CN103768614A - Antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions, and preparation method thereof - Google Patents
Antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions, and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of high-molecular medicine, and particularly relates to an antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions and a preparation method thereof. The preparation method comprises the following steps: firstly, performing amidation reaction on folic acid and amino polyethyleneglycol; then performing amidation reaction on a product obtained in the former step and 7-ethyloic-4-hydroxymethyl coumarin to obtain a polyethyleneglycol flexible chain with a folic acid receptor targeting function and a photoresponse group; finally enabling the polyethyleneglycol flexible chain to be coupled with an antitumor medicine containing amino with an ester activation method to obtain the antitumor medicine conjugate with the folic acid receptor-mediated and photoresponsive functions. The conjugate prepared by the invention can target a tumor cell through a folic acid receptor-mediated function, and enters the cell via the endocytosis to accelerate the accumulation speed of the medicine in the tumor cell; when being irradiated by ultraviolet light with a specific wavelength or near-infrared light, the conjugate is photolyzed to release original medicine, and the medicine quickly reaches the effective concentration, so that controllable 'time/space' treatment is realized; in addition, the method provides a simple and effective manner for preparing target-controllable photoresponsive high-molecular medicine conjugates.
Description
Technical field
The invention belongs to polymer drug technical field, be specifically related to a kind of folacin receptor mediated, photoresponse antitumor drug conjugate and preparation method thereof.
Background technology
In recent years, stimuli responsive type polymer drug conjugate design synthesizes and realizes neoplasm targeted therapy target and brought new approaches.Its core content is by cytotoxicity small-molecule drug and the macromolecule coupling that contains specific groups, thereby forms the drug conjugates of temporary transient non-activity.In vivo, be transported to lesions position with disactivation form, then utilize focus region physiological environment or outside particularity to stimulate, its active parent drug is released.In the structure of many anti-tumor small molecular medicines, contain the amino that acylation reaction can occur; and these amino often affect the chemistry and biology characteristic of medicine; once by other base group modifications, will cause the toxicity of medicine decline, when the modification group drug effect of leaving away is restored.The strategy of macromolecule and drug coupling can prolong drug circulation time in vivo, increases the effective picked-up of lesion tissue cell to medicine, improve medicine bioavailability, reduce the toxic and side effects of medicine.
On the other hand, in order to make medicine reach fast active drug treatment concentration in specific tumors tissue, adopting receptor target strategy, is that the inhomogeneities of utilizing receptor to distribute reaches a kind of effective measures of enhancing medicine enrichment around target cell.
Due to pure property and the time/empty controllability of environment light source, optical dynamic therapy has caused people's very big concern in the treatment of tumor.The present invention adopts coumarin group as photosensitive group, it is high that coumarin has photolysis efficiency, two photon absorption cross section is high, after can occurring in Near-infrared Double photon photolysis and photodissociation, can not produce the advantages such as toxic byproduct, because near infrared light has very low phototoxicity, the larger tissue penetration degree of depth.Therefore, there is good potential applicability in clinical practice
Have not yet to see the bibliographical information of this type of photocleavage receptor target antitumor drug conjugate.
Summary of the invention
An object of the present invention is to provide a kind of folacin receptor mediated targeted, light (ultraviolet light, Near-infrared Double photon) activation type antitumor drug conjugate.
Another object of the present invention is to provide the preparation method of described conjugate.
Object of the present invention is achieved by the following technical programs:
Provide a kind of folacin receptor mediated, photoresponse antitumor drug conjugate, its general structure:
FA is folic acid;
PEG is the Polyethylene Glycol of molecular weight ranges 500～5000Da;
D contains amino antitumor drug toxicity, comprises amycin, paclitaxel, methotrexate, gemcitabine or 5-fluorouracil.
As a typical case, the T in described general structure is folic acid, and D is amycin, paclitaxel, methotrexate, gemcitabine or 5-fluorouracil.
