CN107596383A - The preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses - Google Patents
The preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses Download PDFInfo
- Publication number
- CN107596383A CN107596383A CN201710837083.3A CN201710837083A CN107596383A CN 107596383 A CN107596383 A CN 107596383A CN 201710837083 A CN201710837083 A CN 201710837083A CN 107596383 A CN107596383 A CN 107596383A
- Authority
- CN
- China
- Prior art keywords
- dex
- mgma
- amphipathic
- bar
- oegma
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CCC(*C[C@](*)OC)C(C)(C)*=C(C)Br Chemical compound CCC(*C[C@](*)OC)C(C)(C)*=C(C)Br 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the synthesis field of chemistry and the representational field of biology, is more specifically designed into the amphipathic bar-shaped preparation method and purposes for polymerizeing prodrug that the pH of Figure of abstract is responded.The preparation method of amphipathic bar-shaped polymeric material comprises the following steps：（1）Bar-shaped ATRP initiators are synthesized based on glucan；（2）The hydrophobic block for introducing pH responses is reacted based on ATRP；（3）Introducing hydrophilic block is reacted based on ATRP amphipathic condensation material is obtained with this；（4）PH response precursors are obtained using the ester group of hydrazine hydrate substitution MGMA ends；（5）Hydrazone key is formed using the amino of the carbonyl on adriamycin and polymeric material and obtains the polymerization prodrug of pH responses.The amphipathic bar-shaped polymerization prodrug of gained optionally discharges medicine using faintly acid in cancer cell by pH stimuli responsives.This polymerization prodrug has the advantages that higher micella stability, high drug load, the insoluble drug release of stimuli responsive control.
Description
Technical field
The present invention relates to chemicals and biologic applications field, and in particular to a kind of pH stimuli responsives it is amphipathic bar-shaped poly-
Close prodrug and its preparation and application thereof.
Background technology
Adriamycin（Doxorubicin, DOX）It is one of common cancer therapy drug, its No. CAS：23214-92-8, chemistry
Structural formula：C27H29NO11, relative molecular weight：543.52, it can suppress RNA and DNA synthesis, to RNA inhibitory action most
By force, adriamycin category cell cycle nonspecific agent (CCNSA), there is effect to kinds of tumors, therefore, to the tumour cell of various growth cycles
There is killing action.Adriamycin is primarily adapted for use in acute leukemia, equal to ALL and granulocytic leukemia
There is certain therapeutic action, generally as Second line Drug, i.e., be contemplated that in choice drug resistance using this medicine.It acts on machine
Reason is mainly the medicine intercalation of DNA and suppresses the synthesis of nucleic acid.
It is that water solubility is poor, molecular dimension is smaller and non-selection that anti-tumor drug molecule, which includes the most common problem of adriamycin,
Property, in delivery process, there is that blood circulation stability is poor, drug bioavailability is low, toxic side effect is relatively strong and doctor
The low problem of curative effect rate.In order to realize the application of clinical treatment early, researcher be concentrated mainly at present by nanometer technology with
The delivery system that cancer therapy drug is combined is water-soluble to strengthen it, protects its bio-pharmaceutical active, and increase medicine is uploaded
Amount, this has important scientific meaning to the development for promoting treatment of cancer.
Using nanometer technology with medicine be combined transmission medicine delivery system in, before the amphipathic polymerization of stimuli responsive
Medicine delivery system possesses the advantage such as programmable structure and function, drug bioavailability height, can effectively reduce cancer chemotherapy and control
Poisonous side effect of medicine and the inferior positions such as therapeutic efficiency is low, always were the focus studied both at home and abroad in the last few years during treatment.
For example, CN105943496A discloses a kind of pH response galactose chitosan-poly- second two with neighboring group effect
The adriamycin bonded prodrug of alkoxide polymer, it is to be passed through by the chitosan-polyethylene glycol grafting responded with pH on chemical combination key
Adriamycin in modification and the polymerization prodrug obtained, obtained micella have good pH responses and hepatic targeting, can enter one
Step is developed as the novel targeted preparation for the treatment of liver cancer.In addition, CN105251013A discloses one kind there is redox to ring
The degradable water-soluble antitumor polymeric prodrugs of answering property, the polymerization prodrug have using polylactide as main chain, bonded big on side chain
Measure the special comb-type structure of oligomeric polyethylene glycol side chain and antineoplastic molecule.This water-soluble antitumor polymeric prodrugs carries
Dose is moderate and controllable, degradable, and has redox response.
