CN102631681A - Long-circulating target photosensitive antitumor medicine conjugate and preparation method thereof - Google Patents
Long-circulating target photosensitive antitumor medicine conjugate and preparation method thereof Download PDFInfo
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- CN102631681A CN102631681A CN201210013892XA CN201210013892A CN102631681A CN 102631681 A CN102631681 A CN 102631681A CN 201210013892X A CN201210013892X A CN 201210013892XA CN 201210013892 A CN201210013892 A CN 201210013892A CN 102631681 A CN102631681 A CN 102631681A
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- polyethylene glycol
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Abstract
The invention belongs to the technical field of polymer drugs, and particularly relates to a long-circulating target photosensitive antitumor drug conjugate and a preparation method of the long-circulating target photosensitive antitumor drug conjugate. The preparation method comprises the following steps: firstly, carrying out amidation reaction to a single-end amino polyethylene glycol amino with ligand functionalization and 4-(1-ethoxy)-2- methoxy group-5-nitrobenzoic acid containing a photosensitive group; then carrying out esterification reaction with an esterifying agent; and finally coupling with the antitumor drug containing the amino to obtain the long-circulating target photosensitive antitumor drug conjugate. According to the conjugate prepared by the preparation method, the circulating time of the drug in the body can be prolonged, tumor tissues are accelerated to adsorb drug, and the conjugate has the target to quicken the enrichment speed of the antitumor drug in the tumor tissues. The conjugate is fractured by the photostimulation of specific wavelength to release original drug and quickly achieve treatment concentration, and 'time/space' controllable effective treatment is obtained. Meanwhile, the preparation method provides a simple and effective path for preparing the target controllable photosensitive biological polymer drug.
Description
Technical field
The invention belongs to the polymer drug technical field, be specifically related to a kind of long-circulating target, photosensitive antitumor drug conjugate and preparation method thereof.
Background technology
In recent years, the design of stimuli responsive type polymer drug conjugate synthesizes realization neoplasm targeted therapy target and has brought new approaches.Its core content is with the cytotoxicity small-molecule drug and contains the macromolecule coupling of specific groups, thereby forms the drug conjugates of temporary transient non-activity.In vivo, be transported to lesions position, utilize focus zone physiological environment or outside particularity to stimulate then, its active parent drug is released with the disactivation form.Contain the amino that acylation reaction can take place in the structure of many anti-tumor small molecular medicines; And these amino often affect the chemistry and biology characteristic of medicine; In case by other base group modifications, will cause the toxicity of medicine to descend, when the modification group drug effect of leaving away is able to restore.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, improves bioavailability of medicament, reduces the toxic and side effects of medicine.
On the other hand, in the specific tumors tissue, reaching active drug treatment concentration fast in order to make medicine, adopt the receptor target strategy, promptly is that the inhomogeneities of utilizing receptor to distribute reaches enhancing medicine a kind of effective measures of enrichment around target cell.
Because the pure property of environment light source and the time/empty controllability, optical dynamic therapy has caused people's very big concern in tumor treatment.
Do not see at present the bibliographical information of long circulation photocleavage receptor target antitumor drug conjugate as yet.
Summary of the invention
An object of the present invention is to provide a kind of folacin receptor mediated light (ultraviolet light, two-photon near infrared light) activation type targeting anti-tumor drug conjugates of circulation of growing.
Another object of the present invention provides the method for preparing of said conjugate.
The object of the invention is achieved through following technical scheme:
A kind of long-circulating target, photosensitive antitumor drug conjugate are provided, its general structure:
Wherein T is targeting part unit, comprising: folic acid FA, cyclic oligomer peptide cRGD, biotin, glucose or lactose.
PEG is the Polyethylene Glycol of molecular weight ranges 500～5000Da.
D contains amino antitumor drug toxicity, comprises amycin, paclitaxel, methotrexate, cytosine arabinoside or 5-fluorouracil.
As a typical case, the T in the said general structure is a folic acid, and D is amycin, paclitaxel, methotrexate, 5-fluorouracil.
