CN106349193B - Taxanes dimer, preparation method and its preparation - Google Patents
Taxanes dimer, preparation method and its preparation Download PDFInfo
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- CN106349193B CN106349193B CN201610726985.5A CN201610726985A CN106349193B CN 106349193 B CN106349193 B CN 106349193B CN 201610726985 A CN201610726985 A CN 201610726985A CN 106349193 B CN106349193 B CN 106349193B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
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Abstract
The present invention provides a kind of taxanes dimer, preparation method and its preparation, belongs to biomedicine field.Solving the problems, such as existing taxanes pharmaceutical preparation, dissolubility is low in water.The dimer is made of taxanes and connection molecule, and the taxanes are taxol or Docetaxel, and the connection molecule is dicarboxylic acids or the dicarboxylic acids containing disulfide bond.The present invention also provides a kind of preparation methods of taxanes dimer.The present invention also provides a kind of preparation, the preparation includes amphiphilic polymers and above-mentioned taxanes dimer.Taxanes dimer of the invention has good dissolubility in water or in injection, and solution has very high storage stability, which occurs hydrolysis in physiological conditions, releases taxanes drug, and then play curative effect.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to a kind of taxanes dimer, preparation method and its preparation.
Background technique
Taxol is a kind of anti-micro-pipe agent by extracting in Pacific yew-yewtree needle and bark, since
Since Wani et al. was separated for the first time in 1971 and the structure of taxol has been determined with chemistry and X-ray crystallography method, the I phase
Clinical research and II, III clinical trial phase, which are shown, has apparent Synergistic action to human cancer.This effect be initially
It is found in Advanced Ovarian and tumor of breast, existing lot of documents reports it to cellule and non-small cell lung cancer, head-neck carcinoma
There is remarkable effect with transfer melanoma.But be that its chemical structure has high lipid for clinical Major Difficulties, it is almost insoluble
Yu Shui, solubility in water are only 0.25 μ g mL-1。
The representational paclitaxel injection clinically used at present is that taxol is configured to concentrate solution, i.e., with poly-
(v/v, 1: 1) Compound mixed solution is 7mmol L at concentration for ethylene oxide castor oil and dehydrated alcohol-1Paclitaxel solution, before administration
Final concentration of 0.35~1.4mmol L is diluted to 0.9% physiological saline or 5% Glucose Liquid-1.It can be before this preparation diluent
It is maintained for a long time and never degenerates in the case of 4 DEG C of sealings.But the dosage of Emulsifier EL-60 contained therein will be apparently higher than and match
The dosage of other medicines preparation processed.This toxic effect of auxiliary material, including allergy, vasodilation, expiratory dyspnea and low blood pressure.Face
Bed experiments have shown that, almost can all there is patient to show strong even fatal allergic reaction to it in each stage.These
Allergic reaction is mainly caused by Emulsifier EL-60, and taxol itself is without sensitization.
Docetaxel is artificial synthesized drug, while being also the precursor substance of taxol biosynthesis, is had preferably steady
Determine the effect of micro-pipe, therefore antitumous effect is better than taxol, is suitable for Locally Advanced or metastatic breast cancer and part
The treatment of advanced stage or Metastatic Nsclc.Commercially available representative Taxotere alcohol formulations are that taxotere is (mostly western
He matches injection).40mg mL is made into the pure and mild Tween 80 of Taxotere-1Injection, then be with taxotere solvent-concentration
Injection ethyl alcohol (95%) aqueous solution of 13%w/w is diluted to using concentration.But showing that this preparation has in report makes neutral grain
The adverse reaction of Leukopenia.
So the novel form of development taxol and Docetaxel is always the hot spot of researcher's concern.Make to reduce
Explore the delivery system of a variety of taxols and Docetaxel with organic solvent people, as emulsion, liposome, micro-capsule,
Microballoon, Nano capsule and with cyclodextrin etc..But these delivery system medicament contgs are lower, are generally lower than 10wt%, low
Medicament contg mean to have used a large amount of auxiliary material, may bring some unknown side effects, therefore, exploitation, which has, high carries medicine
The delivery system of amount is the key that exploitation taxol and Docetaxel novel form.