The preparation process of described a kind of folacin receptor mediated, photoresponse antitumor drug conjugate:
(1) folic acid is reacted with amino-end peg, obtain the single-ended amino Polyethylene Glycol of folic acid functionalization;
(2) the single-ended amino Polyethylene Glycol of folic acid functionalization is reacted and obtains the Polyethylene Glycol that main chain end contains hydroxymethylcoumarin with 7-carboxymethyl-4-hydroxymethylcoumarin;
(3) step (2) is obtained to Polyethylene Glycol and the N that end contains hydroxymethylcoumarin, one in N '-succimide carbonic ester, ethyl chloroformate, p-nitrophenyl chloroformate ester is carried out esterification, obtains a kind of Polyethylene Glycol of photosensitive group hydroxyl activation;
(4) step (3) is obtained to the Polyethylene Glycol and antitumor drug generation nucleophilic substitution containing amino of the hydroxyl activation of photosensitive group, obtain polymer drug conjugate.
In step (1), in anhydrous dimethyl sulfoxide DMSO solution, adopt DCC, NHS and triethylamine TEA combination catalyst, folic acid FA, amino-end peg NH
2-PEG-NH
2, DCC, NHS and TEA mole dosage be 1:1:1.5:1.5:5, stirring reaction 5～15 hours under room temperature.
In step (2), in DMF (DMF), add FA-PEG-NH
2with 7-carboxymethyl-4-hydroxymethylcoumarin, under EDC, NHS assembly catalyze, to react, their mole dosage is 1:1:1.5:1.5, stirring reaction 5～15 hours under room temperature.
In step (3), step (2) product is dissolved in acetonitrile, adds catalyst DMAP, then add N, one in N '-bis-succimide carbonic ester, ethyl chloroformate, 4-Nitrobenzol oxygen acyl chlorides is reacted 5～15 hours at 5～60 ℃.
In step (4), the product that step (3) is obtained is dissolved in N, in N '-dimethyl formamide (DMF), then adds the one and the Et that are dissolved with amycin, paclitaxel, methotrexate, gemcitabine or 5-fluorouracil
3the DMF solution of N, stirring reaction 5～15 hours.
The present invention is to be link agent based on the Polyethylene Glycol that contains photocleavage group; carry out acidylate modification to containing the medicines such as amino antitumor drug amycin; and be connected with cell specific ligand folic acid etc.; the synthetic targeting photoactivation formula polymer drug conjugate that carries photocleavage structure and the folacin receptor on tumor cell is there is to high-affinity of success; can make initiatively targeting specific tumors histiocyte surface of antitumor drug; and can under the photostimulation of external environment specific wavelength, discharge original antitumor drug poisoning tumor cell, reach therapeutic effect.
Prepare the main feature of antitumor drug conjugate: (1) is under the mediation of folic acid, conjugate is enriched in tumor cell surface selectively, and less existence on normal tissue cell surface, and enter cell by receptoe mediated endocytosis effect; (2) in conjugate, be connected with Polyethylene Glycol flexible chain, can reduce and the affinity of reticuloendothelial cell film, thereby avoid engulfing of reticuloendothelial cell, the circulation time of prolong drug in blood, strengthens passive target tumor tissues effect; (3) toxicity of the antitumor drug of modifying through acidylate reduces, and destroys hardly Normocellular growth, greatly reduces side effect; (4) this conjugate not only can respond ultraviolet light, can also there is the reaction of Near-infrared Double photon and rupture, discharge the former medicine of antitumor drug, poisoning tumor cell, and folic acid, coumarin and Polyethylene Glycol are nontoxic, especially near infrared light has more advantage than ultraviolet light, because long wavelength's near infrared light is less to histiocyte damage, and can increase the penetration depth to tissue.
The invention provides simple conjugate preparation method simultaneously, there is good field of medicaments application and popularization value.
Accompanying drawing explanation
Fig. 1 is reaction equation of the present invention.
The specific embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not do any type of restriction to the present invention.