The preparation process of said a kind of long-circulating target, photosensitive antitumor drug conjugate:
(1), obtains the single-ended amino Polyethylene Glycol of folic acid functionalization with folic acid and amino-end peg reaction;
(2) single-ended amino Polyethylene Glycol and 4-(1-the ethoxy)-2-methoxyl group-5-nitrobenzoyl acid reaction with the folic acid functionalization obtains the Polyethylene Glycol that the main chain end contains the modification of ortho-nitrophenyl methanol;
(3) step (2) is obtained end and contain Polyethylene Glycol and the N that ortho-nitrophenyl methanol is modified, a kind of esterification of carrying out in N '-succimide carbonic ester, ethyl chloroformate, the 4-Nitrobenzol oxygen acyl chlorides obtains the Polyethylene Glycol that main chain contains the photosensitive group functionalization;
(4) step (3) is obtained the Polyethylene Glycol and the antitumor drug generation nucleophilic substitution that contains amino that main chain contains the photosensitive group functionalization, obtain the polymer drug conjugate.
In step (1), in dimethyl sulfoxine 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: 1.2: 1.2: 3, stirring reaction was 10～24 hours under the room temperature.
In step (2), at N, among the dinethylformamide DMF, FA-PEG-NH
2With 4-(1-ethoxy)-2-methoxyl group-5-nitrobenzoic acid, under EDC, DMAP associating catalysis, to react, their mole dosage is 1: 1: 1.5: 3, stirring reaction is 10～24 hours under the room temperature.
In step (3), step (2) product is dissolved in the acetonitrile, add catalyst DMAP, add N again, a kind of in N-two succimide carbonic esters, ethyl chloroformate, the 4-Nitrobenzol oxygen acyl chlorides is 25～60 ℃ of reactions 10～24 hours down.
In step (4), the product of step (3) gained is dissolved among the DMF, add again and be dissolved with a kind of and Et in amycin, paclitaxel, methotrexate, the 5-fluorouracil
3The DMF solution of N, stirring reaction 10～24 hours.
The present invention is based on the Polyethylene Glycol that contains the photocleavage group and is the link agent; Carry out the acidylate modification to containing amino medicines such as antitumor drug amycin; And link to each other with cell specific ligand folic acid etc.; Success is synthetic to carry the fault structure of light and the folacin receptor on the tumor cell is had the long-circulating target photoactivation formula polymer drug conjugate of high-affinity; Can make initiatively targeting specific tumors histiocyte surface enrichment of antitumor drug, and can under the photostimulation of environment specific wavelength, discharge original antitumor drug poisoning tumor cell, reach therapeutic effect.
Prepare the main feature of antitumor drug conjugate: (1) under the mediation of folic acid, conjugate is enriched in tumor cell surface selectively, and less existence on the normal tissue cell surface; (2) be connected with the Polyethylene Glycol flexible chain in the conjugate, can reduce the affinity with the 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 process acidylate modification reduces, and destroys Normocellular growth hardly; (4) this conjugate not only can respond ultraviolet light; Can also respond the near infrared light that the two-photon reaction takes place and rupture, discharge the former medicine of antitumor drug, the poisoning tumor cell; And folic acid 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 the histiocyte damage, and can increase the penetration depth to tissue.
The invention provides simple conjugate method for preparing simultaneously, have good field of medicaments application and popularization value.
Description of drawings
Fig. 1 is a reaction equation of the present invention.
The specific embodiment
Come further to explain the present invention below in conjunction with embodiment, but embodiment does not do any type of qualification to the present invention.