Therefore, design, build the polymerization prodrug delivery system that collection possesses the function such as carrying capacity and high micella stability on high medicine
System has very strong necessity.
The content of the invention
For the unstability of the micella of current medical delivery system, carrying capacity on relatively low medicine, it is also difficult to ensure medicine
Selective controlled release the defects of, the present invention is intended to provide the superelevation drugloading rate of a kind of pH stimuli responsives is amphipathic bar-shaped poly-
The preparation method of prodrug is closed, the amphipathic bar-shaped polymerization prodrug of the method synthesis has higher drug burst size and cytotoxicity,
So as to realize effective delivering of medicine and efficiently release.
Technical scheme is specific as follows：
The amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses, preparation method comprise the following steps：
（1）Prepare the bar-shaped atomic radicals polymerisation based on glucan（ATRP）Initiator glucan bromine（Dex-Br）, its
Reaction equation is as follows, comprises the following steps：A) under argon gas (Ar, 1-12Pa) ambient conditions, ionic liquid will be dissolved in（1- alkene
Propyl group -3- methylimidazolium chlorides）Glucan（Dex）0 DEG C is cooled to, adds 1-METHYLPYRROLIDONE（NMP）With N, N- bis-
NMF（DMF）Mixed solution, be then slowly added to 2- bromine isobutyl acylbromides（BIBB）, ice bath 0.5-2h, then rise to
Room temperature（25℃）And lucifuge reaction 12-72h, the mixed solution of gained is added dropwise in deionized water and precipitated, it is molten with acetone
Solution gained precipitates, and repeats purification and obtains faint yellow intermediate product three times, in vacuum drying chamber（25-30℃）In dry, b) connect
And the faint yellow intermediate product of gained is dissolved in NMP again, be cooled to 0 DEG C, be then slowly added to BIBB, ice bath 0.5-2h, then
It is warmed to room temperature（25℃）And lucifuge reaction 12-72h, then it is deposited in deionized water, is precipitated obtained by acetone solution, repetition carries
It is pure to obtain pale yellow powder three times, dried for 25-30 DEG C under vacuum condition, obtain product Dex-Br；
（2）Prepare the monomer 2- methoxyl group -2- oxygen ethyl-methyl acrylates of pH responses（MGMA）, its reaction equation is as follows, bag
Include following steps：Under temperature≤0 DEG C and argon gas (Ar, 1-12Pa) ambient conditions, anhydrous methylene chloride is dissolved in（DCM）'s
The solution of a certain amount of methacrylic chloride is slowly dropped to the methyl glycollate and triethylamine being dispersed in anhydrous DCM（TEA）
In mixed solution, it is stirred overnight, washing purifying, silica gel column chromatography obtains pure product MGMA；
（3）The bar-shaped polymerization prodrug prepared（Dex-P(MGMA)）, its reaction equation is as follows, comprises the following steps：In room temperature
（25℃）Under argon gas (Ar, 1-12Pa) ambient conditions, by step（1）Obtained Dex-Br, step（2）Obtained MGMA with
CuBr is dissolved in dimethyl sulfoxide (DMSO)（DMSO）（Or methanol）In solvent, freeze-thaw circulates three times, adds (the 2- diformazans of part three
Amino-ethyl) amine（Me6TREN）（Or part N, N, N ', N ' ', N- pentamethyl-diethylenetriamines（PMEDTA））, then freeze-thaw
Twice, reaction 8-24h, obtained mixture tetrahydrofuran is stirred at room temperature in circulation（THF）Diluted Al2O3Pillar is dense
Contracting, reprecipitation are dissolved with THF and are deposited in again in ether in ether, dried, obtain Dex- (PMGMA)；Wherein DEX-P
(MGMA) m values scope is 20-100 in, and degree of polymerization x values scope is 1~100, and its molecular weight ranges of obtained polymer are
15900~114900 gmol-1；
（4）Prepare amphipathic bar-shaped polymerization prodrug（Dex-P(MGMA)-b-P(OEGMA),(DMO)）, its reaction equation is as follows,
