CN103861116A - Prodrug of antitumor medicament as well as preparation method and application thereof - Google Patents
Prodrug of antitumor medicament as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines and relates to a prodrug of an antitumor medicament as well as a preparation method and application thereof. The prodrug is prepared by connecting vitamin E and the antitumor medicament by virtue of a chemical bond. The chemical bond is one of a sulfide bond, an ester bond, an interval disulfide bond and a hydrazone bond. The antitumor medicament is one of paclitaxel and docetaxel. The prodrug of the antitumor medicament and a pharmaceutically acceptable carrier can be prepared into a clinically acceptable dosage form for injection or oral administration, including lipidosome, an emulsion, a lipid microsphere and a PLGA (Poly(Lactic-co-Glycolic Acid) nanoparticle or microsphere. According to the prodrug and the preparation, the activity of the antitumor medicament can be obviously improved, the toxicity is reduced and the development of the preparation is facilitated.
Description
Technical field
The present invention relates to a kind of antineoplastic agent prodrug, in particular to prodrug of a kind of antitumor drug and its production and use.
Background technology
Paclitaxel, Docetaxel, amycin, 5-fluorouracil etc. are the antitumor drug being most widely used at present, have good curative effect in the treatment of multisystem tumor.But paclitaxel, Docetaxel existence be both insoluble in water and be also insoluble in oily shortcoming, and amycin, 5-fluorouracil good water solubility are but fat-soluble poor, and this physics and chemistry attribute is to formulation development, and especially the exploitation of nanometer formulation has brought very large difficulty.There is the shortcoming that toxic and side effects is large in conventional anti-tumor agent clinically in addition, for example formulation for paclitaxel Taxol adopts the mixed liquor of surfactant polyoxyethylene Oleum Ricini and dehydrated alcohol 1:1 to dissolve paclitaxel, with front first dilution, because of the conversion of solvent, paclitaxel is easily separated out precipitation, and solubilizing agent polyoxyethylene castor oil used easily causes the untoward reaction such as hyperreaction, neurotoxicity, nephrotoxicity, cardiac toxicity.Therefore, as above the character of antitumor drug has limited the application of its product.
Vitamin E (Vitamin E) is a kind of fatsoluble vitamin, claims again tocopherol, is one of topmost antioxidant.Vitamin E has free radical resisting, LPO inhibitor, eliminating chloasma; The activity of restraint of tyrosinase, reduces the effects such as melanin generation.The report vitamin Es such as Tang in 2013 are main structures that surfactant polyethylene 1000 vitamin e succinate TPGS overcome multi-drug resistance of the tumor, there is the function of reverse multiple drug resistance of tumor, but give separately vitamin E without any antitumor action.
In prior art, Pharmacists adopts the whole bag of tricks to improve the activity of antitumor drug, reduces toxicity, thereby the anti-tumor agent of exploitation high-efficiency low-toxicity, but medicine is prepared into prodrug, and the method being especially connected with vitamin E, have not been reported in prior art.
Summary of the invention
Technical problem solved by the invention is to provide a kind of prodrug of antitumor drug.
The present invention is achieved through the following technical solutions:
Fat-soluble vitamin E is connected by chemical bond with antitumor drug.
Described antitumor drug is paclitaxel or Docetaxel.
Described connection vitamin E and the chemical bond of antitumor drug are the one in monosulfidic bond, ester bond, interval disulfide bond (two, interval carbon atom between sulphur atom), hydrazone key etc.
Structure after paclitaxel (PTX) or Docetaxel (DOC) are connected with vitamin E (VE) is:
R
1=-H,-COCH
3
R
2=-OC(CH
3)
3,
X=-CH
2CH
2-,-CH
2SCH
2-,-CH
2SCH
2CH
2SCH
2-
Be preferably as follows compound:
The present invention also provides vitamin E and antitumor drug, the synthetic logical method that especially paclitaxel or Docetaxel connect:
The anhydride (succinic anhydride, thiol guanidine-acetic acid acid anhydride or 2,2 '-(ethyl dithio) ethanedioic acid acid anhydride) that VE and 1-3 doubly measure is dissolved in appropriate dichloromethane, adds the DMAP(4-dimethylamino naphthyridine of 3%-10%) catalysis, stirring at room temperature 1 hour, cessation reaction.Silicagel column separates, and with hexane and ethyl acetate gradient elution (30:1～4:1), obtains white solid (VE-COOH, VE-S-COOH or VE-S-C-C-S-COOH).