The preparation of embodiment 1 folic acid-Polyethylene Glycol-amycin conjugate
(1) synthesizing of folic acid-Polyethylene Glycol-photosensitive coupling agent
1) Polyethylene Glycol of folic acid functionalization is synthetic
Take amino-end peg (NH
2-PEG-NH
2, M
w=3200Da) 640mg is dissolved in the anhydrous DMSO of 10mL, adds 2mL to be dissolved with the DMSO solution of folic acid FA and NHS, then adds successively DCC, TEA (the mole dosage NH of each material
2-PEG-NH
2: FA:NHS:DCC:TEA=1:1:1.5:1.5:5); under nitrogen protection; stirring at room temperature, lucifuge reaction 12h; by 20mL deionized water dilution for reactant mixture, centrifugal under 500rpm, remove by-product of dicyclohexylurea, then add 10mL acetone to remove unreacted folic acid; supernatant is put into the Dialysis tubing that molecular cut off is 3000Da; with the deionized water 48h that dialyses, lyophilization, obtains FA-PEG-NH
2.
2) be connected with the synthetic of photosensitive group Polyethylene Glycol
600mg FA-PEG-NH
2be dissolved in 20mL DMF, then add 7-carboxyl methyl-4-hydroxymethylcoumarin HMC, (mol ratio is FA-PEG-NH for EDC, NHS
2: HMC:EDC:NHS=1:1:1.5:5) pass into nitrogen, stirring at room temperature reaction 14h, adds under the dilution of 20mL water, 500rpm centrifugally, and supernatant is proceeded in Dialysis tubing with after deionized water dialysis 48h, and lyophilization, obtains FA-PEG-HMC.
3) photosensitive group hydroxyl activated carbonate
Taking FA-PEG-HMC500mg (0.13mmol) is dissolved in 5mL anhydrous acetonitrile, add N, N '-bis-succinimdyl carbonate (DSC, 0.4mmol) with catalyst DMAP (0.4mmol), under logical nitrogen protection, stirring at room temperature reaction 10h, by reactant liquor rotary evaporation, then residue is dissolved in 2mL dichloromethane, add again the agent of 30mL ether sedimentation to stir after 30min centrifugal, remove supernatant, then bottoms are dissolved again, precipitation, centrifugal, repeat 5 times, residue drying under reduced pressure, obtain the hydroxyl activated carbonate in photosensitive group.
(2) preparation of folic acid-Polyethylene Glycol-amycin medicine conjugate
The photosensitive group hydroxyl activated carbonate that takes 120mg folic acid functionalization is put into dry flask, be dissolved in completely in 20mL DMF, drip 15 μ LTEA, then add 5mL to be dissolved with the DMF solution of 50mg doxorubicin hydrochloride, after stirring at room temperature reaction 12h, first with the DMF 10h that dialyses, and then with after deionized water dialysis 48h, lyophilizing is for subsequent use.
The preparation of embodiment 2 folic acid-Polyethylene Glycol-5-FU conjugate
(1) according to the synthetic photosensitive group hydroxyl activated carbonate containing folic acid functionalization of the step of embodiment 1;
(2) preparation of folic acid-Polyethylene Glycol-5-FU conjugate
The photosensitive group hydroxyl activated carbonate that takes 150mg folic acid functionalization is dissolved in 20mL DMF, drips 15 μ L TEA, then adds 5mL to be dissolved with the DMF solution of 50mg5-FU, after stirring at room temperature 12h, first with the DMF 10h that dialyses, and then with after deionized water dialysis 48h, lyophilizing is for subsequent use.
The preparation of embodiment 3 folic acid-Polyethylene Glycol-methotrexate conjugate
(1) according to the photosensitive group hydroxyl activated carbonate of the synthetic folic acid functionalization of the step of embodiment 1;
(2) preparation of folic acid-Polyethylene Glycol-methotrexate conjugate
The photosensitive group hydroxyl activated carbonate that takes 200mg folic acid functionalization is dissolved in 25mL DMF, drips 20 μ L TEA, then adds 5mL to be dissolved with the DMF solution of 50mg methotrexate, after stirring at room temperature 12h, first with the DMF 10h that dialyses, and then with after deionized water dialysis 48h, lyophilizing is for subsequent use.