Comprise the following steps：In room temperature（25℃）Under argon gas (Ar, 1-12Pa) ambient conditions, by step（3）Obtained Dex-P
(MGMA), glycolmethacrylate（OEGMA）DMF and DMSO in the mixed solvent are dissolved in CuBr, freeze-thaw follows
Ring three times, adds part Me6TREN（Or part PMEDTA）, then freeze-thaw circulation is twice, reacts 12-48h at 25 DEG C,
Obtained mixture crosses Al after being diluted with THF2O3Pillar, concentration, then dissolved with THF and be deposited in again in ether, dry, obtain
To Dex-P (MGMA)-b-P (OEGMA)；M values scope is 20-100 in wherein Dex-P (MGMA)-b-P (OEGMA), the model of x values
It can be 2~9 to enclose for 1~100, n values, and the scope of degree of polymerization y values is 1~50, and its molecular weight ranges of obtained polymer are 18600
~249900gmol-1；
（5）Prepare the amphipathic bar-shaped polymerization prodrug of pH responses（Dex-P(MGMA-NH2)-b-P(OEGMA), DMO-
hydrazide）, its reaction equation is as follows, comprises the following steps：In room temperature（25℃）With argon gas (Ar, 1-12Pa) atmosphere bar
Under part, Dex-P (MGMA)-P (OEGMA) is dissolved in the in the mixed solvent of a certain proportion of absolute methanol and DMF, then added
A certain amount of hydrazine hydrate, 6-36h is reacted at 25 DEG C, obtained mixture is dialysed two days with water, freeze-drying, obtains Dex-P
(MGMA-NH2)-b-P(OEGMA)；Wherein Dex-P (MGMA-NH2) m values scope is 20-100 in-b-P (OEGMA), the model of x values
It can be 2~9 to enclose for 1~100, n values, and the scope of degree of polymerization y values is 1~50；
（6）Prepare the amphipathic bar-shaped adriamycin polymerization prodrug of pH responses（Dex-P(MGMA-DOX)-b-P(OEGMA), DMO@
DOX）, its reaction equation is as follows, comprises the following steps：In room temperature（25℃）, will under argon gas (Ar, 1-12Pa) ambient conditions
Dex-P(MGMA-NH2)-b-P (OEGMA) and adriamycin（DOX）It is dissolved in a certain amount of absolute methanol and DMF, instills 2-3
The trifluoroacetic acid of drop（TFA）, lucifuge reacts 12-72h at 25 DEG C, and obtained mixture is dialysed with methanol, is freeze-dried, obtains
Product Dex-P (MGMA-DOX)-b-P (OEGMA)；M values scope is 20- in wherein Dex-P (MGMA-DOX)-b-P (OEGMA)
The scope of 100, x values is that 1~100, n values can be 2~9, and the scope of degree of polymerization y values is 1~50；
（7）The amphipathic spherical nano-micelle of pH responses is prepared, is comprised the following steps：In room temperature（25℃）, take a certain amount of step
（6）Obtained Dex-P (MGMA-DOX)-b-P (OEGMA) material is dissolved in appropriate DMF or DMSO, and lucifuge stirring 5~
120min is slowly dropped in a certain amount of water under agitation, stirs 5~60min, and removing organic solvent with water dialysis just obtains
The spherical nano-micelle aqueous solution.
Further, the step（1）A) glucan in（Dex）And ionic liquid（1- pi-allyl -3- methyl chloride miaows
Azoles）Mol ratio be 1：（10~1000）, anhydrous NMP and DMF solution volume ratio are 1：（0.1~10）, NMP and DMF's is mixed
The cumulative volume for closing solution is 2 times of ionic liquid volume, the step（1）B) the faint yellow centre being dissolved in in anhydrous NMP
The molL of molar concentration scope 0.015~0.03 of product-1。
Further, the step（2）In be dissolved in methyl glycollate in anhydrous DCM and TEA molar concentration scope point
Wei not 0.2~10 molL-1With 0.3~20 molL-1；The molar concentration model for the methacrylic chloride being dissolved in anhydrous DCM
Enclose for 0.5~18 molL-1。
Further, the step（3）Middle Dex-Br, MGMA, CuBr and part Me6TREN（Or part PMEDTA）Rub
You are 1 than scope：（6~3000）：（2~100）：（4~400）；Wherein Dex-Br molar concentration is 0.2~20 mmol
L-1。
Further, the step（4）Middle Dex-P (MGMA), OEGMA, CuBr and part Me6TREN（Or part
PMEDTA）Molar ratio range be 1：（6~2000）：（3~100）：（3~100）；In DMF and DMSO in the mixed solvent
DMF:DMSO volume ratio is 1：(0.1~5).