Studies have shown that the solubility of taxol and Docetaxel in water is extremely low, this is the tired of their novel forms exploitation
Where difficult, on the other hand on the one hand it is it that extremely low solubility is the highly lipophilic property and hydrophobicity due to their molecular structures
Excellent crystallinity.If changing the systematicness of their molecular structures, their crystallinity is destroyed, their dissolutions in water
Property or compatibility in the carrier will be significantly improved.The solubility of taxol in water itself is only 0.25-5 μ g mL-1。
Summary of the invention
The purpose of the present invention is to solve the existing taxanes pharmaceutical preparation low problems of dissolubility in water, and mention
For a kind of taxanes dimer, preparation method and its preparation.
Present invention firstly provides a kind of taxanes dimer, which is made of taxanes and connection molecule, institute
The taxanes stated are taxol or Docetaxel, and the connection molecule is dicarboxylic acids or the dicarboxylic acids containing disulfide bond.
Preferably, the dicarboxylic acid structure formula is HOOC- (CH2)n- COOH, wherein n=2-8；
The dicarboxylic acid structure formula containing disulfide bond is HOOC- (CH2)n-XX-(CH2)n- COOH, wherein X=S, n
=2-5.
The present invention also provides a kind of preparation methods of taxanes dimer, this method comprises:
Step 1: taxanes solution and connection molecule are mixed, mixed liquor is obtained；
Step 2: EDC and DMAP is added in the mixed liquor that step 1 obtains and is reacted, taxanes dimer is obtained；
The taxanes solution is paclitaxel solution or Taxotere alcoholic solution, and the connection molecule is dicarboxylic acids
Or the dicarboxylic acids containing disulfide bond.
Preferably, the taxanes solution is that taxanes are dissolved in organic solvent to obtain, and described has
Solvent is methylene chloride, chloroform, dimethyl sulfoxide or dimethylformamide.
Preferably, the molar ratio of the taxanes and connection molecule is 1:(0.55-0.56).
Preferably, the reaction temperature of the step two is room temperature, and the reaction time is 24~48 hours.
Preferably, the molar ratio of the taxanes, EDC and DMAP are 1:(3-3.1): 0.2.
The present invention also provides a kind of preparation, the preparation includes amphiphilic polymers and above-mentioned taxanes dimer.
Preferably, the amphiphilic polymers include poly(ethylene glycol)-polylactic acid, poly(ethylene glycol)-polycaprolactone,
Poly- (lactic acid-is in oneself for poly(ethylene glycol)-polyglycolic acid, poly(ethylene glycol)-poly (lactic acid-glycolic acid) or poly(ethylene glycol)-
Ester).
Preferably, in the preparation, the content of taxanes dimer is 10%~90%.
Beneficial effects of the present invention
Present invention firstly provides a kind of taxanes dimer, which is made of taxanes and connection molecule, institute
The taxanes stated are taxol or Docetaxel, and the connection molecule is dicarboxylic acids or the dicarboxylic acids containing disulfide bond.
It compares with the prior art, taxanes dimer of the invention has good dissolubility, solution tool in water or in injection
There is very high storage stability, which occurs hydrolysis in physiological conditions, releases taxanes medicine
Object, and then play curative effect.
The present invention also provides a kind of preparation method of taxanes dimer, this method is incited somebody to action under the action of condensing agent
Esterification occurs for the carboxyl end group of hydroxyl and connection molecule on 2 ' position of taxol or Docetaxel, is condensed into taxanes two
Aggressiveness.The preparation method is simple, raw material is easy to get, and the taxanes dimer being prepared has good dissolubility.
The present invention also provides a kind of preparation, the preparation includes amphiphilic polymers and above-mentioned taxanes dimer.
There is said preparation very strong cellkilling capacity also to present similar antitumous effect on mouse melanin tumor model,
But without the sensitivity response and general toxicity of commercially available paclitaxel injection and docetaxel injection, and in solid pharmaceutical preparation
Medicament contg is up to 30~60%, but there is good dissolubility in water or in injection.
