CN103263675B - Poly (epsilon-caprolactone) supported anti-tumor prodrug and preparation method thereof - Google Patents
Poly (epsilon-caprolactone) supported anti-tumor prodrug and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a poly (epsilon-caprolactone) supported anti-tumor prodrug and a preparation method thereof. The preparation method comprises the following steps of: performing ring opening polymerization on alpha-site bromo-epsilon-caprolactone to generate poly (alpha-site bromo-epsilon-caprolactone); performing a click chemical reaction of mercapto-alpha-site bromo-ester of thiomalic acid on the alpha-site of the poly (alpha-site bromo-epsilon-caprolactone) to obtain poly (epsilon-caprolactone) containing a pendant carboxyl group; and performing a substitution reaction on the poly (epsilon-caprolactone) containing the pendant carboxyl group and anti-tumor medicinal molecules, neutralizing with a strong alkali and weak acid salt solution of an alkali metal, extracting to remove impurities, and dialyzing the purified solution to obtain the anti-tumor prodrug. The anti-tumor prodrug is high in water solubility, can be completely biodegraded, is high in drug carrying quantity and high in purity, and contains groups capable of being further modified; and the preparation method is economic, efficient and nontoxic, and can realize industrialized production.
Description
Technical field
The present invention relates to anti-tumor predrug of a kind of poly-epsilon-caprolactone load and preparation method thereof, belong to antitumor drug modification field.
Background technology
Paclitaxel belongs to antitumor drug, and it has been proved to be has good clinical effectiveness in breast carcinoma, ovarian cancer, nonsmall-cell lung cancer and carcinoma of prostate.The toxicity of paclitaxel causes by interacting with the microtubule in cell, and this interaction has been upset the mitosis of cancerous cell thus caused cancer cell death.Although paclitaxel is good anticarcinogen, their super-oleophilic causes the dissolubility in water very poor.
In order to overcome paclitaxel deliquescent problem in water, formulation for paclitaxel is clinically dissolved in by paclitaxel in the mixed solution of polyoxyethylene castor oil and dehydrated alcohol (50:50, v/v) at present, and concentration is 7mmol/L.The trade mark of this preparation is
Although formulation for paclitaxel
be widely used, but still Shortcomings:
(1) polyoxyethylene castor oil is not inertia, and it can cause many side reactions, as anaphylaxis and neurotoxicity.
(2), before injectable drug, usually need to add corticosteroid and antihistaminic, thus may untoward reaction be occurred.
(3) 2006 years, the research of Figg showed:
in polyoxyethylene castor oil reduce the antitumor curative effect of medicine.
In order to overcome
in problem, there has been proposed four kinds of strategies: (1) designs new paclitaxel derivant; (2) paclitaxel formula is changed; (3) share with other antitumor drug; (4) prodrugs of paclitaxel is prepared.Wherein, prodrug is the biorebersible derivative of active parent drug, and it is often used to some shortcomings overcoming former medicine, as low water solublity, and low permeability, low oral absorption, low stability, toxicity and non-target tropism.The term of prodrug also can be defined as: one does not almost have activated chemical drugs, but after it absorbs in vivo or distribute, can be converted into former medicine and play drug effect.
During calendar year 2001 to 2002, the medicine that the whole world is given the ratification has at least 14% to be prodrug.This trend causes studies the research to prodrug, and especially about the research of cancer medicine prodrug, the derivant of paclitaxel is one of study hotspot.
From current bibliographical information, prodrugs of paclitaxel mainly divides two classes:
One class is small numerator modified prodrugs of paclitaxel, and the micromolecule group major part be introduced into is ionogenic, comprises ammonium salt, carboxylate, sulfonate and phosphate.
Another kind of is water-soluble polymer prodrugs of paclitaxel, thus the water solublity of raising drug molecule, stability and bioavailability, improve the pharmacokinetics of drug molecule, by strengthening infiltration and retaining (EPR) effect passive target tumor tissues.Simultaneously polymer support is after drug release, can not long time integration in vivo, is absorbed after can excreting or be hydrolyzed.This water-soluble polymer of current report has: Polyethylene Glycol (PEG), N-(2-hydroxypropyl) Methacrylamide, carboxymethyl cyclodextrin, polyglutamic acid, dendritic.
At present the research of polymeric prodrugs system is become to the focus of current new drug development, because polymer is to the enhancing infiltration of tumor tissues uniqueness and retention characteristic, former medicine can be delivered to tumor locus by design polymeric prodrugs effectively, improve its water solublity, these improve the effect that method that medicine water solublity carries out small numerator modified former medicine do not reach simultaneously.In addition, polymeric prodrugs is relative to small numerator modified former medicine, and the former just can make prodrug under the price of relative moderate.