By white solid obtained above and equimolar PTX or DOC at DCC(dicyclohexylcarbodiimide, 1.1 times of equivalents) and the DMAP stirring at room temperature of 3%-10% 2 hours, sucking filtration, except the DCU that dereaction generates, silica gel column chromatography separates, and chloroform and methanol gradient elution (500:1～100:1) obtain target product PTX-VE, PTX-DOC, PTX-S-VE, DOC-S-VE, PTX-S-C-C-S-VE or DOC-S-C-C-S-VE.
PTX-VE nuclear magnetic data:
1h-NMR (CDCl
3): δ 0.8 (m, CH
3), 1.05-1.1 (m, CH
2), 1.1-1.2 (m, CH
3), 1.14 (s, 16-CH
3), 1.2-1.5 (m, CH), 1.24 (s, 17-CH
3), 1.68 (s, 19-CH
3), 1.7 (m, CH
2), 1.79 (s, 18-CH
3), 1.88 (ddd, 6-β CH
2), 1.9-2.0 (s, CH), 1.98 (bs, 1-OH), 2.23 (s ,-OAc), 2.28 (ddd, 14-α CH
2), 2.35 (dd, 14-β CH
2), 2.38 (s ,-OAc), 2.48 (brs, 7-OH), 2.54 (ddd, 6-α CH
2), 2.57 (m, CH2), 2.7-2.9 (m ,-OOC-CH
2cH
2-COO-) .79 (d, 3-CH), 4.19 (dd, 20-β CH
2), 4.30 (dd, 20-α CH
2), 4.40 (dd, 7-CH), 4.78 (s, 2 '-CH), 4.94 (d, 5-CH), 5.67 (d, 2-CH), 5.78 (d, 3 '-CH),
6.23(qt,13-βCH),6.27(s,10-αCH),7.01(d,NH),7.35(m,3′-PhH),7.40(m,m-NHCOPhH),7.42(m,3′-PhH),7.48(m,3′-PhH),7.49(m,p-NHCOPhH),7.51(m,m-OCOPhH),7.61(t,p-OCOPhH),7.74(dd,o-NHCOPhH),8.13(dd,o-OCOPhH).
PTX-S-VE nuclear magnetic data:
1h NMR (400MHz, CDCl
3, ppm): δ 8.15 (2H, d), 7.72 (2H, d), 7.60 (1H, m), 7.51-7.49 (2H, m), 7.37 (4H, m), 7.31-7.26 (4H, m), 6.30 (2H, s), 6.04 (1H, dd), 5.69 (1H, d), 5.50 (1H, d), 4.99-4.96 (1H, m), 4.48-4.43 (1H, m), 4.32-4.30 (1H, d), 4.21-4.19 (1H, d), 3.81-3.83 (1H, d), 3.71-3.68 (1H, d), 3.50-3.40 (4H, m), 2.60 (3H, m), 2.49 (1H, d), 2.42 (3H, s), 2.23 (3H, s), 2.10 (3H, s), 2.03-1.93 (10H, s), 1.70-1.68 (4H, m), 0.88-0.83 (17H, m).
The prepared prodrug of the present invention can be prepared into and can, for the dosage form of injection or oral administration, for improving the activity of antitumor drug, reduce its toxicity, thereby be beneficial to clinical practice with pharmaceutically acceptable excipient.
Described dosage form comprises liposome, Emulsion, lipoid microsphere, PLGA nanoparticle or microsphere etc.
Described Emulsion comprises prodrug, oil for injection, emulsifying agent, and wherein, the weight ratio of described prodrug, oil for injection, emulsifying agent is 1 part: 3～20 parts: 1～20 part.Preferred: 1 part: 6～12 parts: 4～10 parts.
