CN109771657A - A kind of bonding vascular disrupting agents and the high molecular antineoplastic drug of immunomodulator and preparation method thereof - Google Patents
A kind of bonding vascular disrupting agents and the high molecular antineoplastic drug of immunomodulator and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of bonding vascular disrupting agents and the high molecular antineoplastic drug of immunomodulator and preparation method thereof；The high molecular antineoplastic drug is grafted bonding vascular disrupting agents and immunomodulator drug molecule using polyethylene glycol and two block of polylactide as main chain, by the chemical reaction such as sulfydryl-alkene light click-reaction and esterification and nitrine-alkynes cycloaddition reaction simultaneously on main chain.The high molecular antineoplastic drug is acted synergistically by tumor vessel Blocking therapy and immunotherapy, anticancer activity is improved in the case where reducing drug dose, it avoids classic chemotherapy drug and is difficult to the defects of penetrating into inside tumor cells and drug resistance, the long-lasting kill tumour cell of patient's self immune system is activated using immunotherapy again simultaneously, effectively prevent the transfer and recurrence of clinically tumour.Furthermore the features such as synthetic method of antitumor high molecule bonding drug has and is simple and efficient, and reaction condition is mild.
Description
Technical field
The present invention relates to a kind of high molecular antineoplastic drugs, in particular to a kind of to be bonded vascular disrupting agents and immune tune simultaneously
The antitumor high molecule bonding drug for saving agent, further relates to preparation method；Belong to biological medicine polymeric material field.
Background technique
The tumour public health problem global as one, greatly endangers the health of the mankind, and have become
The main reason of new century human death.Treatment of cancer at present mainly has the primary hands such as chemotherapy, operative treatment, radiotherapy
Section, although classic chemotherapy is by prolonged progress, however it remains anticancer drug be difficult to penetrate into inside tumor, make for a long time
The problems such as with drug resistance is generated, so that therapeutic effect is unsatisfactory, and there is toxic side effects for radiotherapy and operative treatment
Greatly, the defects of easily leading to tumour cell diffusion transfer, thus how to prevent tumour diffusion transfer, how more efficient lasting kill
How tumour cell solves anticancer drug and is difficult to penetrate into the emphasis and difficulty that inside tumor is present researcher research
Point.
Blood vessel blocking therapy and immunotherapy have attracted numerous researchers' note that blood vessel blocking therapy is mainly in recent years
By inhibiting the formation of tumor neogenetic blood vessels outgrowth factor VEGF, vascular endothelial cell natural apoptosis is induced, tumor neogenetic is destroyed
Rete vasculosum leads to the death of tumour cell.Immunotherapy is as a kind of activation patient's autoimmunity cell (such as T cell, B cell
And macrophage) to induce the treatment method for being directed to cancer specific immune response, immune system can be certainly in normal bio body
Dynamic to identify and kill tumour cell, principal immune process is as follows: the antigen that tumour cell generates is thin by internal antigen presentation first
Born of the same parents (APC) capture, proinflammatory cytokine etc. of the tumour cell release of apoptosis as nutriment promote antigen presenting cell at
Ripe, the antigen presenting cell then activated marches to internal lymph node and tumour specific antigen is presented to T cell, causes to be directed to
The initiation and activation of the effector T cell response of tumour specific antigen.The effector T cell of activation enters and penetrates into tumor bed,
They pass through T cell receptor specific recognition cancer cell and kill cancer cell there.And tumour cell position can then block
" immune evasion " phenomenon occurs for immune circulation, and the activity of depression effect T cell is to inhibit the identification and attack of immune system.
Combretastatin (CA-4) is used as a kind of novel vascular blocking agent, directly acts on vascular endothelial cell, effectively blocks
Tumour cell, for the growth, breeding, diffusion transfer of tumour, causes tumor center position because lacking from oxygen and nutrient is nearby drawn
Weary oxygen and nutrient and Large Scale Death.Imiquimod (R837) is used as a kind of Toll-like receptor (TLR7) agonist, belongs to miaow
Azoles quinolines, can generate proinflammatory cytokine etc. with internal TLR sample zygotic induction can efficiently stimulate internal antigen presentation
The maturation of cell makes it that tumour specific antigen are quickly delivered to internal lymph node position, so that activation has specifically in vivo
The panimmunities relevant cells such as the effector T cell of property killing tumor cell.Immunotherapy have can activate patient's autoimmunity system
System has the ability of the long-term killing tumour of specificity, and can act synergistically efficiently long-term treating cancer with blood vessel blocking therapy.