The preparation of embodiment 1 folic acid-Polyethylene Glycol-amycin conjugate
(1) folic acid-Polyethylene Glycol-photosensitive coupling agent is synthetic
1) Polyethylene Glycol of folic acid functionalization is synthetic
Take by weighing amino-end peg (NH
2-PEG-NH
2, M
w=3200Da) 640mg is dissolved among the anhydrous DMSO of 10mL, adds the DMSO solution that 2mL is dissolved with folic acid FA and NHS, adds DCC, TEA (mol ratio NH then successively
2-PEG-NH
2: FA: NHS: DCC: TEA=1: 1: 1.2: 1.2: 3), under logical nitrogen situation, stirring at room, lucifuge reaction 12h; Reactant mixture with 20mL deionized water dilution, centrifugal under 500rpm, is removed by-product of dicyclohexylurea, add 10mL acetone again to remove unreacted folic acid; Supernatant is put into the Dialysis tubing that molecular cut off is 1000Da; 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 among the 20mL DMF, add 4-(1-ethoxy)-2-methoxyl group-5-nitrobenzoic acid ONB, DCC then, (mol ratio is FA-PEG-NH to DMAP
2: ONB: DCC: DMAP=1: 1: 1.5: 3) feed nitrogen, stirring at room reaction 18h adds under the dilution of 20mL water, the 500rpm centrifugally, and supernatant is changed in the Dialysis tubing with behind the deionized water dialysis 48h, and lyophilization obtains FA-PEG-ONB.
3) end contains Polyethylene Glycol maleimide carbonic ester synthetic of folic acid
Take by weighing FA-PEG-ONB 500mg (0.13mmol) and be dissolved in the 5mL anhydrous acetonitrile, add N, N ' dimaleimide carbonic ester (DSC; 0.4mmol) and catalyst DMAP (0.4mmol), under logical nitrogen protection, stirring at room reaction 10h; With the reactant liquor rotary evaporation, then residue is dissolved in the 2mL dichloromethane, add the agent of 30mL ether sedimentation again and stir behind the 30min centrifugal; Remove supernatant, then with bottoms dissolve again, deposition, centrifugal, repeat 5 times; The residue drying under reduced pressure obtains the Polyethylene Glycol maleimide carbonic ester that an end contains folic acid.
(2) preparation of folic acid-Polyethylene Glycol-amycin medicine conjugate
The Polyethylene Glycol maleimide carbonic ester that takes by weighing 100mg folic acid functionalization is put into exsiccant flask; Be dissolved in fully among the 20mL DMF, drip 20 μ L TEA, add the DMF solution that 5mL is dissolved with the 77mg doxorubicin hydrochloride then; Behind the stirring at room reaction 12h; Earlier with the DMF 10h that dialyses, and then with behind the deionized water dialysis 48h, lyophilizing is subsequent use.
The preparation of embodiment 2 folic acid-Polyethylene Glycol-5-FU conjugate
(1) according to the synthetic Polyethylene Glycol maleimide carbonic ester that contains the folic acid functionalization of the step of embodiment 1;
(2) preparation of folic acid-Polyethylene Glycol-5-FU conjugate
Take by weighing the Polyethylene Glycol maleimide carbonic ester that 150mg contains folic acid and be dissolved among the 22mL DMF, drip 15 μ L TEA, add the DMF solution that 5mL is dissolved with 50mg 5-FU then; Behind the stirring at room 12h; Earlier with the DMF 10h that dialyses, and then with behind the deionized water dialysis 48h, lyophilizing is subsequent use.
The preparation of embodiment 3 folic acid-Polyethylene Glycol-methotrexate conjugate
(1) according to the synthetic Polyethylene Glycol maleimide carbonic ester that contains the folic acid functionalization of the step of embodiment 1;
(2) preparation of folic acid-Polyethylene Glycol-methotrexate conjugate
Take by weighing the Polyethylene Glycol maleimide carbonic ester that 170mg contains folic acid and be dissolved among the 25mL DMF, drip 15 μ LTEA, add the DMF solution that 5mL is dissolved with the 50mg methotrexate then; Behind the stirring at room 12h; Earlier with the DMF 10h that dialyses, and then with behind the deionized water dialysis 48h, lyophilizing is subsequent use.