Detailed description of the invention
Fig. 1 is the mass spectrogram for the taxol dimer that the embodiment of the present invention 1 is prepared；
Fig. 2 is poly(ethylene glycol)-polylactic acid (mPEG that embodiment 10 is prepared2K-PDLLA2K) package by suberic acid is
The taxol dimer of connection molecule forms the transmission electron microscope picture of micella M (DPTX-C8)；
Fig. 3 is poly(ethylene glycol)-polylactic acid (mPEG that embodiment 10 is prepared2K-PDLLA2K) package by suberic acid is
The taxol dimer of connection molecule forms the grain size stability figure of micella M (DPTX-C8) in 10% fetal calf serum.
Specific embodiment
Present invention firstly provides a kind of taxanes dimer, which is made of taxanes and connection molecule, institute
The taxanes stated are taxol or Docetaxel, and the connection molecule is dicarboxylic acids or the dicarboxylic acids containing disulfide bond.
According to the present invention, the dicarboxylic acid structure formula is preferably HOOC- (CH2)n- COOH, wherein n=2-8；Including but
It is not limited to succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid or decanedioic acid.
According to the present invention, the dicarboxylic acid structure formula containing disulfide bond is HOOC- (CH2)n-XX-(CH2)n- COOH,
Wherein X=S, n=2-5.
The present invention also provides a kind of preparation methods of taxanes dimer, this method comprises:
Step 1: taxanes solution and connection molecule are mixed, mixed liquor is obtained；
Step 2: EDC and DMAP is added in the mixed liquor that step 1 obtains and is reacted, taxanes dimer is obtained；
According to the present invention, first taxanes are dissolved in organic solvent, obtain taxanes solution, described is organic molten
Agent is not particularly limited, and can dissolve taxanes, preferably methylene chloride, chloroform, dimethyl sulfoxide or dimethyl
Formamide；The mass concentration of the taxanes solution is preferably 10-20mg mL-1。
According to the present invention, above-mentioned taxanes solution and connection molecule are mixed, after completely dissolution, obtain mixed liquor；Institute
The molar ratio of the taxanes and connection molecule stated is preferably 1:(0.55-0.56).
According to the present invention, by EDC (1- (3- dimethyl aminopropyl) -3- ethyl carbimide) and DMAP (4- dimethylamino
Pyridine) it is added in above-mentioned mixed liquor and reacts, it obtains reaction mixture after post treatment, obtains taxanes dimer.It is described
Reaction temperature be preferably room temperature, the reaction time is preferably 24-48 hours.The adding manner of the EDC and DMAP are without spy
Different limitation, is preferably added in two portions in mixed liquor, specifically: EDC and DMAP is first added and reacts 1h into mixed liquor, it is described
The molar ratio of taxanes, EDC and DMAP is preferably 1:(2-2.1): 0.1, it then adds EDC and DMAP and is relayed to mixed liquor
Continuous reaction, the molar ratio of the taxanes, EDC and DMAP are 1:1:0.1.
According to the present invention, the last handling process is after preferably filtering reaction mixture, with silica gel post separation, flowing
It is mutually preferably the mixed solvent (being eluted from 8:1 to 2:1) of methylene chloride and ethyl acetate, column temperature is room temperature, is then collected containing purple
The efflux fraction of China fir alcohols dimer removes solvent, obtains taxanes dimer.
According to the present invention, the EDC and DMAP be as condensing agent, by 2 ' position of taxanes hydroxyl with connect point
Esterification occurs for the carboxyl end group of son, is condensed into taxanes dimer.
The present invention also provides a kind of preparation, the preparation includes amphiphilic polymers and above-mentioned taxanes dimer.