Vascular disrupting agents and this kind of small-molecule drug of immunomodulator can be cooperateed with by the different pharmaceutical mechanism of action to be used, energy
Drug dose is reduced, cost is reduced, reduces toxic side effect, therapeutic effect is greatly improved and can be kept for a long time.However above-mentioned two class
Small-molecule drug combine there are the metabolisming property of different pharmaceutical, tissue and organ distribution, penetrate films at different levels ability difference
The problem of, it is difficult to control initial concentration when a variety of drugs for reaching final target spot still keep injection.Therefore, before using polymer
Medicine or nano-medicament carrier become the optimal strategy of drug combination.It is well known that nano-medicament carrier have can be by suitable
Size and structure design are distributed and with internal by the excellent of EPR effect realization passive target to change the pharmacokinetics of drug
Point.
Currently, a kind of imiquimod of (107661336 A of CN) patent report and the double medicament-carried nano bodies of dinitrofluorobenzene
System forms nano particle using ultrasonic conductivity gauge target administration by a kind of double medicament-carried nano carrier physically encapsulation imiquimods
Cooperate chemotherapeutics synergistic treatment, this mode is simple and convenient, drugloading rate is higher and improves by immunotherapy pernicious black
Melanoma curative effect, but because of under physically encapsulation in vivo release conditions, not can control rate of release, be easy to appear drug and shift to an earlier date
Situations such as release, drug violent release；(Acta Biomaterialia 53 (2017) 179-189) reports a kind of using polyglutamic
The high molecular nanometer medicine-carried system of acid bonding Combretastatin, the water for successfully solving Combretastatin small molecule pro-drug are insoluble
Property, Half-life in vivo is short, classic chemotherapy drug can not penetrate into the problems such as inside tumor plays curative effect, but individual blood vessel
Blocking agent curative effect can not activate the specific response of self immune system, kill tumour cell that cannot be permanently effective, be easy to lead
Situations such as oncogenic recurrence.
Summary of the invention
Can not be penetrated by being easy to produce drug resistance, chemotherapeutics for classic chemotherapy by easy to recur turn of inside tumor, tumour
The problems such as moving diffusion, leads to the defects of human body is low to the practical efficiency of drug, and clinical chemotherapy effect is barely satisfactory.Of the invention
First purpose is to be to provide one kind using biodegradable amphipathy macromolecule as carrier, while being bonded vascular disrupting agents and exempting from
Epidemic disease regulator obtains the polymer bond drug of blood vessel blocking therapy and immunotherapy synergy；The drug is thin by blocking tumour
Born of the same parents' nutrient absorption, tumor angiogenesis and human activin normal immunological circulation improve anti-in such a way that specificity kills tumour cell etc.
Cancer activity, effectively avoid classic chemotherapy drug from being difficult to permeate, drug resistance the problems such as, while reducing side effect of the drug to human body,
And its good biocompatibility, drug ratios and drugloading rate can arbitrarily regulate and control and realize and be effectively sustained in tumor locus, can be used for
Clinical research.
Another object of the present invention be to provide it is a kind of prepare in a mild condition and meanwhile be bonded vascular disrupting agents with
The method of the Biodegradable high-molecular anti-tumor drug of immunomodulator, this method reaction condition is mild, economical, efficiently and nothing
Poison.
In order to achieve the above technical purposes, the present invention provides a kind of high scores for being bonded vascular disrupting agents and immunomodulator
Sub- anti-tumor drug has 1 structure of formula:
Wherein,
A is vascular disrupting agents group；
B is immunomodulator group；
It is 2~20, y is 1~10 that n, which is 45~454, x, and-y≤19 1≤x；
R1、R2And R3Independently selected from C1~C4Alkylidene；
Preferred scheme, A are the blood vessel blockings class pharmaceutical groups such as Combretastatin, Combretastatin disodium hydrogen phosphate.
Preferred scheme, the imidazole quinolines amine drug group such as B R837, R848, R842.