Further, the step（5）In be dissolved in Dex-P (MGMA)-b-P's (OEGMA) in absolute methanol and DMF
Molar concentration scope is 0.001~1mmolL-1；The volume range of hydrazine hydrate, methanol and DMF is 1:(5~30):(1~
15)。
Further, the step（6）Middle Dex-P (MGMA-NH2)-b-P (OEGMA) and DOX molar concentration scope point
Wei not 0.001~0.5 molL-1With 0.001~1 molL-1, absolute methanol and DMF volume ratio are 1：(0.1~10).
Further, the step（7）In the concentration range of obtained adriamycin polymerization prodrug amphipathic molecule be
0.01mg·L-1~1000 mgL-1;The proportion of organic solvent and water is 1：(3~1000);Gained after being dialysed with water
Its diameter range of spherical nano-particle is 5~1000nm.
Major advantage：
1. for micella existing for current drug delivery system is unstable and the problems such as low drugloading rate, this project creatively carries
Go out the delivery system of the amphipathic bar-shaped adriamycin polymerization prodrug of a kind of pH responses, this polymeric material can be by adjusting hydrophobe
Ratio, carrying capacity and micella stability on medicine, and the size of regulation and control nano-micelle can be effectively improved, solves current medical
Some shortcomings existing for delivery system, make it possible that the Precise Diagnosis of tumour is treated early.
2. the amphipathic bar-shaped adriamycin polymerization prodrug in the present invention, has pH stimulating responsives, according to phase in cancer cell
To relatively low pH value, the hydrazone key in material can be promoted to be broken and effectively quick release cancer therapy drug, therefore, realized to cancer
Effective treatment.
Brief description of the drawings
In order that the purpose of the present invention, technical scheme and beneficial effect are clearer, the present invention provides drawings described below：
Fig. 1 is that amphipathic pH responds bar-shaped adriamycin polymerization prodrug in embodiment 1（Dex-P(MGMA-DOX)-b-P(OEGMA),
DMO@DOX）Synthetic line schematic diagram.
Fig. 2 is that amphipathic pH responds bar-shaped adriamycin polymer in embodiment 1（Dex-P(MGMA-DOX)-b-P
(OEGMA), DMO@DOX）Nuclear-magnetism schematic diagram.
Fig. 3 is TEM the and DLS schematic diagrames of amphipathic bar-shaped polymer/nanometer micella in embodiment 1.
Fig. 4 is that the sensitive bar-shaped polymerization prodrugs of amphipathic pH discharge schematic diagram in embodiment 1.
Fig. 5 is that amphipathic pH responds bar-shaped adriamycin polymerization prodrug in embodiment 1（Dex-P(MGMA-DOX)-b-P
(OEGMA), DMO@DOX）Toxicity schematic diagram.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
Embodiment 1 prepares the amphipathic bar-shaped polymerization prodrugs of Dex-P (MGMA)-b-P (OEGMA) of pH responses
（1）Prepare Dex-Br：Under the conditions of argon atmosphere, ionic liquid will be dissolved in（1- pi-allyl -3- methylimidazolium chlorides）'s
Glucan（Dex）0 DEG C is cooled to, adds 1-METHYLPYRROLIDONE（NMP）With N,N-dimethylformamide（DMF）Mixing it is molten
Liquid, it is then slowly added to 2- bromine isobutyl acylbromides（BIBB）, ice bath 0.5-2h, then it is warmed to room temperature（25℃）And lucifuge reaction 12-
72h, then it is deposited in deionized water, is precipitated obtained by acetone solution, repeats purification and obtain faint yellow intermediate product three times,
In vacuum drying chamber（25-30℃）In dry, then the yellowish intermediate product of gained is dissolved in NMP, is cooled to 0 DEG C, it is then slow
It is slow to add BIBB, ice bath 0.5-2h, then it is warmed to room temperature（25℃）And lucifuge reaction 12-72h, then it is deposited in deionized water
In, precipitated obtained by acetone solution, repeat purification and obtain pale yellow powder three times, dry for 25-30 DEG C, produced under vacuum condition
Thing Dex-Br；
（2）Prepare MGMA：It is a certain amount of to be dissolved in anhydrous DCM under temperature≤0 DEG C and argon gas (Ar) ambient conditions（60 mL）'s
Methacrylic chloride（0.144 mol）It is added dropwise to methyl glycollate（0.144 mol）、TEA（0.288mol）, anhydrous DCM
（100 mL）In solution, it is stirred overnight, washing purifying, column chromatography obtains pure product.