According to the present invention, the amphiphilic polymers include but is not limited to poly(ethylene glycol)-polylactic acid, poly(ethylene glycol)-
Polycaprolactone, poly(ethylene glycol)-polyglycolic acid, poly(ethylene glycol)-poly (lactic acid-glycolic acid) or the poly- (cream of poly(ethylene glycol)-
Acid-caprolactone), the wherein molecular weight of hydrophilic block poly(ethylene glycol) preferably 1000~10000, more preferable 2000~5000, parent
Rouge block polylactic acid, polycaprolactone, polyglycolic acid and their copolymers molecular weight be preferably 1000~10000, more preferably
2000~5000.
According to the present invention, the content of the taxanes dimer is preferably 10%~90%, more preferable 30%~
60%.
According to the present invention, the dosage form of the preparation is preferably nano-micelle aqueous solution or nano-micelle freeze-dried powder, described
Nano-micelle aqueous solution can direct injection or drop, nano-micelle freeze-dried powder is through water for injection such as physiological saline or 5% grape
Injection and drop after sugared dissolved dilution.
The preparation method of invention formulation is not particularly limited, and can be obtained according to customary preparation methods, wherein nano-micelle
The preparation method of freeze-dried powder, preferably are as follows:
(1) in organic solvent by amphiphilic polymers and the dissolution of taxanes dimer, mixed solution is obtained, it is described
The mass ratio of amphiphilic polymers and taxanes dimer is preferably (10-90): (10-90), more preferably (40-70):
(30-60)；The 50 of ml preferably taxanes dimer and the amphiphilic polymers gross mass grams of organic solvent volume
~500 times；Organic solvent includes but is not limited to tetrahydrofuran, dimethyl sulfoxide or dimethylformamide；
(2) above-mentioned mixed solution is added drop-wise to the distilled water of 2~10 times of liquor capacities under agitation or buffered molten
In liquid, nano micellar solution is formed；
(3, by rotary evaporation or dialysis, remove organic solvent；
(4) nano micellar solution is freeze-dried, and obtains nano-micelle freeze-dried powder preparation.
After the completion of the above operating procedure (3), without freeze-drying, but the concentration of micellar solution is adjusted to 1 ‰~
1%, progress is filling, then obtains nano micellar solution preparation.
Taxanes dimer and their nano-micelle preparations prepared by the present invention, it is shown that and Taxol injection
The similar cellkilling capacity of liquid, docetaxel injection also presents similar anti-on mouse melanin tumor model
Tumor effect, but without the sensitivity response and general toxicity of commercially available paclitaxel injection and docetaxel injection, Er Qiegu
Medicament contg in body preparation is up to 30~60%, but there is good dissolubility in water or in injection, and solution has very high
Storage stability, thus be expected to be applied to clinic.
The invention will be further described combined with specific embodiments below, and the raw material being related in embodiment is commercially available obtains
?.
Embodiment 1: the taxol dimer being coupled by suberic acid synthesizes
It weighs taxol (molecular weight 853.92) (136mg, 0.16mmol) and is dissolved in methylene chloride, suberic acid is then added
(15.5mg, 0.089mmol), EDC (67.1mg, 0.35mmol) and DMAP (2.2mg, 0.018mmol), after 1 hour, again plus
Enter EDC (32.6mg, 0.17mmol) and DMAP (2.2mg, 0.018mmol), after reacting 24 hours at room temperature, with oily phase filter
Filtering then slowly increases polarity elution pillar, until under product stream, finally production with dichloro and ethyl acetate from 8:1 to 2:1
Dichloro and ethyl acetate in object are spin-dried for, and obtain solid powder.
Fig. 1 is the mass spectrogram for the taxol dimer that the embodiment of the present invention 1 is prepared, and Fig. 1 illustrates that the present invention successfully makes
The standby taxol dimer for having obtained suberic acid coupling.
Embodiment 2: the synthesis of the dimer of taxol containing disulfide bond
It weighs taxol (molecular weight 853.92) (204.9mg, 0.24mmol) and is dissolved in methylene chloride, be then added 3,
Bis- hydrogen-oxygen quinoline of 3'- is sour (27.3mg, 0.13mmol), EDC (97.77mg, 0.51mmol) and DMAP (3.05mg, 0.025mmol),
After 1 hour, EDC (47.93mg, 0.25mmol) and DMAP (3.05mg, 0.025mmol) are added again, reacts 48 at room temperature
Hour, it is filtered with oily phase filter, then slowly increases polarity elution pillar from 8:1 to 2:1 with dichloro and ethyl acetate, until producing
Under logistics, finally the organic solvent in product is spin-dried for, obtains solid powder.