The present invention also provides the preparations of a kind of bonding vascular disrupting agents and the high molecular antineoplastic drug of immunomodulator
Method, comprising the following steps:
1) lactide containing norbornene is caused with poly glycol monomethyl ether and carries out ring-opening polymerisation, obtain side containing norbornene
Poly glycol monomethyl ether-b- the polylactide co polymer of base；Poly glycol monomethyl ether-the b- of the side group containing norbornene poly- third is handed over
Ester copolymer carries out sulfydryl-alkene light click-reaction with the carboxylic acid compound containing sulfydryl, obtains the carrier polymer of oxatyl-containing lateral group；
The carrier polymer of the oxatyl-containing lateral group and the azido compound of hydroxyl carry out esterification, obtain the side group containing azido
2 carrier polymer of formula；
2) the diphenyl cyclooctyne compound that the vascular disrupting agents of hydroxyl are activated with 3 succinimide ester of formula is esterified
Reaction obtains the vascular disrupting agents of 4 functional group of cyclooctyne containing diphenyl of formula；Amino-containing immunomodulator and 3 succinimide of formula
The diphenyl cyclooctyne compound of ester activation carries out amidation process and obtains the immunological regulation of 5 functional group of cyclooctyne containing diphenyl of formula
Agent；
3) 5 functional group of cyclooctyne containing diphenyl of the vascular disrupting agents of 4 functional group of cyclooctyne containing diphenyl of formula and formula is immune
Carrier polymer described in regulator and formula 2 make every effort to promote nitrine-alkynes cycloaddition reaction to get；
Wherein,
A is vascular disrupting agents group；
B is immunomodulator group；
It is 2~20, y is 1~10 that n, which is 45~454, x, and-y≤19 1≤x；
R1、R2And R3Independently selected from C1~C4Alkylidene；
Preferred scheme, the vascular disrupting agents containing hydroxyl be Combretastatin, in Combretastatin disodium hydrogen phosphate at least
It is a kind of.
Preferred scheme, the immunomodulator containing amino are at least one of R837, R848, R842.
Preferred scheme, it is described make every effort to promote nitrine-alkynes cycloaddition reaction be in DMF solvent, at room temperature, reaction 24~
48h.Technical solution of the present invention by make every effort to promote nitrine-alkynes cycloaddition reaction on polymer support and meanwhile be grafted vascular disrupting agents and
Immunomodulator, on the one hand, make every effort to promote nitrine-alkynes cycloaddition reaction mild condition, reaction efficiency height, can effectively solve above-mentioned two
The problems such as planting low drug response activity, poorly water-soluble, on the other hand, the vascular disrupting agents of 4 functional group of cyclooctyne containing diphenyl of formula
Ratio with two kinds of drug molecules of immunomodulator of 5 functional group of cyclooctyne containing diphenyl of formula can be any by design grafting amount
It adjusts, and the ratio of 2 carrier polymer of two kinds of drug molecules and formula can also be adjusted arbitrarily, ability of regulation and control is strong, can be according to need
Want any adjusting.Two kinds of drugs by being grafted on same high polymer main chain by the present invention, when solution different pharmaceutical is used in combination,
There are the distributions of the metabolisming property of different pharmaceutical, tissue and organ, the difference for the ability for penetrating films at different levels, cause to be difficult between drug
The problems such as reaching synergistic action effect, and two kinds of drugs are grafted on same macromolecular chain simultaneously, and concentration can be adjusted arbitrarily
Section, has well solved above-mentioned technical problem, has enhanced the synergistic effect between drug.
Preferred scheme makes every effort to promote reaction product obtained by nitrine-alkynes cycloaddition reaction using the bag filter of Mw=1000 in DMF
After dialysing for 24 hours in solvent, be transferred to dialyse in THF solvent and remove DMF for 24 hours, be then spin-dried for, be dried in vacuo it is anti-up to pure macromolecule
Tumour medicine.
By the present invention in that can effectively solve anti-tumor drug hardly possible with blood vessel blocking therapy and immunotherapy synergy
The problem of to penetrate into inside tumor, and the resistance cancer permanently effective using activation patient's self immune system.