（3）Prepare Dex-P (MGMA)：Under room temperature and argon gas (Ar) ambient conditions, by Dex-Br（0.01 mmol）,
MGMA（8.4 mmol）, CuBr（0.21mmol）It is dissolved in DMSO（5 mL）In solvent, freeze-thaw is circulated three times, and addition is matched somebody with somebody
Body Me6TREN（0.42 mmol）, then freeze-thaw circulation is twice, reacts 8-24h at 25 DEG C.Obtained mixture THF
Diluted Al2O3Pillar, concentration, reprecipitation is in ether, drying.
（4）Prepare Dex-P (MGMA)-b-P (OEGMA) (DMO)：Under room temperature and argon gas (Ar) ambient conditions, by Dex-P
(MGMA)（0.01 mmol）, OEGMA（5.25 mmol）, CuBr（0.21 mmol）It is dissolved in DMF（3.0 mL）And DMSO（3.0
mL）In solvent, freeze-thaw circulates three times, adds part Me6TREN（0.21 mmol）, then freeze-thaw circulation is twice,
12-48h is reacted at 25 DEG C.Obtained mixture diluted Al with THF2O3Pillar, concentration, reprecipitation is in ether, drying.Such as
The nuclear-magnetism figure of DMO in Fig. 2, the peak that 3.38 ppm and 3.65 ppm occur in figure can be seen that Dex-P (MGMA)-b-P
(OEGMA) successful synthesis.
（5）Prepare the Dex-P (MGMA-NH of pH responses2)-b-P(OEGMA)( DMO-hydrazide)：In room temperature and argon
Under gas (Ar) ambient conditions, by Dex-P (MGMA)-b-P (OEGMA)（0.005 mmol）It is dissolved in absolute methanol（10 mL）With
DMF（3.75 mL）In, add a certain amount of hydrazine hydrate（1.5 mL）, react 6-36h at 25 DEG C.Obtained mixture water
Dialysis, freeze-drying.The nuclear-magnetism figure of DMO-hydrazide in 2 in such as figure, characteristic peaks of the MGMA at 3.76 ppm in figure
Disappearance it can be seen that diazanyl successfully instead of MGMA methoxyl group, be Dex-P (MGMA-NH2)-b-P (OEGMA) success
Synthesis.
（6）Prepare amphipathic adriamycin polymerization prodrug Dex-P (MGMA-DOX)-b-P (OEGMA)（DMO@DOX）：In room temperature
Under argon gas (Ar) ambient conditions, by Dex-P (MGMA-NH2)-b-P(OEGMA)（0.128mmol）And DOX（0.32mmol）It is molten
Solution is in absolute methanol（8 mL）With DMF (8 mL）In, the TFA of 2-3 drops is instilled, lucifuge reacts 12-72h at 25 DEG C.Obtain
Mixture is dialysed with methanol, freeze-drying.As the peak in DMO@DOX in Fig. 2 near 8 ppm between 4-6 ppm shows Dex-
P (MGMA-DOX)-b-P (OEGMA) successful synthesis.