Embodiment 3: the Docetaxel dimer formed by succinic acid synthesizes
It weighs Docetaxel (molecular weight 807.88) (200mg, 0.25mmol) and is dissolved in methylene chloride, fourth is then added
Diacid (16.53mg, 0.14mmol), EDC (95.85mg, 0.50mmol) and DMAP (3.05mg, 0.025mmol), after 1 hour,
EDC (49.84mg, 0.26mmol) and DMAP (3.05mg, 0.025mmol) are added again, reacts 24 hours at room temperature, with oil
The filtering of phase filter then slowly increases polarity elution pillar, until under product stream, most with dichloro and ethyl acetate from 8:1 to 2:1
The organic solvent in product is spin-dried for afterwards, obtains solid powder.
Embodiment 4: the synthesis of the dimer of Docetaxel containing disulfide bond
It weighs Docetaxel (molecular weight 807.88) (202mg, 0.25mmol) and is dissolved in methylene chloride, be then added 3,
Bis- hydrogen-oxygen quinoline of 3'- is sour (29.4mg, 0.14mmol), EDC (97.77mg, 0.51mmol) and DMAP (3.18mg, 0.026mmol),
After 1 hour, EDC (49.84mg, 0.26mmol) and DMAP (3.05mg, 0.025mmol) are added again, reacts 48 at room temperature
Hour, it is filtered with oily phase filter, then slowly increases polarity elution pillar from 8:1 to 2:1 with dichloro and ethyl acetate, until producing
Under logistics, finally the organic solvent in product is spin-dried for, obtains solid powder.
Embodiment 5: the taxol dimer that poly(ethylene glycol)-polylactic acid package suberic acid is formed
The taxol dimer and 1mg mPEG that the suberic acid that 1mg embodiment 1 is prepared is formed2K-PDLLA2KIt is dissolved in
It in 4mL THF, is then dripped in 10mL secondary distilled water under stiring, after organic solvent THF volatilization completely, high speed centrifugation is removed
The taxol dimer for going the suberic acid not wrapped up to be formed can be obtained the nanometer for the taxol dimer that package suberic acid is formed
Dispersion liquid.After dispersion liquid freeze-drying, the taxol dimer freeze-dried powder that the suberic acid containing carrier is formed is obtained.
Embodiment 6: poly(ethylene glycol)-polylactic acid wraps up two sulphur taxol dimers
The two sulphur taxol dimers and 1mg mPEG that 1mg embodiment 2 is prepared2K-PDLLA2KIt is dissolved in 4mL THF
In, it is then dripped in 10mL secondary distilled water under stiring, after organic solvent THF volatilization completely, high speed centrifugation removing is not wrapped
The two sulphur taxol dimers wrapped up in can be obtained the nano dispersion fluid of two sulphur taxol dimers of package.After dispersion liquid freeze-drying, obtain
To the two sulphur taxol dimer freeze-dried powders containing carrier.
Embodiment 7: the Docetaxel dimer that poly(ethylene glycol)-polylactic acid package succinic acid is formed
The Docetaxel dimer and 1mg mPEG that the succinic acid that 1mg embodiment 3 is prepared is formed2K-PDLLA2K
Be dissolved in 4mL THF, then dripped in 10mL secondary distilled water under stiring, after organic solvent THF volatilization completely after, at a high speed from
The heart removes the Docetaxel dimer that the succinic acid not wrapped up is formed, and can be obtained the Docetaxel that package succinic acid is formed
The nano dispersion fluid of dimer.After dispersion liquid freeze-drying, obtains the Docetaxel dimer that the succinic acid containing carrier is formed and freeze
Dry powder.