The preparation method of poly glycol monomethyl ether-b- polylactide co polymer of the invention:
By L- lactide and N- bromo-succinimide (NBS), using carbon tetrachloride as solvent, with dibenzoyl peroxide
(BPO) catalyst is made, substitution reaction occurs at 60~90 DEG C, obtains bromo lactide；Obtained bromo lactide is with dichloro
Methane is as solvent, and elimination reaction occurs under the action of triethylamine, at 0~5 DEG C and obtains double bond lactide；Then double bond third is handed over
Ester and the new cyclopentadiene that steams are in carbon tetrachloride or benzole soln, argon gas protection, at 60~90 DEG C, are reacted by Diels-Alder
Afterwards, the lactide of the side group containing norbornene is obtained；
Then using poly glycol monomethyl ether as macromole evocating agent, TBD is catalyst, and methylene chloride is solvent, 20~40
The lactide for causing the side group containing norbornene at DEG C carries out ring-opening polymerisation and obtains the copolymerization of poly glycol monomethyl ether-b- polylactide
Object.
The preparation of the poly glycol monomethyl ether-b- polylactide (carrier polymer) of side group functional group containing nitrine of the invention
Method:
First pass through obtain side group after the sulfydryl-alkene light click-reaction carrier polymer containing carboxyl functional group, this reflecting point
Hit high-efficient, no coupling product generation；
DIC condensation reaction is recycled to obtain the carrier polymer that side group is azido functional group.This reaction efficiency is high, secondary anti-
Should less and reaction product is easily purified, it can avoid the generation of extremely toxic substance DCU after tradition DCC is condensed.
The vascular disrupting agents of the functional group of cyclooctyne containing diphenyl of the invention and being immunized for the functional group of cyclooctyne containing diphenyl
The preparation method of regulator:
With the vascular disrupting agents and dibenzo cyclo-octene-succinimide ester of hydroxyl at 4-dimethylaminopyridine (DMAP)
Esterification is directly carried out under catalytic action obtains the vascular disrupting agents of the functional group of cyclooctyne containing diphenyl；Also with containing amino
Immunomodulator and dibenzo cyclo-octene-succinimide ester under 4-dimethylaminopyridine (DMAP) catalytic action directly into
Row esterification obtains the vascular disrupting agents of the functional group of cyclooctyne containing diphenyl；Above-mentioned reaction can be high by the low drug molecule of activity
The quick functionalization simultaneous reactions mild condition of effect, and the ester bond that generates and amido bond is more stable can effectively carry out subsequent high score
The preparation of sub-key conjunction medicine；
The synthetic route of the high molecular antineoplastic drug of bonding vascular disrupting agents and immunomodulator of the invention is as follows:
With Combretastatin (CombretastatinA4/CA-4) for vascular disrupting agents, with imiquimod (Imiquimod/
R837 it) selects to be specifically described for a kind of most typical synthetic method for immunomodulator:
Technical solution of the present invention devises the side that synergistic effect is combined using blood vessel blocking therapy and immunotherapy
Formula can be effectively improved classic chemotherapy drug and be difficult to penetrate into inside tumor reduction curative effect of medication problem, can use simultaneously
Immunotherapy changes cancer patient's vivo immunization and inhibits microenvironment, stimulates tumour cell to the sensibility of drug, can obviously improve
The drug resistance that classic chemotherapy drug long-term treatment generates blocks tumour cell to draw but also vascular disrupting agents can be played preferably
The effect of neighbouring oxygen and nutrient, inside tumor cells, can also be effective as oxygen and nutrient is insufficient and Large Scale Death
The problems such as inhibiting tumour cell diffusion transfer, and immunomodulator imiquimod is as Toll-like receptor (TLR7) agonist,
The maturation of patient's body antigen presenting cell can efficiently be stimulated by generating proinflammatory cytokine with internal TLR sample zygotic induction, be made
Tumour specific antigen is quickly delivered to internal lymph node position by it, so that activation has specific killing tumour cell in vivo
The panimmunities relevant cell such as effector T cell.Immunotherapy has the length that patient's self immune system can be activated to have specificity
Phase kills the ability of tumour, and can act synergistically efficiently long-term treating cancer with blood vessel blocking therapy.
The present invention selects the polylactic acid (PLA) of fully biodegradable and gathering for low molecular weight in constructing polymer main chain
Glycol monoethyl ether is as main chain, and wherein PLA can voluntarily degrade and nontoxic in body, and poly glycol monomethyl ether not only has
There are good biocompatibility and biodegradability, and its preferable water solubility to be easy to be self-assembly of in water phase
Nano-micelle particle extends the circulation time of drug in vivo, can avoid drug and inactivates or mention in cyclic process in vivo
Preceding release, improves drug effect, reduces immune responsiveness.