The selection of polymer-modified dose is the key that drug molecule is modified, and aliphatic polyester is as polylactic acid (PLA), and Poly(D,L-lactide-co-glycolide (PLGA) and poly-epsilon-caprolactone (PCL) belong to biodegradable polymer.Come into one's own because its molecular weight can be controlled in quite wide scope.Particularly after forming block copolymer with PEG, not only there is biodegradability, and significantly improve the biocompatibility of material and human body, during as drug carrier material, extend medicine circulation time in vivo, improve drug effect, reduce immune responsiveness, become the focus of people's research.
Biodegradable prodrugs of paclitaxel disclosed in Chinese patent CN1629150A and Polyethylene Glycol-aliphatic poly ester block copolymer and paclitaxel bondedly to form.This prodrug has amphipathic, can make water-base preparation, overcomes existing formulation for paclitaxel poorly water-soluble and the shortcoming such as anaphylaxis is serious.It is carrier with PEG that Chinese patent CN101543632A discloses a kind of, with hydroxyacetic acid, Pfansteihl or their oligomer for linking arm, with paclitaxel or Docetaxel generation bonding reaction, obtains novel paclitaxel or Docetaxel prodrug.Chinese patent CN101618220A discloses anti-tumor predrug and the preparation method that a kind of novel degradable dendritic macromole that is branching unit based on glycerol is carrier.This novel biodegradable amphipathic dendritic macromolecules is based on glycerol and hydroxyacetic acid oligomer, lactic acid oligomers, the alternately oligomer of hydroxyacetic acid and lactic acid, hydroxyacetic acid, lactic acid and the amino acid whose oligomer and their copolymerization oligomer and PEG of replacing are constructed.Gained dendritic condensing agent exist under with antitumor drug, carry out bonding reaction, obtain the prodrug of antitumor drug.Chinese invention patent CN1425706A and CN1711989A discloses poly glycol monomethyl ether-poly-epsilon-caprolactone amphipathic nature block polymer can by the method for chemical bonding, make the therapeutic agent of some slightly solubilities as paclitaxel, amycin etc. enter into the micelle that formed, form micelle medicine carrying system, and then realize the controlled release to medicine.In above-mentioned method of modifying, linking arm as dressing agent is all that some are easy to degrade and the low molecular weight polyester harmless to organism, but because PEG itself does not have biological degradability, the PEG only having molecular weight to be less than 5000 in addition could excrete by cytophagy or by kidney, and some Polyethylene Glycol-aliphatic polyester amphipathic nature block polymer is also limited to the drug loading of drug molecule, also be difficult to modify further its structure simultaneously, limit its application.
In existing document, yet there are no the homopolymer of cyclic ester monomers or copolymer as main chain, do not use PEG, and directly with small numerator modified water-soluble polymer prodrug of making.
Summary of the invention
The present invention is directed to anti-tumor predrug in prior art is carrier mainly through PEG-6-caprolactone block copolymer, there is medicine carrying low, PEG nonbiodegradability, the defect of modification further can not be carried out to molecule, one of object is that to be to provide a kind of water-soluble good, fully biodegradable, and drug loading is high, purity is high, containing can the anti-tumor predrug of poly-epsilon-caprolactone load of modification group.
Another object of the present invention is a kind of method of anti-tumor predrug being to additionally provide economy, the above-mentioned poly-epsilon-caprolactone load of efficient and nontoxic preparation.
The invention provides a kind of anti-tumor predrug of poly-epsilon-caprolactone load, this anti-tumor predrug has formula 1 and/or formula 2 structure:
Formula 1
Formula 2
M is one or more in alkali metal atom;
D is antitumor drug molecular radical;
R is selected from C
1 ~ 6alkoxyl in a kind of;
X is 1 ~ 100, y be 1 ~ 100, z is 3 ~ 300, and z > x+y, x, y and z are integer;
N is 10 ~ 300.
Described antitumor drug molecular radical is preferably one or more in paclitaxel group, Docetaxel group, amycin group or camptothecine group.
Described antitumor drug molecular radical is the group formed after the carboxyl side group generation substitution reaction on antitumor drug molecule and poly-epsilon-caprolactone.
Described M is preferably one or more in lithium atom, sodium atom or potassium atom; To be particularly preferably in sodium atom or potassium atom one or both.
Described anti-tumor predrug, R is preferably C
1 ~ 6unbranched alkoxy in a kind of.