The preparation of embodiment 4 folic acid-Polyethylene Glycol-amycin conjugate
(1) step according to embodiment 1 obtains the terminal Polyethylene Glycol that contains the ortho-nitrophenyl methanol groups;
(2) preparation of folic acid-Polyethylene Glycol-amycin conjugate
Take by weighing the Polyethylene Glycol that the 120mg end contains the ortho-nitrophenyl methanol groups and be dissolved among the 20mL DMF, drip 15 μ L TEA, add 2 μ L ethyl chloroformates then, stirring at room 2h; The DMF solution that 5mL is dissolved with the 50mg amycin adds in the above-mentioned solution, and behind the stirring at room 12h, earlier with the DMF 10h that dialyses, and then with behind the deionized water dialysis 48h, lyophilizing is subsequent use.
The preparation of embodiment 5 folic acid-Polyethylene Glycol-amycin conjugate
(1) step according to embodiment 1 obtains the terminal Polyethylene Glycol that contains the ortho-nitrophenyl methanol groups;
(2) preparation of folic acid-Polyethylene Glycol-amycin conjugate
Take by weighing the Polyethylene Glycol that the 300mg end contains the ortho-nitrophenyl methanol groups and be dissolved among the 25mL DMF, drip 15 μ L TEA, add 5 μ L 4-Nitrobenzol oxygen acyl chlorides then, stirring at room 2h; The DMF solution that 5mL is dissolved with the 50mg amycin adds in the above-mentioned solution, and behind the stirring at room 12h, earlier with the DMF 10h that dialyses, and then with behind the deionized water dialysis 48h, lyophilizing is subsequent use.
Claims (7)
1. a long-circulating target, photosensitive antitumor drug conjugate is characterized in that its structural formula:
Wherein T is the targeting part, comprising: folic acid (FA), cyclic oligomer peptide (cRGD), biotin, glucose or lactose;
PEG is the Polyethylene Glycol of molecular weight ranges 500～5000Da;
D contains amino antitumor drug toxicity, comprises amycin, paclitaxel, methotrexate, cytosine arabinoside or 5-fluorouracil.
2. according to the said a kind of long-circulating target of claim 1, photosensitive antitumor drug conjugate, it is characterized in that the T in the said general structure is a folic acid, D is amycin, paclitaxel, methotrexate, 5-fluorouracil.
3. the method for preparing of claim 1 or 2 said a kind of long-circulating targets, photosensitive antitumor drug conjugate is characterized in that may further comprise the steps:
(1), obtains the single-ended amino Polyethylene Glycol of folic acid functionalization with folic acid and amino-end peg reaction;
(2) single-ended amino Polyethylene Glycol and 4-(1-the ethoxy)-2-methoxyl group-5-nitrobenzoyl acid reaction with the folic acid functionalization obtains the Polyethylene Glycol that the main chain end contains the modification of ortho-nitrophenyl methanol;
(3) step (2) is obtained end and contain Polyethylene Glycol and the N that ortho-nitrophenyl methanol is modified, a kind of esterification of carrying out of N '-in imidodicarbonic diamide carbonic ester, ethyl chloroformate, 4-Nitrobenzol oxygen acyl chlorides obtains the Polyethylene Glycol that main chain contains the photosensitive group functionalization;
(4) main chain is contained the Polyethylene Glycol of photosensitive group functionalization and contains amino antitumor drug generation nucleophilic substitution, obtain polymer drug conjugate (I).
4. method for preparing according to claim 3; It is characterized in that in the step (1); In dimethyl sulfoxide solution, adopt dicyclohexylcarbodiimide (DCC), N-hydroxyl maleimide (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: 1.2: 1.2: 3, stirring reaction was 10～24 hours under the room temperature.
5. method for preparing according to claim 3 is characterized in that in the step (2), at N, in the dinethylformamide, adds FA-PEG-NH
2And 4-(1-ethoxy)-2-methoxyl group-5-nitrobenzoic acid, under EDC, dimethylamino naphthyridine (DMAP) associating catalysis, to react, their mole dosage is 1: 1: 1.5: 3, stirring reaction is 10～24 hours under the room temperature.