The present invention is in polymer bond drug synthesis process due to vascular disrupting agents Combretastatin and immunomodulator miaow quinoline
Mo Te has that active group is few, reactivity is low, and being bound directly to main polymer chain can cause drugloading rate too low, instead
It answers efficiency too low, therefore introduces and make every effort to promote nitrine-alkynes cycloaddition (SPAAC) reaction, make every effort to promote nitrine-alkynes cycloaddition reaction conduct
A kind of efficient green click-reaction, compared with the prior art nitrine-alkynes cycloaddition of the copper catalyst system of middle extensive utilization
(CuAAC), not only have the characteristics that efficient, and without introducing the metal cations such as Cu, can effectively reduce system cytotoxicity.Benefit
One step of drug of a variety of different function is bonded on polymer with making every effort to promote nitrine-alkynes cycloaddition (SPAAC) and realizing one kettle way,
Enormously simplify the purifies and separates process of processing step and drug.
Technical solution of the present invention carries the anticarcinogen of two kinds of different function using one kettle way simultaneously on polymer lateral chain
Object, the more simple intelligence of method；In addition, can be in normal pH for acid-sensitives keys such as ester bond and amido bonds between drug molecule and main chain
Under the conditions of long-time body-internal-circulation, avoid drug in cyclic process due to the unstable of chemical bond and the drug that causes of degrading is de-
Situations such as falling violent release, and can be effective due to a variety of drugs of unstable realization under chemical bond acid condition in tumor locus region
Sustained release, the polymer micelle that this polymer bond drug is formed in vivo can be by suffering from the high-permeability and retention effect of cancerous tissue
(EPR effect) realizes the passive target of drug, to increase utilization ratio of drug；
The present invention is carrier using Biodegradable high-molecular polymer, by can be by arbitrarily regulating and controlling two kinds of drugs
Ingredient proportion controls the scion grafting ratio between different pharmaceutical, to make two kinds of drugs reach synergy, to realize
It is administered in combination.
Compared with the prior art, technical solution of the present invention bring the utility model has the advantages that
1) compared with existing antitumor polymer bond drug, the maximum advantage of antitumor polymer bond drug of the invention
It is the mode to act synergistically using blood vessel blocking therapy and immunotherapy treating cancer long-term effectively, vascular disrupting agents can be with
Tumour cell is blocked to draw neighbouring oxygen and nutrient, so that inside tumor Large Scale Death, avoids classic chemotherapy drug difficult
The problems such as to penetrate into inside tumor cells, blocks tumour new if Combretastatin directly acts on tumor vascular endothelial cell
The formation of angiogenic outgrowth factor VEGF induces vascular endothelial cell natural apoptosis；Immunotherapy mainly passes through activation patient
Autoimmunity cell (such as T cell, B cell and macrophage) is with induction for the treatment of the immune response of cancer, such as immune tune
Section agent imiquimod can stimulate the maturation of patient's body antigen presenting cell, so that activation has specific killing tumour in vivo
The panimmunities relevant cell such as effector T cell of cell.
2) another advantage of antitumor high molecule bonding drug of the invention is vascular disrupting agents Combretastatin and exempts from
Epidemic disease regulator imiquimod is bonded on macromolecule carrier simultaneously, and two kinds of drugs, which correspond to the different mechanism of action, can be improved treatment
Effect and by the Combined effects of two kinds of different role mechanism the dosage of every kind of drug is reduced, anticancer effect but can
It is promoted, reduces the cytotoxicity of drug itself, improve curative effect and utilization ratio of drug.
3) advantage of the preparation method of antitumor polymer bond drug of the invention is that the clicks such as introducing nitrine-cycloalkyne are anti-
It answers, high effect nontoxic, makes functionalized polymer that can complete to be bonded by treating different things alike with a variety of drugs after modified with functional group,
Yield is high, no side reaction, and post-processing is simple.Also it can arbitrarily regulate and control the ingredient proportion of two kinds of drugs to control between different pharmaceutical
Graft ratio is realized and is administered in combination so that two kinds of drugs be made to reach synergy.