（7）Prepare adriamycin polymerization prodrug nano-micelle：5 mg Dex-P (MGMA-DOX)-b-P (OEGMA) are taken to be dissolved in
In 1 mL DMF or DMSO, it is distributed in 6 mL water, micella is made with water dialysis 48h.In the size such as Fig. 3 of micella
TEM and the DLS of aqueous phase and DMF phases figure, it can be seen that the size of micella is thirties nanometers and size uniform, is shown
This micella can rapidly enter cell.Fig. 4 drug release profiles can be seen that burst size is up to 91% to this micella after 72 hours,
Fig. 5 cytotoxicity figure can be seen that medicine acts on cervical cancer cell after 72 hours（HeLa）And human breast cancer cell（MCF-
7）Survival rate as little as 20% and 15%, illustrate that this pharmaceutical carrier is larger to the toxicity of cancer cell.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
Cross above preferred embodiment the present invention is described in detail, it is to be understood by those skilled in the art that can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (8)
1. the preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses, it is characterised in that：Including following step
Suddenly：
（1）Prepare the bar-shaped atomic radicals polymerisation based on glucan（ATRP）Initiator glucan bromine（Dex-Br）, its
Reaction equation is as follows, comprises the following steps：A) under argon gas (Ar, 1-12Pa) ambient conditions, ionic liquid will be dissolved in（1- alkene
Propyl group -3- methylimidazolium chlorides）Glucan（Dex）0 DEG C is cooled to, adds 1-METHYLPYRROLIDONE（NMP）With N, N- bis-
NMF（DMF）Mixed solution, be then slowly added to 2- bromine isobutyl acylbromides（BIBB）, ice bath 0.5-2h, then rise to
Room temperature（25℃）And lucifuge reaction 12-72h, the mixed solution of gained is added dropwise in deionized water and precipitated, it is molten with acetone
Solution gained precipitates, and repeats purification and obtains faint yellow intermediate product three times, in vacuum drying chamber（25-30℃）In dry, b) connect
And the faint yellow intermediate product of gained is dissolved in NMP again, be cooled to 0 DEG C, be then slowly added to BIBB, ice bath 0.5-2h, then
It is warmed to room temperature（25℃）And lucifuge reaction 12-72h, then it is deposited in deionized water, is precipitated obtained by acetone solution, repetition carries
It is pure to obtain pale yellow powder three times, dried for 25-30 DEG C under vacuum condition, obtain product Dex-Br；
（2）Prepare the monomer 2- methoxyl group -2- oxygen ethyl-methyl acrylates of pH responses（MGMA）, its reaction equation is as follows, bag
Include following steps：Under temperature≤0 DEG C and argon gas (Ar, 1-12Pa) ambient conditions, anhydrous methylene chloride is dissolved in（DCM）'s
The solution of a certain amount of methacrylic chloride is slowly dropped to the methyl glycollate and triethylamine being dispersed in anhydrous DCM（TEA）
In mixed solution, it is stirred overnight, washing purifying, silica gel column chromatography obtains pure product MGMA；
（3）The bar-shaped polymerization prodrug prepared（Dex-P(MGMA)）, its reaction equation is as follows, comprises the following steps：In room temperature
（25℃）Under argon gas (Ar, 1-12Pa) ambient conditions, by step（1）Obtained Dex-Br, step（2）Obtained MGMA with
CuBr is dissolved in dimethyl sulfoxide (DMSO)（DMSO）（Or methanol）In solvent, freeze-thaw circulates three times, adds (the 2- diformazans of part three
Amino-ethyl) amine（Me6TREN）（Or part N, N, N ', N ' ', N- pentamethyl-diethylenetriamines（PMEDTA））, then freeze-thaw
Twice, reaction 8-24h, obtained mixture tetrahydrofuran is stirred at room temperature in circulation（THF）Diluted Al2O3Pillar is dense
Contracting, reprecipitation are dissolved with THF and are deposited in again in ether in ether, dried, obtain Dex- (PMGMA)；Wherein DEX-P
(MGMA) m values scope is 20-100 in, and degree of polymerization x values scope is 1~100, and its molecular weight ranges of obtained polymer are
15900~114900 gmol-1；
（4）Prepare amphipathic bar-shaped polymerization prodrug（Dex-P(MGMA)-b-P(OEGMA),(DMO)）, its reaction equation is as follows,