Embodiment 8: poly(ethylene glycol)-polylactic acid wraps up the dimer of Docetaxel containing disulfide bond
The dimer of Docetaxel containing disulfide bond and 1mg mPEG that 1mg embodiment 4 is prepared2K-PDLLA2KIt is dissolved in
It in 4mL THF, is then dripped in 10mL secondary distilled water under stiring, after organic solvent THF volatilization completely, high speed centrifugation is removed
The Docetaxel containing disulfide bond not wrapped up dimer is removed, can be obtained the nanometer of the package dimer of Docetaxel containing disulfide bond
Dispersion liquid.After dispersion liquid freeze-drying, the dimer freeze-dried powder of Docetaxel containing disulfide bond containing carrier is obtained.
Embodiment 9: the poly(ethylene glycol) of different proportion-polylactic acid wraps up two sulphur taxol dimers
The two sulphur taxol dimers and poly(ethylene glycol)-polylactic acid that embodiment 2 is prepared are according to mass percent
10/90 to 90/10 is dissolved in THF, then drips in secondary distilled water under stiring, high after organic solvent THF volatilization completely
Speed is centrifuged off the two sulphur taxol dimers not wrapped up, can be obtained the nano dispersion fluid of two sulphur taxol dimers of package.
After dispersion liquid freeze-drying, the two sulphur taxol dimer freeze-dried powders containing carrier are obtained.
The results showed that when two sulphur taxol dimers/poly(ethylene glycol)-polylactic acid mass percent is 90/10, most
Big entrapment efficiency can achieve 85%.
Embodiment 10: the taxol dimer assembling that the poly(ethylene glycol) of different proportion-polylactic acid package suberic acid is formed
Performance study
The taxol dimer and mPEG formed according to the method for embodiment 5, the suberic acid that embodiment 1 is prepared2K-
PDLLA2KIt is 10/90 to 90/10 to prepare nano dispersion fluid according to mass ratio, studies their partial size, potential and in water,
In 10% fetal calf serum, 0.9% physiological saline and 5% glucose solution in stability, nano dispersion fluid be prepared into need
The treatment conditions wanted: 10% fetal calf serum, 0.9% physiological saline and 5% glucose solution, with particle size instrument nano-dispersed
The change of size of liquid filters out the mass ratio of polymer and dimer and arrives for 30/70 to judge the stability of nano dispersion fluid
60/40 nano dispersion fluid, their (about 200 nanometers) of particle size are suitble to by tumour cell endocytosis, surface negative electricity it is quiet
Electricity repulsive interaction make nanoparticle stablize, in 10% fetal calf serum, 0.9% physiological saline and 5% glucose solution in
It has good stability, for the concentration of micellar solution is adjusted to 1 ‰~1%, progress is filling, obtains the nanometer by taxol dimer
Micellar solution preparation provides good fact basis.
Fig. 2 is poly(ethylene glycol)-polylactic acid (mPEG that embodiment 10 is prepared2K-PDLLA2K) package by suberic acid is
The taxol dimer (mass ratio of polymer and dimer is 30/70) of connection molecule forms the transmission of micella M (DPTX-C8)
Electron microscope picture, Fig. 2 illustrate: being nanometer systems with what is formed after parents' polymer wrapped taxol, nanometer system is because have
EPR effect (passive target), so can more assemble in tumor tissues, the utilization rate for being conducive to enhance drug is (to tumor group
The total amount knitted) and reduce normal tissue murder by poisoning.
Fig. 3 is poly(ethylene glycol)-polylactic acid (mPEG that embodiment 10 is prepared2K-PDLLA2K) package by suberic acid is
The taxol dimer (mass ratio of polymer and dimer is 30/70) of connection molecule forms micella M (DPTX-C8) 10%
Fetal calf serum in grain size stability figure, Fig. 3 explanation: partial size stablizes main reflection preparation stabilization.10% fetal calf serum mould
Intend intracorporal physiological environment, on the one hand Fig. 3 illustrates that M (DPTX-C8) is really highly stable, provide guarantor for transport and long-term preservation
Card；On the other hand illustrate: can be still stabilized under the conditions of M (DPTX-C8) is physiological, it will not be by protein adsorption and by human body
It removes, so as to effectively be utilized by human body.