4) macromolecule carrier of the invention is biodegradable system, biodegradable without to human body after drug release
Generate toxic side effect.The poly glycol monomethyl ether for introducing low molecular weight, can be effectively improved the biocompatibility and biology of drug
Degradability, and nano-micelle particle can be self-assembled into aqueous phase liquid, extend the circulation time of drug in vivo, realizes slow
The purpose of Slow release reduces the side effect of polymer drug, improves drug effect.
5) antitumor high molecule bonding medicament preparation of the invention is simple, and reaction condition is mild, and side reaction is few, and yield is high
And it is safe and non-toxic, it is easy to regulate and control the practical drugloading rate of polymer bond drug, meets demand of industrial production.
Detailed description of the invention:
[Fig. 1] is the nucleus magnetic hydrogen spectrum figure of the block polymer for the side group containing norbornene that poly glycol monomethyl ether causes；
[Fig. 2] is the nucleus magnetic hydrogen spectrum figure of the poly glycol monomethyl ether-b- polylactide of oxatyl-containing lateral group；
[Fig. 3] is the nucleus magnetic hydrogen spectrum figure of the poly glycol monomethyl ether-b- polylactide of the side group containing azido；
[Fig. 4] is the nucleus magnetic hydrogen spectrum figure of the Combretastatin of the functional group of cyclooctyne containing diphenyl；
[Fig. 5] is the nucleus magnetic hydrogen spectrum figure of the imiquimod of the functional group of cyclooctyne containing diphenyl；
[Fig. 6] is the nucleus magnetic hydrogen spectrum figure for being bonded the antitumor polymer bond drug of Combretastatin and the double medicines of imiquimod；
[Fig. 7] figure A is the graph of molecular weight distribution of poly glycol monomethyl ether, and figure B is poly glycol monomethyl ether initiation containing drop
The graph of molecular weight distribution of the block polymer poly glycol monomethyl ether-b- polylactide of bornylene side group,
[Fig. 8] figure C is the molecular weight distribution of the poly glycol monomethyl ether-b- polylactide carrier polymer of oxatyl-containing lateral group
Figure, figure D are the graph of molecular weight distribution of the poly glycol monomethyl ether-b- polylactide carrier polymer of the side group containing azido, and figure E is
The graph of molecular weight distribution of polymer bond drug containing Combretastatin and the double medicines of imiquimod；
[Fig. 9] figure F is that the Fourier of the poly glycol monomethyl ether-b- polylactide carrier polymer of oxatyl-containing lateral group is infrared
Spectrogram, figure G are the FTIR spectrum of the poly glycol monomethyl ether-b- polylactide carrier polymer of the side group containing azido
Figure, figure H are the FTIR spectrum figure of the polymer bond drug containing Combretastatin and the double medicines of imiquimod.
Specific embodiment
Following embodiment is intended to further illustrate the content of present invention, rather than limits the protection of the claims in the present invention
Range.
Embodiment 1
1, the preparation of poly glycol monomethyl ether-b- polylactide:
Weigh 1.0g (4.9mmol) norbornene lactide and 0.8g (0.16mmol) poly glycol monomethyl ether (molecular weight
For in the ampere bottle for having toasted drying anaerobic three times, 1, the 5,7- tri- of catalytic amount then 5000) is added under protection of argon gas
The methylene chloride of azabicyclic [4.4.0] decyl- 5- alkene (TBD) and 5.0mL purification is placed in reaction 48 hours under room temperature, instead
It is settled three times after answering using anhydrous ether, is dried in vacuo after standing centrifugation up to poly glycol monomethyl ether-b- poly- third repeatedly
Lactide.Its structural characterization is shown in that nucleus magnetic hydrogen spectrum figure Fig. 1, graph of molecular weight distribution Fig. 7 (B) illustrate that the polymer successfully synthesizes.