Present invention also offers a kind of preparation method of anti-tumor predrug as above, this preparation method is that α position bromo 6-caprolactone is first generated poly-α position bromo 6-caprolactone by ring-opening polymerisation; On the α position of poly-α position bromo 6-caprolactone, there is the click chemistry reaction of the Qiu Ji – α position brominated esters of mercaptosuccinic acid. again, obtain the poly-epsilon-caprolactone of oxatyl-containing lateral group; After the poly-epsilon-caprolactone of oxatyl-containing lateral group that obtains and antitumor drug molecule generation substitution reaction, with alkali-metal strong base weak acid saline solution neutralization, extract impurity, the solution after the removal of impurity, after dialysis, to obtain final product.
Described ring-opening polymerization temperature is 80 ~ 200 ° of C; Be preferably 80 ~ 140 ° of C.
Described ring-opening polymerization time 42 ~ 54h.
The catalyst used in described ring opening polymerisation process is nontoxic or the stannous octoate of low toxicity, zinc alkyl or alkyl aluminum; The consumption of described catalyst is 0.5 ~ 2% of α position bromo 6-caprolactone quality.
Described ring-opening polymerisation carries out in solvent dry toluene, oxolane or dimethylbenzene.
The initiator that described ring-opening polymerisation adopts is C
1 ~ 6alcohols, be preferably C
1 ~ 6straight chain alcohol.
The molecular weight of described poly-α position bromo 6-caprolactone by the ratio of monomer with the amount of substance of initiator, and the response time decide.
Described Qiu Ji – α position brominated esters click chemistry reaction temperature is 0 ~ 40 ° of C.
Described sulfydryl-α position brominated esters click chemistry the response time is 18 ~ 30h.
Described sulfydryl-α position brominated esters click chemistry reaction carries out in solvent DMF or dimethyl sulfoxide; Triethylamine or aliphatic amine is adopted to be acid binding agent.
Described antitumor drug molecule be paclitaxel, Docetaxel, amycin or camptothecine one or more.
Described alkali-metal strong base weak acid saline solution is one or more in sodium carbonate liquor, sodium bicarbonate solution, solution of potassium carbonate or potassium bicarbonate solution.
Described neutralization with pH between 8 ~ 9 for terminal.
Described substitution reaction reaction temperature is 0 ~ 40 ° of C.
The described substitution reaction response time is 20 ~ 28h.
Described substitution reaction adds DMAP as acylating reagent.
After the poly-epsilon-caprolactone of the oxatyl-containing lateral group obtained in said method and antitumor drug molecule generation substitution reaction, cross and filter insoluble matter, then add the neutralization of alkali-metal strong base weak acid saline solution until pH value is stabilized in after between 8 ~ 9, go out impurity with organic solvent extraction; To remain soluble salt solutions distill water dialysis, filter, last lyophilization obtains water-soluble antitumor prodrug; The extractant that described extraction adopts is chloroform, dichloromethane or ethyl acetate; Described alkali-metal strong base weak acid saline solution is one or more in sodium carbonate liquor, sodium bicarbonate solution, solution of potassium carbonate or potassium bicarbonate solution.
The preparation method of α position of the present invention bromo 6-caprolactone:
Ketohexamethylene is issued raw free radical substitution reaction with N-bromo-succinimide at 0 ~ 100 ° of C under ammonium acetate catalytic action, obtains α position bromo Ketohexamethylene; The α position bromo Ketohexamethylene metachloroperbenzoic acid obtained, by after Baeyer-Villiger oxidation reaction, obtains α position bromo 6-caprolactone; Wherein, the solvent that free radical substitution reaction adopts is absolute ether, carbon tetrachloride, chloroform, dichloromethane, oxolane, acetonitrile or methanol; Baeyer-Villiger oxidizing reaction temperature is 0 ~ 40 ° of C, and the solvent of employing is dichloromethane, chloroform, acetonitrile, acetone or oxolane.
The anti-tumor predrug synthetic route of poly-epsilon-caprolactone load of the present invention is as follows:
With antitumor drug molecule, Paclitaxcl=
alkali-metal strong base-weak acid salt adopts NaHCO
3for example:
Beneficial effect of the present invention:
Compared with existing aliphatic poly ester prodrugs, the invention has the advantages that: poly-epsilon-caprolactone of the present invention by mercaptosuccinic acid. as linking arm, α position carbon on each 6-caprolactone construction unit containing two side carboxyls, thus makes the water solublity of its drug loading and polymer sodium salt all increase; As paclitaxel can reach 66wt% in load capacity; The anti-tumor predrug of poly-epsilon-caprolactone load of the present invention avoids and uses PEG, the Biodegradable of poly-epsilon-caprolactone is strong, and side radix object increases, thus overcome some Polyethylene Glycol-aliphatic polyester amphipathic nature block polymer exist limited to the drug loading of drug molecule, be difficult to modify further PEG structure and the PEG of high molecular is difficult to the shortcoming that excretes; By neutralization in the inventive method, extraction and dialysis procedure, reach the anti-tumor predrug of a good purification poly-epsilon-caprolactone load of the present invention; Preparation method cost of the present invention is low, and productive rate is high, safety non-toxic, can extensive use.