Embodiment 11: poly(ethylene glycol)-polylactic acid wraps up the research of two sulphur taxol dimer solubility properties
The solubility of taxol in water is 0.25 μ g mL-1, and the two sulphur taxol dimers prepared by embodiment 6
Nano micellar solution in the solubility of two sulphur taxol dimers can achieve 150mg mL-1.The purple therein actually dissolved
China fir alcohol has reached 136mg mL-1, very it is big level on improve the solubility of taxol in water.It is taxol by micellar solution
Concentration is adjusted to 1 ‰~1%, and progress is filling, and the nano micellar solution preparation for obtaining two sulphur taxol dimers provides convenience.
12: two sulphur Docetaxel dimer of embodiment releases active anti-cancer drug Docetaxel
As the pro-drug of Docetaxel, two sulphur Docetaxel dimers must release active Docetaxel
Competence exertion anticancer therapeutic.In view of the degradability of ester bond, intracellular enzyme environment is simulated with protease k.Protease k's
Under enzyme environment, the ester bond chain rupture of two sulphur Docetaxel dimers releases the pure and mild connection molecule of Taxotere.The tool of this process
Gymnastics is made as follows: the two sulphur Docetaxel dimer nano dispersion fluids that embodiment 4 is prepared are mounted in bag filter, make it
It is in the buffer external environment of protease k, takes out the release liquid in external environment at specific time point, add new consubstantiality
In external environment, the amount of the Docetaxel in release liquid is measured the long-pending buffer containing protease k by efficient liquid phase.It is more
Western taxol plays anticancer effect, connection molecule be it is nontoxic, as metabolism excretes.
Embodiment 13: poly(ethylene glycol)-polylactic acid wraps up two sulphur Docetaxel dimers and releases active anti-cancer drug
Docetaxel
As the pro-drug of Docetaxel, two sulphur Docetaxel dimers must release active Docetaxel
Competence exertion anticancer therapeutic.In view of the degradability of ester bond, intracellular enzyme environment is simulated with protease k, protease k's
Under enzyme environment, poly(ethylene glycol)-polylactic acid wraps up the ester linkage breaking in the carrier in two sulphur Docetaxel dimers, and micella is received
The grain of rice is gone to sticks and staves, and two sulphur Docetaxel dimer therein is exposed under protease k effect, and it is more to release activity for ester bond chain rupture
Western taxol and connection molecule.The concrete operations of this process are as follows: poly(ethylene glycol)-polylactic acid that embodiment 8 is prepared
Two sulphur Docetaxel dimer nano dispersion fluids are wrapped up in bag filter, it is made to be in the buffer external environment of protease k
In, take out the release liquid in external environment at specific time point, add the buffer containing protease k of new same volume in
In external environment, the amount of the Docetaxel in release liquid is measured by efficient liquid phase.Docetaxel plays anticancer effect, connection
Molecule be it is nontoxic, as metabolism excretes.
Embodiment 14: poly(ethylene glycol)-polylactic acid wraps up the anticancer therapeutic of two sulphur taxol dimers
Poly(ethylene glycol)-polylactic acid two sulphur taxol dimers of package are in the cervical cancer cell of people and the melanin of source of mouse
The cytotoxicity of oncocyte is tested.The equivalent paclitaxel concentrations of two sulphur taxol dimers is set from 0.0001-10 micromole,
With cytotoxicity and commercially available paclitaxel injection Taxol compare (with Emulsifier EL-60 and dehydrated alcohol (v/v, 1:
1)).The concrete operations of this this process are as follows: first the melanoma cells of the cervical cancer cell of people and source of mouse being passed on, make its patch
Cell dissociation is got off kind into 96 orifice plates after covering with, every hole 2*10 by wall growth3A cell adds after its is adherent and uses culture medium
It is diluted to the poly(ethylene glycol)-that the embodiment 6 of certain concentration (equivalent paclitaxel concentration from 0.0001-10 micromole) is prepared
Polylactic acid wraps up two sulphur taxol dimers and Taxol, later plus specifically detection reagent (MTT, 3- (4,5- dimethylthiazoles-
2) -2,5- diphenyltetrazolium bromide bromide), finally with the inhibition cell growth status of microplate reader measurement preparation.The results showed that
Two sulphur taxol dimers and Taxol have almost comparable cytotoxicity, illustrate two sulphur taxol dimer esterases in cell
Under the action of, taxol bioactive molecule can be released, anticancer therapeutic is played.