2, the preparation of the poly glycol monomethyl ether-b- polylactide of oxatyl-containing lateral group:
Above-mentioned poly glycol monomethyl ether-b- the polylactide polymer of 1.2g (0.169mmol) is weighed in equipped with magnetite
In 50mL single necked round bottom flask, the 3- mercaptopropionic acid (5.08mmol) of 0.538g and the chloroform of 30ml purification is added and adds
The dimethoxybenzoin (DMPA) for entering catalytic amount makees photoinitiator, and ultraviolet light reacts 65min under protection of argon gas, wait react
After settled repeatedly three times using anhydrous ether, Characterization of The Products is shown in nucleus magnetic hydrogen spectrum figure Fig. 2, graph of molecular weight distribution Fig. 8 (C), Fu
In leaf infrared spectrogram Fig. 9 (F)；
3, the preparation of the poly glycol monomethyl ether-b- polylactide of the side group containing azido:
Weigh the poly glycol monomethyl ether-b- polylactide polymer of the above-mentioned oxatyl-containing lateral group of 1.0g (0.123mmol)
In in the 25mL single necked round bottom flask equipped with magnetite, 0.232g (1.84mmol) N, N- diisopropylcarbodiimide (DIC) is added
Chloroform is refined with 10ml, is placed in 45min in ice-water bath under protection of argon gas, is then added under protection of argon gas and is dissolved in purification
It is small to be transferred to stirring 24 at 35 DEG C by the 2- nitrine ethyl alcohol of methylene chloride 0.211g (2.45mmol) and the DMAP of catalytic amount for reaction
When, stop reaction, be spin-dried for solvent, leach out white urea salt, reuses anhydrous ether sedimentation three times to get the side group containing azido
Poly glycol monomethyl ether-b- polylactide carrier polymer, Characterization of The Products are shown in nucleus magnetic hydrogen spectrum figure Fig. 3, graph of molecular weight distribution Fig. 8
(D), FTIR spectrum figure Fig. 9 (G)；
6, the synthesis of the Combretastatin of the functional group of cyclooctyne containing diphenyl:
It weighs Combretastatin 0.048g (0.151mmol), dibenzo cyclo-octene-succinimide ester 0.03g
(0.075mmol) is sufficiently dissolved in the chloroform that 10mL purification in the 25mL single necked round bottom flask equipped with magnetite, is added, in argon
4-dimethylaminopyridine (DMAP) 0.003g for having been dissolved in the chloroform of purification is added dropwise under gas shielded, is placed in anti-under room temperature
36h is answered, the Combretastatin of the functional group of cyclooctyne containing diphenyl is obtained by silicagel column column separation after reaction.Its structure table
Sign is shown in nucleus magnetic hydrogen spectrum figure Fig. 4；
7, the synthesis of the imiquimod of the functional group of cyclooctyne containing diphenyl:
Weigh dibenzo cyclo-octene-succinimide ester 0.03g (0.075mmol), imiquimod 0.036g
(0.15mmol) in equipped with magnetite 25mL single necked round bottom flask in, it is molten with 10mL chloroform: DMF=20:1 mixed solvent
Then 4-dimethylaminopyridine (DMAP) 0.003g for having been dissolved in the chloroform of 1mL purification, room is added dropwise in solution under argon gas is protected
After the lower stirring 1h of temperature, it is transferred at 35 DEG C and reacts 36h, it is pungent to obtain basic ring containing hexichol by silicagel column column separation after reaction
The imiquimod of alkynes functional group.Its structural characterization is shown in nucleus magnetic hydrogen spectrum figure Fig. 5.
8, the preparation of the polymer bond drug containing Combretastatin and the double medicines of imiquimod；
Weigh the poly glycol monomethyl ether-b- polylactide carrier polymer of the side group containing azido of 0.2g (0.023mol)
In in the 25mL single necked round bottom flask equipped with magnetite, the functional group of cyclooctyne containing diphenyl of 0.045g (0.075mmol) is added
Simultaneously 15mL refining DMF is added in Combretastatin, the imiquimod of the functional group of cyclooctyne containing diphenyl of 0.039g (0.075mmol),
And in argon gas protect it is lower react 36h, dialysed in DMF for 24 hours using the bag filter of Mw=1000 after reaction, after in THF
DMF is removed in dialysis for 24 hours, is spin-dried for, is dried in vacuo to obtain the final product, structural characterization is shown in nucleus magnetic hydrogen spectrum figure Fig. 6, graph of molecular weight distribution Fig. 8
(E), FTIR spectrum figure Fig. 9 (H).