Described oil for injection is selected from one or more the mixture in safflower oil, fish oil, Oleum Fructus Bruceae, soybean oil, triglyceride, vitamin E, decanoyl/octanoyl glycerides, Radix Oenotherae erythrosepalae oil, Fructrs Hippophae seed oil, Oleum Helianthi; Emulsifying agent is selected from one or more mixture of the mixture of vitamin E polyethylene glycol succinic acid ester (TPGS), lecithin, Tween80, Span20, polyoxyethylene castor oil, glyceryl monooleate.
Wherein oil for injection is preferred: vitamin E, emulsifying agent is preferred: TPGS.Preferred 1:6-9 part of its weight ratio: 4-8 part.
Described Emulsion also comprises pharmaceutically acceptable antioxidant, antiseptic etc.
Prodrug of the present invention also can be prepared into liposome with pharmaceutically acceptable adjuvant.
Described prodrug liposome comprises prodrug, phospholipid, stabilizing agent, and the weight ratio of described prodrug, phospholipid, stabilizing agent is 1 part: 5-100 part: 1-30 part, preferred weight ratio is 1 part: 10-20 part: 2-5 part.
Described phospholipid is selected from one or more mixture of natural extract phospholipid, semi-synthetic phospholipid, complete synthesis phospholipid; Stabilizing agent is selected from one or more mixture of cholesterol, tetradecylic acid, 18-amine., vitamin E, TPGS, distearoyl phosphatidylcholine, Determination of Polyoxyethylene Non-ionic Surfactants, amphipathic ethylene glycol derivative.The wherein preferred natural extract phospholipid of phospholipid, preferably fabaceous lecithin; The preferred cholesterol of stabilizing agent.
Described liposome also comprises pharmaceutically acceptable antioxidant, antiseptic etc.
Prodrug involved in the present invention and the preparation of being made up of prodrug thereof have the antitumor curative effect of raising, fall hypotoxic effect, are more suitable for clinical use.
Compared with prior art, the present invention has following beneficial effect: (1) prodrug of the present invention can improve the dissolubility of female medicine paclitaxel, Docetaxel; (2) related precursor medicinal preparation can improve medicine long circulation time in vivo; (3) related precursor medicinal preparation has the effect that improves antitumous effect; (4) related precursor medicinal preparation has the hypotoxic effect of falling.
Accompanying drawing explanation
Curve when Fig. 1 is PTX-VE breast and the interior medicine of Comparative formulation Taxol Mice Body;
Fig. 2 is PTX-VE breast and Comparative formulation Taxol and vitamin E tumor-bearing mice effect experiment result, and dosage is counted 5mg/kg by PTX;
Fig. 3 is PTX-S-VE liposome and Comparative formulation Taxol tumor-bearing mice effect experiment result, and dosage is counted 5mg/kg by PTX;
Fig. 4 is PTX-S-VE breast and Comparative formulation Taxol tumor-bearing mice effect experiment result, and dosage is counted 5mg/kg by PTX;
Fig. 5 is PTX-S-VE liposome and Comparative formulation Taxol tumor-bearing mice effect experiment result, and dosage is counted 5mg/kg by PTX;
Fig. 6 is PTX-S-VE liposome and Comparative formulation Taxol tumor-bearing mice effect experiment result, and dosage is counted 5mg/kg by PTX.
The specific embodiment
Embodiment 1
Prescription
| PTX-VE | 1g |
| Vitamin E | 9g |
| TPGS | 4g |
| Buffer salt solution extremely | 500mL |
Take or measure prodrug, oil for injection, emulsifying agent by formula ratio, under 20-80 ℃ of condition, mix and blend dissolves to obtain oil phase, measure water for injection by formula, and add appropriate isoosmotic adjusting agent to obtain water, oil phase and water are mixed under 20-80 ℃ of condition, adopt the method for emulsification pretreatment or stirring and emulsifying to prepare colostrum; Colostrum is prepared into prodrug injectable emulsion by high pressure homogenizer, ultrasonic emulsification, colloid mill emulsion dispersion or microjet instrument.