Accompanying drawing explanation
[Fig. 1] is the nucleus magnetic hydrogen spectrum figure of poly-α position bromo 6-caprolactone.
The nucleus magnetic hydrogen spectrum figure of the poly-epsilon-caprolactone that [Fig. 2] is oxatyl-containing lateral group.
[Fig. 3] is the nucleus magnetic hydrogen spectrum figure of the poly-epsilon-caprolactone of taxol drug molecule on side chain keyed jointing.
[Fig. 4] is poly-α position bromo 6-caprolactone for the present invention gathers gel chromatography figure: a before and after α position bromo 6-caprolactone load antitumor drug, and b is the poly-epsilon-caprolactone of oxatyl-containing lateral group, and c is the poly-epsilon-caprolactone of taxol drug molecule on side chain keyed jointing.
[Fig. 5] gathers the infrared spectrogram before and after α position bromo 6-caprolactone load antitumor drug for the present invention: a is poly-α position bromo 6-caprolactone, and b is the poly-epsilon-caprolactone of oxatyl-containing lateral group, and c is the poly-epsilon-caprolactone of taxol drug molecule on side chain keyed jointing.
Detailed description of the invention
Following examples further illustrate of the present invention, instead of restriction the present invention.
Embodiment 1
1, the preparation of α position bromo Ketohexamethylene
Add 20.00g (0.20mol) Ketohexamethylene, 38.14g (0.21mol) N-bromo-succinimide, 1.54g (0.02mol) ammonium acetate and 300mL absolute ether being equipped with in flask at the bottom of the 500mL of Magnetitum, sandwich on iron stand, then condensing tube is loaded onto, condensing tube connects a nitrogen bag, under 25 ° of C, react 0.5h; After having reacted, filter, filtrate is with distilling washing three times; Organic facies anhydrous magnesium sulfate drying, filters, and after concentrated solvent, silicagel column is walked post and is separated (petrol ether/ethyl acetate=10:1), obtains 30.09g (85.0%) pale yellowish oil liquid.
2, the preparation of α position bromo 6-caprolactone
In the 500mL single necked round bottom flask that Magnetitum is housed, add 17.70g (0.10mol) α position bromo Ketohexamethylene and 20.64g (0.12mol) metachloroperbenzoic acid, then add 300mL dichloromethane, under 25 ° of C, react 48h.After having reacted, filter, filtrate inserts an evening in refrigerator, and then excessively filters m-chlorobenzoic acid; Filtrate washes three times with saturated sodium thiosulfate respectively, saturated sodium bicarbonate three times, distillation washing three times; Organic facies anhydrous magnesium sulfate drying, filters, and after concentrated solvent, silicagel column is walked post and is separated (petroleum ether/dichloromethane=10:1), obtains colourless oil liquid α position bromo 6-caprolactone 8.68g (44.9%); Before polymerization, the mixed solvent of α position bromo caprolactone absolute ether and petroleum ether recrystallization three times under-25 ° of C.
3, the preparation of poly-α position bromo 6-caprolactone
Under nitrogen protection by 1.00g (0.005mol) monomer α position bromo 6-caprolactone, 1.7mg (0.52mmol) initiator absolute methanol, the sub-stannum of 21mg (0.5mmol) octoate catalyst, 5mL solvent toluene adds in dry schlenk bottle, evacuation is filled with nitrogen three times again, is placed in 110 ° of C under nitrogen protection; React 48h in oil bath pan, after reaction terminates, be spin-dried for toluene, dissolve through dichloromethane, with freezing absolute methanol sedimentation three times, drain final vacuum dry a whole night, to obtain final product.(as shown in Figure 1, molecular weight distribution is shown in Fig. 4 a to nuclear-magnetism, infraredly sees Fig. 5 a).
