethyl -2- oxazoline)-Temozolomide (M of embodiment 7n PEtOz=4700Da) nano-micelle preparation
Poly- (2- ethyl -2- oxazoline)-Temozolomide nano-micelle is prepared by direct water soluble method.Detailed process is: will
Poly- (2- ethyl -2- the oxazoline)-Temozolomide of 2mg is dissolved directly into 2ml secondary water, stirs evenly, and polymer can be obtained
Prodrug nano-micelle.The partial size for the polymeric prodrugs nano-micelle being prepared is 130.0nm, and particle diameter distribution (PDI) is 0.20.
8 polyethylene glycol of embodiment-Temozolomide nano-micelle (Mn PEG=5000Da) preparation
Polyethylene glycol-Temozolomide nano-micelle is prepared by direct water soluble method.Detailed process is: by 2mg polyethylene glycol-
Temozolomide is dissolved directly into 2ml secondary water, is stirred evenly, and polymeric prodrugs nano-micelle can be obtained.It is prepared
The partial size of polymeric prodrugs nano-micelle is 157.7nm, and particle diameter distribution (PDI) is 0.20.
Poly- (the 2- ethyl -2- oxazoline) of different molecular weight and gathering for different hydrophilic section are prepared according to embodiment one to eight
Object prodrug polyethylene glycol-Temozolomide nano-micelle is closed, and tests the size and distribution of gained nano-micelle, as a result such as table 1
It is shown.
The polymeric prodrugs nano-micelle of 1 different hydrophilic section of table
Poly- (2- ethyl -2- the oxazoline)-Temozolomide of 9 Temozolomide polymeric prodrugs of embodiment and polyethylene glycol-be not for
The half-life measurement of azoles amine
The half-life measurement method of the polymeric prodrugs is using ultraviolet spectroscopy.At measurement λ 328-330nm
The variation of absorption peak can measure polymer-Temozolomide half-life period.2mg Temozolomide polymeric prodrugs are dissolved in
It in the PBS buffer solution of pH7.4, with 37 DEG C in constant temperature oscillation case, is incubated under conditions of 200rpm, within the corresponding interval time
The absorption peak at its λ 328-330nm is measured, normalizes absorbance (A/A finally by drawing0) with the index of incubation time variation
Attenuation curve replaces not azoles to obtain poly- (2- ethyl -2- the oxazoline)-Temozolomide of Temozolomide polymeric prodrugs and polyethylene glycol -
The half-life period of amine.
According to the half-life period for the Temozolomide polymeric prodrugs that embodiment nine measures, the results are shown in Table 2.
The half-life period of 2 Temozolomide polymeric prodrugs of table
The result shows that: by the Temozolomide polymeric prodrugs of Temozolomide and polymer-bound preparation, effectively extend
The half-life period of TMZ.
The above is only a preferred embodiment of the present invention, it should be pointed out that: for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (8)
1. a kind of preparation method of Temozolomide polymeric prodrugs, which comprises the following steps:
S1: synthesis end is the hydrophilic polymer of hydroxyl；
S2: synthesis end group is the Temozolomide derivative of carboxyl；
S3: it is reacted by the hydroxyl of hydrophilic polymer end with the carboxyl of Temozolomide derivative, Temozolomide is bonded to
Hydrophilic polymer end obtains the polymeric prodrugs of Temozolomide.
2. preparation method according to claim 1, which is characterized in that the molecular weight of the hydrophilic polymer be 1000~
30000Da。
3. preparation method according to claim 1, which is characterized in that the step S2 is specifically included:
In concentrated sulfuric acid by Temozolomide dissolution, obtained yellow solution is cooled to 0 DEG C under a nitrogen, sodium nitrite is added dropwise
Aqueous solution；Mixture is warmed to room temperature, at the same be protected from light stirring a period of time after, mixture is cooled to 0 DEG C and is quenched with ice；
Futher stirring at 0 DEG C makes it generate white solid precipitating, isolated by vacuum filtration precipitating, and cold water washing is dried in vacuo, must hold
Base is the Temozolomide derivative of carboxyl.
4. preparation method according to claim 1, which is characterized in that the step S3 is specifically included:
The Temozolomide derivative that end group is carboxyl is suspended in DCM and obtains suspension, is the hydrophilic polymer of hydroxyl by end
Object and 4-dimethylaminopyridine are added in suspension, and 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide, room is then added
Stirring a period of time obtains mixture in protective atmosphere under temperature, and evaporating mixture obtains solid；By solid be dissolved in solvent into
Row dialysis, after dialysis, by gained liquid freezing it is dry Temozolomide polymeric prodrugs.
5. the Temozolomide polymeric prodrugs of the preparation of the preparation method as described in any of the above-described claim.
6. a kind of polymeric prodrugs nano-micelle, which is characterized in that the polymeric prodrugs nano-micelle is by claim 5
Temozolomide polymeric prodrugs are self-assembly of in water, and the shell of nano-micelle is constituted by hydrophilic polymer is poly-, kernel by
Small molecule Temozolomide is constituted, and is connected between shell and kernel by ester bond.
7. a kind of polymeric prodrugs nano-micelle according to claim 6, which is characterized in that the partial size of the nano-micelle
It is 0.01~0.30 for 10~300nm, particle diameter distribution PDI.
8. the application in preparation of anti-tumor drugs of Temozolomide polymeric prodrugs described in claim 5.
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| CN111228218A (en) * | 2020-02-21 | 2020-06-05 | 江苏师范大学 | Temozolomide nano prodrug micelle and preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111228218A (en) * | 2020-02-21 | 2020-06-05 | 江苏师范大学 | Temozolomide nano prodrug micelle and preparation method and application thereof |
| CN111228218B (en) * | 2020-02-21 | 2021-11-02 | 江苏师范大学 | Temozolomide nano prodrug micelle and preparation method and application thereof |
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