The prodrug of vitamin E of the present invention and paclitaxel has better pharmacokinetics behavior.Adopt the administering mode of rat intravenous injection, give respectively prodrug Emulsion and paclitaxel commercial preparation Taxol that the vitamin E of same dose is connected with paclitaxel, get blood in different time points, adopt radioactive label method to measure blood Chinese medicine concentration, result shows, the AUC of the prodrug that vitamin E is connected with paclitaxel is 500 times of Taxol.(see figure 1)
The prodrug of vitamin E of the present invention and paclitaxel has the behavior of better antitumor drug effect.To the mouse model of set up inoculated tumour drug resistance KB-8-5 cell, within the 0th day, the 2nd day, the 4th day, the 6th day, the 8th day after model is successfully established, give respectively the Taxol of same dose and the prodrug of vitamin E and paclitaxel, and measure gross tumor volume.Result shows, vitamin E has stronger antitumor drug effect with the prodrug of paclitaxel than Taxol.(see figure 2)
The prodrug of vitamin E of the present invention and paclitaxel has lower toxicity.15 SD mices are equally divided into 3 groups at random, one group of contrast, the prodrug of one day, another two groups of intervals, respectively continuously injection vitamin E and paclitaxel and Taxol5 time, get mouse blood and carry out hepatic and renal function detection, result shows that the aspartate transaminase (AST) of Taxol group compares matched group with alanine aminotransferase (ALT) and significantly raise, and prodrug group is compared matched group and significantly do not distinguished.
| ? | AST(U/L) | ALT(U/L) | Blood urea nitrogen (mg/dL) |
| Contrast | 133.8±9.7 | 65.8±17.3 | 22.4±1.5 |
| Taxol | 217.2±54.4 | 99.2±19.4 | 24.6±1.5 |
| Prodrug | 125.9±23.2* | 57.6±3.5* | 23.6±2.5 |
Embodiment 2:
| PTX-VE | 1g |
| Vitamin E | 6g |
| TPGS | 8g |
| Buffer salt solution extremely | 500mL |
Preparation method is with embodiment 1.
Embodiment 3:
| PTX-S-VE | 1g |
| Vitamin E | 6g |
| TPGS | 8g |
| Buffer salt solution extremely | 500mL |
Preparation method is with embodiment 1.
Embodiment 4:
| PTX-VE | 1g |
| Vitamin E | 9g |
| TPGS | 4g |
| Buffer salt solution extremely | 500mL |
Preparation method is with embodiment 1.
Embodiment 5:
| PTX-S-VE | 1g |
| Vitamin E | 12g |
| TPGS | 10g |
| Buffer salt solution extremely | 500mL |
Preparation method is with embodiment 1.
Embodiment 6:
| PTX-S-VE | 1g |
| Injection fabaceous lecithin | 20g |
| Cholesterol | 2g |
| Vitamin E | 1g |
| Sucrose | 5g |
| Mannitol | 1g |
| Buffer salt solution | To 200mL |
| ? | ? |
The prodrug of recipe quantity, phospholipid, cholesterol, vitamin E are dissolved in organic solvent and pour pear shape bottle into, under 60 ℃ of water bath condition, rotate evaporate to dryness organic solvent, recipe quantity sucrose and mannitol are dissolved in buffer, pour pear shape bottle into, rotation aquation, thick gained suspension is once passed through to 0.8 μ m, 0.45 μ m, 0.22 μ m microporous filter membrane 1-10 time, obtain final prodrug liposome solutions.
PTX-S-VE prodrug of the present invention has the behavior of better antitumor drug effect.To the mouse model of set up inoculation Hela adenocarcinoma of the uterine cervix cell, after model is successfully established the 0th day, the 2nd day, the 4th day, the 6th day, within the 8th day, give respectively the Taxol of same dose and the prodrug PTX-S-VE Liposomal formulation of vitamin E and Docetaxel, and measure gross tumor volume.Result shows, PTX-S-VE Liposomal formulation has stronger antitumor drug effect than Taxol.(see figure 3)
Embodiment 7:
| PTX-S-VE | 1g |
| Injection fabaceous lecithin | 10g |
| Cholesterol | 5g |
| Vitamin E | 1g |
| Sucrose | 5g |
| Mannitol | 1g |
| Buffer salt solution | To 200mL |
| ? | ? |
Prodrug PTX-S-VE, phospholipid, cholesterol, the vitamin E of recipe quantity are dissolved in organic solvent and pour pear shape bottle into, under 60 ℃ of water bath condition, rotate evaporate to dryness organic solvent, recipe quantity sucrose and mannitol are dissolved in buffer, pour pear shape bottle into, rotation aquation, thick gained suspension is once passed through to 0.8 μ m, 0.45 μ m, 0.22 μ m microporous filter membrane 1-10 time, obtain final prodrug liposome solutions.