The preparation of embodiment 4 folic acid-Polyethylene Glycol-amycin conjugate
(1) obtain the Polyethylene Glycol of end containing hydroxymethylcoumarin group according to the step of embodiment 1;
(2) preparation of folic acid-Polyethylene Glycol-amycin conjugate
Take 120mg end and be dissolved in 20mL DMF containing the Polyethylene Glycol of hydroxymethylcoumarin group, drip 10 μ L TEA, then add 2 μ L ethyl chloroformates, stirring at room temperature 2h; The DMF solution that 5mL is dissolved with to 50mg amycin adds in above-mentioned solution, and after stirring at room temperature 12h, first with the DMF 10h that dialyses, and then with after deionized water dialysis 48h, lyophilizing is for subsequent use.
The preparation of embodiment 5 folic acid-Polyethylene Glycol-amycin conjugate
(1) obtain the Polyethylene Glycol of end containing hydroxymethylcoumarin group according to the step of embodiment 1;
(2) preparation of folic acid-Polyethylene Glycol-amycin conjugate
Take 300mg end and be dissolved in 25mL DMF containing the Polyethylene Glycol of hydroxymethylcoumarin group, drip 15 μ L TEA, then add 5 μ L4-Nitrobenzol oxygen acyl chlorides, stirring at room temperature 2h; The DMF solution that 5mL is dissolved with to 50mg amycin adds in above-mentioned solution, and after stirring at room temperature 12h, first with the DMF 10h that dialyses, and then with after deionized water dialysis 48h, lyophilizing is for subsequent use.
Claims (7)
1. folacin receptor mediated, a photoresponse antitumor drug conjugate, is characterized in that its structural formula:
Wherein FA is folic acid;
PEG is the Polyethylene Glycol of molecular weight ranges 500～5000Da;
D is the antitumor drug toxicity that contains amino or hydroxyl, comprises amycin, paclitaxel, methotrexate, gemcitabine or 5-fluorouracil.
2. a kind of folacin receptor mediated, photoresponse antitumor drug conjugate according to claim 1, is characterized in that the D in described general structure is amycin, paclitaxel, methotrexate, gemcitabine or 5-fluorouracil.
3. a kind of preparation method of folacin receptor mediated, photoresponse antitumor drug conjugate described in claim 1 or 2, is characterized in that comprising the following steps:
(1) folic acid is reacted with amino-end peg, obtain the single-ended amino Polyethylene Glycol of folic acid functionalization;
(2) the single-ended amino Polyethylene Glycol of folic acid functionalization is reacted and obtains the Polyethylene Glycol that main chain end contains coumarin photosensitive group with carboxymethyl coumarin;
(3) step (2) is obtained to Polyethylene Glycol and the N that end contains coumarin photosensitive group, one in N '-succimide carbonic ester, ethyl chloroformate, 4-Nitrobenzol oxygen acyl chlorides is carried out esterification, obtains a kind of photosensitive group polymer of hydroxyl activation;
(4) by the photosensitive group polymer of hydroxyl activation and containing amino antitumor drug generation nucleophilic substitution, obtain polymer drug conjugate.
4. preparation method according to claim 3, it is characterized in that in step (1), in dimethyl sulfoxide solution, adopt dicyclohexylcarbodiimide (DCC), N-hydroxy-succinamide (NHS) and triethylamine (TEA) combination catalyst, folic acid (FA), amino-end peg NH
2-PEG-NH
2, DCC, NHS and TEA mole dosage be 1:1:1.5:1.5:5, stirring reaction 5～15 hours under room temperature.
5. preparation method according to claim 3, is characterized in that, in step (2), in DMF (DMF), adding FA-PEG-NH
2with 7-carboxymethyl-4-hydroxymethylcoumarin, under EDC, NHS assembly catalyze, to react, their mole dosage is 1:1:1.5:1.5, stirring reaction 5～15 hours under room temperature.