Embodiment 2
Other experimental procedures and experiment condition such as embodiment 1, only by main chain norbornene lactide and polyethyleneglycol
Methyl ether (molecular weight 5000) molar ratio is adjusted to 10:1；20:1；The polyethyleneglycol of different molecular weight is prepared in 40:1
Methyl ether-b- polylactide block polymer.Poly glycol monomethyl ether-b- polylactide block polymer is used for subsequent grafting again
Combretastatin and imiquimod equally obtain drug similar to Example 1.
Embodiment 3
Other steps and experiment condition such as embodiment 1, it is only that basic ring containing hexichol in polymer bond drug preparation process is pungent
The additional proportion of the Combretastatin of alkynes functional group and the imiquimod of the functional group of cyclooctyne containing diphenyl is adjusted to 7:1；7:2, system
It is standby to obtain the polymer bond drug under two kinds of drug difference graft ratios.
Claims (7)
1. a kind of high molecular antineoplastic drug for being bonded vascular disrupting agents and immunomodulator, it is characterised in that: have 1 knot of formula
Structure:
Wherein,
A is vascular disrupting agents group；
B is immunomodulator group；
It is 2~20, y is 1~10 that n, which is 45~454, x, and-y≤19 1≤x；
R1、R2And R3Independently selected from C1~C4Alkylidene.
2. the high molecular antineoplastic drug of bonding vascular disrupting agents and immunomodulator according to claim 1, feature
Be: the A is at least one of Combretastatin, Combretastatin disodium hydrogen phosphate blood vessel blocking class pharmaceutical group.
3. the high molecular antineoplastic drug of bonding vascular disrupting agents and immunomodulator according to claim 1, feature
Be: the B is at least one of R837, R848, R842 imidazole quinoline amine drug group.
4. the high molecular antineoplastic drug of the described in any item bonding vascular disrupting agents of claims 1 to 3 and immunomodulator
Preparation method, it is characterised in that: the following steps are included:
1) lactide containing norbornene is caused with poly glycol monomethyl ether and carries out ring-opening polymerisation, obtain the side group containing norbornene
Poly glycol monomethyl ether-b- polylactide co polymer；Poly glycol monomethyl ether-b- the polylactide of the side group containing norbornene
Copolymer carries out sulfydryl-alkene light click-reaction with the carboxylic acid compound containing sulfydryl, obtains the carrier polymer of oxatyl-containing lateral group；Institute
The azido compound of the carrier polymer and hydroxyl of stating oxatyl-containing lateral group carries out esterification, obtains the formula of the side group containing azido
2 carrier polymers；
2) vascular disrupting agents of hydroxyl and the diphenyl cyclooctyne compound of 3 succinimide ester of formula activation be esterified anti-
It answers, obtains the vascular disrupting agents of 4 functional group of cyclooctyne containing diphenyl of formula；Amino-containing immunomodulator and 3 succinimide of formula
The diphenyl cyclooctyne compound of ester activation carries out amidation process, obtains the immune tune of 5 functional group of cyclooctyne containing diphenyl of formula
Save agent；
3) immunological regulation of 5 functional group of cyclooctyne containing diphenyl of the vascular disrupting agents of 4 functional group of cyclooctyne containing diphenyl of formula and formula
Agent and 2 carrier polymer of formula make every effort to promote nitrine-alkynes cycloaddition reaction to get；
Wherein,
A is vascular disrupting agents group；
B is immunomodulator group；
It is 2~20, y is 1~10 that n, which is 45~454, x, and-y≤19 1≤x；
R1、R2And R3Independently selected from C1~C4Alkylidene.
5. the preparation side of the high molecular antineoplastic drug of bonding vascular disrupting agents according to claim 4 and immunomodulator
Method, it is characterised in that: the vascular disrupting agents containing hydroxyl are at least one of Combretastatin, Combretastatin disodium hydrogen phosphate.
6. the preparation side of the high molecular antineoplastic drug of bonding vascular disrupting agents according to claim 4 and immunomodulator
Method, it is characterised in that: the immunomodulator containing amino is at least one of R837, R848, R842.
7. the high molecular antineoplastic medicine of bonding vascular disrupting agents and immunomodulator according to any one of claim 4 to 6
The preparation method of object, it is characterised in that: the nitrine-alkynes cycloaddition reaction of making every effort to promote at room temperature, is reacted in DMF solvent
24~48h.
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