The prodrug of vitamin E of the present invention and paclitaxel has the behavior of better antitumor drug effect.To the mouse model of set up inoculation HepG2 hepatoma carcinoma cell, after model is successfully established the 0th day, the 2nd day, the 4th day, the 6th day, within the 8th day, give respectively the Taxol of same dose and the prodrug PTX-S-VE Liposomal formulation of vitamin E and paclitaxel, and measure gross tumor volume.Result shows, PTX-S-VE Liposomal formulation has stronger antitumor drug effect than Taxol.(see figure 4)
Embodiment 8:
| PTX-S-VE | 1g |
| Injection fabaceous lecithin | 20g |
| Cholesterol | 5g |
| Vitamin E | 1g |
| Sucrose | 5g |
| Mannitol | 1g |
| Buffer salt solution | To 200mL |
| ? | ? |
Prodrug PTX-S-VE, phospholipid, cholesterol, the vitamin E of recipe quantity are dissolved in organic solvent and pour pear shape bottle into, under 60 ℃ of water bath condition, rotate evaporate to dryness organic solvent, recipe quantity sucrose and mannitol are dissolved in buffer, pour pear shape bottle into, rotation aquation, thick gained suspension is once passed through to 0.8 μ m, 0.45 μ m, 0.22 μ m microporous filter membrane 1-10 time, obtain final prodrug liposome solutions.
The prodrug of vitamin E of the present invention and paclitaxel has the behavior of better antitumor drug effect.To the mouse model of set up inoculation MCF7 human breast cancer cell, after model is successfully established the 0th day, the 2nd day, the 4th day, the 6th day, within the 8th day, give respectively the Taxol of same dose and the prodrug PTX-S-VE Liposomal formulation of vitamin E and paclitaxel, and measure gross tumor volume.Result shows, PTX-S-VE Liposomal formulation has stronger antitumor drug effect than Taxol.(see figure 5)
Embodiment 9:
| PTX-S-VE | 1g |
| Injection fabaceous lecithin | 15g |
| Cholesterol | 2g |
| Vitamin E | 1g |
| Sucrose | 5g |
| Mannitol | 1g |
| Buffer salt solution | To 200mL |
| ? | ? |
Prodrug PTX-S-VE, phospholipid, cholesterol, the vitamin E of recipe quantity are dissolved in organic solvent and pour pear shape bottle into, under 60 ℃ of water bath condition, rotate evaporate to dryness organic solvent, recipe quantity sucrose and mannitol are dissolved in buffer, pour pear shape bottle into, rotation aquation, thick gained suspension is once passed through to 0.8 μ m, 0.45 μ m, 0.22 μ m microporous filter membrane 1-10 time, obtain final prodrug liposome solutions.
The prodrug of vitamin E of the present invention and paclitaxel has the behavior of better antitumor drug effect.To the mouse model of set up inoculation SKOV3 ovarian cancer cell, after model is successfully established the 0th day, the 2nd day, the 4th day, the 6th day, within the 8th day, give respectively the Taxol of same dose and the prodrug PTX-S-VE Liposomal formulation of vitamin E and paclitaxel, and measure gross tumor volume.Result shows, PTX-S-VE Liposomal formulation has stronger antitumor drug effect (see figure 6) than Taxol.
Claims (10)
1. a prodrug for antitumor drug, is characterized in that, vitamin E is connected by chemical bond with antitumor drug.
2. the prodrug of antitumor drug as claimed in claim 1, is characterized in that, antitumor drug refers to the one in paclitaxel, Docetaxel.
3. the prodrug of antitumor drug as claimed in claim 1, is characterized in that, described chemical bond is the one in monosulfidic bond, ester bond, interval disulfide bond, hydrazone key.
4. a pharmaceutical preparation, is characterized in that: the prodrug by claim 1-3 described in any one is combined with pharmaceutically acceptable excipient that be prepared into can be for the dosage form of injection or oral administration.
5. pharmaceutical preparation as claimed in claim 4, is characterized in that: described dosage form is liposome, Emulsion, lipoid microsphere, PLGA nanoparticle or microsphere.