6. preparation method according to claim 3, it is characterized in that in step (3), step (2) product is dissolved in acetonitrile, add catalyst DMAP, add again N, one in N '-bis-succimide carbonic ester, ethyl chloroformate, 4-Nitrobenzol oxygen acyl chlorides is reacted 5～15 hours at 5～60 ℃.
7. preparation method according to claim 3, it is characterized in that in step (4), the product that step (3) is obtained is dissolved in N, in N '-dimethyl formamide (DMF), then add the one and the Et that are dissolved with amycin, paclitaxel, methotrexate, gemcitabine or 5-fluorouracil
3the DMF solution of N, stirring reaction 5～15 hours.
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| CN106008955A (en) * | 2016-06-07 | 2016-10-12 | 沈阳药科大学 | Preparation method for ibuprofen polyethylene glycol ester and ibuprofen polyethylene glycol ester preparation |
| CN106279667A (en) * | 2016-07-28 | 2017-01-04 | 河南大学 | Polyethylene Glycol hollow ball, its preparation method and the application of a kind of pH sensitivity photo-crosslinking |
| CN107501363A (en) * | 2017-07-24 | 2017-12-22 | 福建医科大学孟超肝胆医院 | A kind of adriamycin precursor compound and its preparation and application with photoresponse degraded |
| CN108578427A (en) * | 2018-03-01 | 2018-09-28 | 苏州大学 | Gold nano grain of modified with folic acid and preparation method thereof and the application in preparing radiosensitization medicine |
| CN108743980A (en) * | 2018-07-06 | 2018-11-06 | 重庆医科大学 | A kind of folate-targeted visualization photo-thermal-chemotherapeutant and preparation method thereof |
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| CN106008955A (en) * | 2016-06-07 | 2016-10-12 | 沈阳药科大学 | Preparation method for ibuprofen polyethylene glycol ester and ibuprofen polyethylene glycol ester preparation |
| CN106279667A (en) * | 2016-07-28 | 2017-01-04 | 河南大学 | Polyethylene Glycol hollow ball, its preparation method and the application of a kind of pH sensitivity photo-crosslinking |
| CN106279667B (en) * | 2016-07-28 | 2017-12-12 | 河南大学 | A kind of polyethylene glycol hollow ball, its preparation method and the application of pH sensitivities photo-crosslinking |
| CN107501363A (en) * | 2017-07-24 | 2017-12-22 | 福建医科大学孟超肝胆医院 | A kind of adriamycin precursor compound and its preparation and application with photoresponse degraded |
| CN107501363B (en) * | 2017-07-24 | 2019-12-03 | 福建医科大学孟超肝胆医院(福州市传染病医院) | A kind of adriamycin precursor compound and its preparation and application with photoresponse degradation |
| CN109568593A (en) * | 2017-09-28 | 2019-04-05 | 叶衍铭 | A kind of folacin receptor mediated, phot-luminescence sensitizing drug conjugate and preparation method thereof |
| CN108578427A (en) * | 2018-03-01 | 2018-09-28 | 苏州大学 | Gold nano grain of modified with folic acid and preparation method thereof and the application in preparing radiosensitization medicine |
| CN108578427B (en) * | 2018-03-01 | 2020-11-17 | 苏州大学 | Folic acid modified gold nanoparticle, preparation method thereof and application of gold nanoparticle in preparation of radiosensitization treatment drug |
| CN108743980A (en) * | 2018-07-06 | 2018-11-06 | 重庆医科大学 | A kind of folate-targeted visualization photo-thermal-chemotherapeutant and preparation method thereof |
| CN108743980B (en) * | 2018-07-06 | 2021-05-18 | 重庆医科大学 | Folic acid targeted visual photothermal-chemotherapy therapeutic agent and preparation method thereof |
| CN109453378A (en) * | 2018-11-21 | 2019-03-12 | 华中科技大学 | A kind of laser nano-control particle assembly body and the preparation method and application thereof |
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