6. method for preparing according to claim 3; It is characterized in that in the step (3); Step (2) product is dissolved in the acetonitrile, adds catalyst DMAP, add N again; A kind of in N '-two succimide carbonic ester, ethyl chloroformate, the 4-Nitrobenzol oxygen acyl chlorides is 25～60 ℃ of reactions 10～24 hours down.
7. method for preparing according to claim 3 is characterized in that in the step (4), and the product that step (3) is obtained is dissolved in the dimethylformamide (DMF), adds a kind of and Et that is dissolved with amycin, paclitaxel, methotrexate, 5-fluorouracil again
3The DMF solution of N, stirring reaction 10～24 hours.
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Cited By (8)
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| CN102875841A (en) * | 2012-09-22 | 2013-01-16 | 复旦大学 | Photosensitive cross-linking agent and preparation method thereof |
| CN103768614A (en) * | 2013-11-08 | 2014-05-07 | 盐城工学院 | Antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions, and preparation method thereof |
| CN105688230A (en) * | 2016-02-02 | 2016-06-22 | 史春梦 | Heptamethine indocyanine dye-polyethylene glycol-folate compound, as well as preparation method and application thereof |
| CN106083898A (en) * | 2016-05-31 | 2016-11-09 | 彭咏波 | A kind of tumor-targeting gambogic acid compounds and its production and use |
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| KR20200085178A (en) * | 2019-01-04 | 2020-07-14 | 한국외국어대학교 연구산학협력단 | Composition and preparation for photoactivatable fluorescent probes |
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2012
- 2012-01-07 CN CN201210013892XA patent/CN102631681A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102875841A (en) * | 2012-09-22 | 2013-01-16 | 复旦大学 | Photosensitive cross-linking agent and preparation method thereof |
| CN103768614A (en) * | 2013-11-08 | 2014-05-07 | 盐城工学院 | Antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions, and preparation method thereof |
| CN105688230A (en) * | 2016-02-02 | 2016-06-22 | 史春梦 | Heptamethine indocyanine dye-polyethylene glycol-folate compound, as well as preparation method and application thereof |
| CN105688230B (en) * | 2016-02-02 | 2018-12-11 | 史春梦 | Seven methine indoles cyanine dyes-polyethylene glycol-folic acid composite and preparation method and application |
| CN106083898A (en) * | 2016-05-31 | 2016-11-09 | 彭咏波 | A kind of tumor-targeting gambogic acid compounds and its production and use |
| CN106083898B (en) * | 2016-05-31 | 2019-02-12 | 彭咏波 | A kind of tumor-targeting gambogic acid compounds and its preparation method and application |
| KR102159181B1 (en) | 2019-01-04 | 2020-09-23 | 한국외국어대학교 연구산학협력단 | Composition and preparation for photoactivatable fluorescent probes |
| KR20200085178A (en) * | 2019-01-04 | 2020-07-14 | 한국외국어대학교 연구산학협력단 | Composition and preparation for photoactivatable fluorescent probes |
| CN109678992A (en) * | 2019-01-09 | 2019-04-26 | 上海应用技术大学 | A kind of folic acid functional modification polyvinyl alcohol pharmaceutical polymers and preparation method thereof for soluble micropin |
| CN109678992B (en) * | 2019-01-09 | 2021-02-26 | 上海应用技术大学 | Folic acid functionalized modified polyvinyl alcohol medicinal polymer material for soluble microneedle and preparation method thereof |
| CN113633780A (en) * | 2020-09-11 | 2021-11-12 | 上海邈基生物科技有限公司 | Small molecule conjugate and application thereof |
| CN113633780B (en) * | 2020-09-11 | 2023-08-29 | 上海邈基生物科技有限公司 | Small molecule conjugate and application thereof |
| CN112957311A (en) * | 2021-03-04 | 2021-06-15 | 嘉兴市第二医院 | Light-operated nano robot with variable particle size, preparation method thereof and application thereof in tumor inhibition |
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Application publication date: 20120815 |