6. pharmaceutical preparation according to claim 5, is characterized in that, described Emulsion comprises prodrug, oil for injection, emulsifying agent, and the weight ratio of prodrug, oil for injection, emulsifying agent is 1 part: 3～20 parts: 1～20 part.
7. pharmaceutical preparation according to claim 6, is characterized in that described oil for injection is selected from one or more the mixture in safflower oil, fish oil, Oleum Fructus Bruceae, soybean oil, triglyceride, vitamin E, decanoyl/octanoyl glycerides, Radix Oenotherae erythrosepalae oil, Fructrs Hippophae seed oil, Oleum Helianthi; Emulsifying agent is selected from one or more mixture of the mixture of vitamin E polyethylene glycol succinic acid ester, lecithin, Tween80, Span20, polyoxyethylene castor oil, glyceryl monooleate.
8. pharmaceutical preparation according to claim 5, is characterized in that, described liposome comprises prodrug, phospholipid, stabilizing agent, and the weight ratio of prodrug, phospholipid, stabilizing agent is 1 part: 5-100 part: 1-30 part.
9. pharmaceutical preparation according to claim 8, is characterized in that, described phospholipid is selected from one or more mixture of natural extract phospholipid, semi-synthetic phospholipid, complete synthesis phospholipid; Stabilizing agent is selected from one or more mixture of cholesterol, tetradecylic acid, 18-amine., vitamin E, TPGS, distearoyl phosphatidylcholine, Determination of Polyoxyethylene Non-ionic Surfactants, amphipathic ethylene glycol derivative.
10. the prodrug of claim 1-3 described in any one or the pharmaceutical preparation described in the claim 4-9 application in preparation treatment cancer drug, described cancer is breast carcinoma, ovarian cancer, hepatocarcinoma, oral cancer, pulmonary carcinoma, solid tumor, head and neck cancer, cancer of pancreas, cerebral glioma, lymphatic cancer, esophageal carcinoma, cervical cancer, renal carcinoma.
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| CN108245683A (en) * | 2018-01-26 | 2018-07-06 | 华中科技大学 | A kind of anti-tumor predrug and preparation method with the inhibition of P- glycoprotein |
| CN108424405A (en) * | 2018-03-06 | 2018-08-21 | 华东师范大学 | The total prodrug and the preparation method and application thereof of Vorinostat and taxol |
| CN108478803A (en) * | 2018-04-08 | 2018-09-04 | 沈阳药科大学 | The structure of redox hypersensitization disulfide bond bridging prodrug self-assembled nanometer grain |
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| CN105833284A (en) * | 2016-03-31 | 2016-08-10 | 沈阳药科大学 | Construction of paclitaxel-oleic acid small-molecular prodrug self-assembled nanoparticles |
| CN105833284B (en) * | 2016-03-31 | 2019-04-02 | 沈阳药科大学 | The building of taxol-oleic acid small molecule prodrugs self-assembled nanometer grain |
| CN105884719A (en) * | 2016-04-14 | 2016-08-24 | 沈阳药科大学 | Preparation and application of taxane prodrug |
| CN108245683A (en) * | 2018-01-26 | 2018-07-06 | 华中科技大学 | A kind of anti-tumor predrug and preparation method with the inhibition of P- glycoprotein |
| CN108245683B (en) * | 2018-01-26 | 2020-02-14 | 华中科技大学 | Anti-tumor prodrug with P-glycoprotein inhibition function and preparation method thereof |
| CN108424405A (en) * | 2018-03-06 | 2018-08-21 | 华东师范大学 | The total prodrug and the preparation method and application thereof of Vorinostat and taxol |
| CN108478803A (en) * | 2018-04-08 | 2018-09-04 | 沈阳药科大学 | The structure of redox hypersensitization disulfide bond bridging prodrug self-assembled nanometer grain |
| CN114181200A (en) * | 2021-11-24 | 2022-03-15 | 华中科技大学 | Cationic liposome with high gene transfection efficiency and preparation and application thereof |
| CN114181200B (en) * | 2021-11-24 | 2023-09-29 | 华中科技大学 | Cationic liposome with efficient gene transfection efficiency and preparation and application thereof |
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