Claims (9)
1. a kind of taxanes dimer, which is characterized in that the dimer is made of taxol and connection molecule dicarboxylic acids, or by
The pure and mild connection molecule dicarboxylic acids of Taxotere or dicarboxylic acids containing disulfide bond are constituted；
The dicarboxylic acid structure formula is HOOC- (CH2)n- COOH, wherein n=2-8；
The dicarboxylic acid structure formula containing disulfide bond is HOOC- (CH2)n-XX-(CH2)n- COOH, wherein X=S, n=2-5.
2. a kind of preparation method of taxanes dimer according to claim 1, which is characterized in that this method comprises:
Step 1: taxanes solution and connection molecule are mixed, mixed liquor is obtained；
Step 2: EDC and DMAP is added in the mixed liquor that step 1 obtains and is reacted, taxanes dimer is obtained；
The taxanes solution is paclitaxel solution or Taxotere alcoholic solution, and the connection molecule is dicarboxylic acids or contains
There is the dicarboxylic acids of disulfide bond.
3. a kind of preparation method of taxanes dimer according to claim 2, which is characterized in that the taxol
Class solution is that taxanes are dissolved in organic solvent to obtain, and the organic solvent is methylene chloride, chloroform, diformazan
Base sulfoxide or dimethylformamide.
4. a kind of preparation method of taxanes dimer according to claim 2, which is characterized in that the taxol
The molar ratio of class and connection molecule is 1:(0.55-0.56).
5. a kind of preparation method of taxanes dimer according to claim 2, which is characterized in that the step two
Reaction temperature be room temperature, the reaction time be 24~48 hours.
6. a kind of preparation method of taxanes dimer according to claim 2, which is characterized in that the taxol
The molar ratio of class, EDC and DMAP is 1:(3-3.1): 0.2.
7. a kind of preparation, which is characterized in that the preparation includes amphiphilic polymers and taxanes described in claim 1
Dimer.
8. a kind of preparation according to claim 7, which is characterized in that the amphiphilic polymers include poly- (second two
Alcohol)-polylactic acid, poly(ethylene glycol)-polycaprolactone, poly(ethylene glycol)-polyglycolic acid, the poly- (lactic acid-hydroxyl of poly(ethylene glycol)-
Acetic acid) or poly(ethylene glycol)-it is poly- (lactic acid-caprol acton).
9. a kind of preparation according to claim 7, which is characterized in that in the preparation, taxanes dimer contains
Amount is 10%~90%.
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| CN109288813B (en) * | 2017-07-24 | 2021-03-12 | 复旦大学 | Selenium-containing taxol dimer prodrug polymer nanoparticles and preparation method thereof |
| CN110812327A (en) * | 2019-11-28 | 2020-02-21 | 云南大学 | Self-assembled nano drug-loaded micelle and preparation method and application thereof |
| CN113264906B (en) * | 2020-02-15 | 2022-09-13 | 沈阳药科大学 | Docetaxel dimer micromolecular prodrug and construction of self-assembled nanoparticle thereof |
| JP2023520668A (en) * | 2020-03-26 | 2023-05-18 | セラベスト カンパニー，リミテッド | Nanoparticles containing drug dimers and uses thereof |
| CN112250647A (en) * | 2020-06-30 | 2021-01-22 | 浙江大学 | Taxane prodrug, preparation method and application |
| CN114796513B (en) * | 2021-01-19 | 2024-01-30 | 沈阳药科大学 | Diselenide bridge Lian Duo cetime dimer prodrug and self-assembled nanoparticles thereof |
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