4, the preparation of the poly-epsilon-caprolactone of oxatyl-containing lateral group
Under nitrogen protection 1g mercaptosuccinic acid. is dissolved in 10mLDMF; until completely dissolved; in reaction system, slowly drip 6mL triethylamine, then the 0.5g dissolved with DMF is gathered α position bromo 6-caprolactone and be slowly added drop-wise in reaction system, room temperature reaction 24h.After reaction terminates, use NaCO
3it is 8 ~ 9 that system is adjusted to pH by aqueous solution, three times are respectively extracted by dichloromethane and ethyl acetate, then aqueous solvent is adjusted to pH by dropping dilute hydrochloric acid is 3 ~ 5, system has solid to separate out, pour out upper water solution, then with distillation washing three times, last lyophilization or vacuum drying obtain product (nuclear-magnetism as shown in Figure 2, molecular weight distribution is shown in Fig. 4 b, infraredly sees Fig. 5 b).
5, a kind of preparation of water-soluble polymer prodrugs of paclitaxel of 6-caprolactone main chain
0.1g (0.45mmol) side carboxyl is gathered α position bromo caprolactone to be dissolved in 5mLDMF, add 0.065g (0.08mmol) paclitaxel, in 10min, the solution of 0.024g (0.085mmol) DCC in DMF is joined in 25mL reaction bulb, add the DMAP of catalytic amount again, stir 24h at normal temperatures; After reaction terminates, cross and filter insoluble matter; Use NaHCO
3it is 8 ~ 9 that system is adjusted to pH by aqueous solution, respectively extracts three times by dichloromethane and ethyl acetate, and by soluble salt solutions distill water dialysis, filter, last lyophilization obtains water-soluble antitumor prodrug 0.15g, productive rate 89.1%.
In gained prodrug, dripping dilute hydrochloric acid solution, to be adjusted to pH be 3 ~ 5, system separates out sticky mass, drain postlyophilization, the polymer of paclitaxel on keyed jointing on the poly-epsilon-caprolactone main chain obtaining oxatyl-containing lateral group, nuclear-magnetism as shown in Figure 3, molecular weight distribution is shown in Fig. 4 c, infraredly sees Fig. 5 c), this step resulting polymers is mainly used in test and characterizes.
Claims (5)
1. an anti-tumor predrug for poly-epsilon-caprolactone load, is characterized in that, has formula 1 and/or formula 2 structure:
Formula 1
Formula 2
M is one or more in alkali metal atom;
D is antitumor drug molecular radical;
R is selected from C
1 ~ 6alkoxyl in a kind of;
X is 1 ~ 100, y be 1 ~ 100, z is 3 ~ 300, and z > x+y, x, y and z are integer;
N is 10 ~ 300;
Described antitumor drug molecular radical is one or more in paclitaxel group, Docetaxel group, amycin group or camptothecine group.
2. anti-tumor predrug as claimed in claim 1, it is characterized in that, described M is one or more in lithium atom, sodium atom or potassium atom.
3. anti-tumor predrug as claimed in claim 1, it is characterized in that, R is C
1 ~ 6unbranched alkoxy in a kind of.
4. a preparation method for the anti-tumor predrug as described in any one of claims 1 to 3, is characterized in that, α position bromo 6-caprolactone is first generated poly-α position bromo 6-caprolactone by ring-opening polymerisation; On the α position of poly-α position bromo 6-caprolactone, there is the click chemistry reaction of the Qiu Ji – α position brominated esters of mercaptosuccinic acid. again, obtain the poly-epsilon-caprolactone of oxatyl-containing lateral group; After the poly-epsilon-caprolactone of oxatyl-containing lateral group that obtains and antitumor drug molecule generation substitution reaction, with alkali-metal strong base weak acid saline solution neutralization, extract impurity, the solution after the removal of impurity, after dialysis, to obtain final product.
5. preparation method as claimed in claim 4, it is characterized in that, described alkali-metal strong base weak acid saline solution is one or more in sodium carbonate liquor, sodium bicarbonate solution, solution of potassium carbonate or potassium bicarbonate solution.
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| CN1629150A (en) * | 2004-10-26 | 2005-06-22 | 中国科学院长春应用化学研究所 | Paclitaxol predrug of biodegradable polymer and its synthesis method |
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| CN1629150A (en) * | 2004-10-26 | 2005-06-22 | 中国科学院长春应用化学研究所 | Paclitaxol predrug of biodegradable polymer and its synthesis method |
Non-Patent Citations (2)
| Title |
|---|
| Novel self-associating poly(ethylene oxide)-b-poly(-caprolactone) based drug conjugates and nano-containers for paclitaxel delivery;Mostafa Shahin et al.;《International Journal of Pharmaceutics》;20100118;第389卷;213-222页 * |
| 己内酯的开环聚合与应用研究;邓冰锋 等;《材料开发与应用》;20121231;第27卷(第6期);72-77页 * |
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