Comprise the following steps：In room temperature（25℃）Under argon gas (Ar, 1-12Pa) ambient conditions, by step（3）Obtained Dex-P
(MGMA), glycolmethacrylate（OEGMA）DMF and DMSO in the mixed solvent are dissolved in CuBr, freeze-thaw follows
Ring three times, adds part Me6TREN（Or part PMEDTA）, then freeze-thaw circulation is twice, reacts 12-48h at 25 DEG C,
Obtained mixture crosses Al after being diluted with THF2O3Pillar, concentration, then dissolved with THF and be deposited in again in ether, dry, obtain
To Dex-P (MGMA)-b-P (OEGMA)；M values scope is 20-100 in wherein Dex-P (MGMA)-b-P (OEGMA), the model of x values
It can be 2~9 to enclose for 1~100, n values, and the scope of degree of polymerization y values is 1~50, and its molecular weight ranges of obtained polymer are 18600
~249900gmol-1；
（5）Prepare the amphipathic bar-shaped polymerization prodrug of pH responses（Dex-P(MGMA-NH2)-b-P(OEGMA), DMO-
hydrazide）, its reaction equation is as follows, comprises the following steps：In room temperature（25℃）With argon gas (Ar, 1-12Pa) atmosphere bar
Under part, Dex-P (MGMA)-P (OEGMA) is dissolved in the in the mixed solvent of a certain proportion of absolute methanol and DMF, then added
A certain amount of hydrazine hydrate, 6-36h is reacted at 25 DEG C, obtained mixture is dialysed two days with water, freeze-drying, obtains Dex-P
(MGMA-NH2)-b-P(OEGMA)；Wherein Dex-P (MGMA-NH2) m values scope is 20-100 in-b-P (OEGMA), the model of x values
It can be 2~9 to enclose for 1~100, n values, and the scope of degree of polymerization y values is 1~50；
（6）Prepare the amphipathic bar-shaped adriamycin polymerization prodrug of pH responses（Dex-P(MGMA-DOX)-b-P(OEGMA), DMO@
DOX）, its reaction equation is as follows, comprises the following steps：In room temperature（25℃）, will under argon gas (Ar, 1-12Pa) ambient conditions
Dex-P(MGMA-NH2)-b-P (OEGMA) and adriamycin（DOX）It is dissolved in a certain amount of absolute methanol and DMF, instills 2-3
The trifluoroacetic acid of drop（TFA）, lucifuge reacts 12-72h at 25 DEG C, and obtained mixture is dialysed with methanol, is freeze-dried, obtains
Product Dex-P (MGMA-DOX)-b-P (OEGMA)；M values scope is 20- in wherein Dex-P (MGMA-DOX)-b-P (OEGMA)
The scope of 100, x values is that 1~100, n values can be 2~9, and the scope of degree of polymerization y values is 1~50；
（7）The amphipathic spherical nano-micelle of pH responses is prepared, is comprised the following steps：In room temperature（25℃）, take a certain amount of step
（6）Obtained Dex-P (MGMA-DOX)-b-P (OEGMA) material is dissolved in appropriate DMF or DMSO, and lucifuge stirring 5~
120min is slowly dropped in a certain amount of water under agitation, stirs 5~60min, and removing organic solvent with water dialysis just obtains
The spherical nano-micelle aqueous solution.
2. the preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses according to claim 1, its
It is characterised by：The step（1）A) glucan in（Dex）And ionic liquid（1- pi-allyl -3- methylimidazolium chlorides）Mole
Than for 1：（10~1000）, anhydrous NMP and DMF solution volume ratio are 1：（0.1~10）, NMP and DMF mixed solution it is total
Volume is 2 times of ionic liquid volume, the step（1）B) mole for the faint yellow intermediate product being dissolved in in anhydrous NMP
The molL of concentration range 0.015~0.03-1。
3. the preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses according to claim 1, its
It is characterised by：The step（2）In the methyl glycollate that is dissolved in anhydrous DCM and TEA molar concentration scope be respectively 0.2
~10 molL-1With 0.3~20 molL-1；The molar concentration scope for the methacrylic chloride being dissolved in anhydrous DCM is 0.5
~18 molL-1。
4. the preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses according to claim 1, its
It is characterised by：The step（3）Middle Dex-Br, MGMA, CuBr and part Me6TREN（Or part PMEDTA）Molar ratio range
For 1：（6~3000）：（2~100）：（4~400）；Wherein Dex-Br molar concentration is 0.2~20 mmolL-1。
5. the preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses according to claim 1, its
It is characterised by：The step（4）Middle Dex-P (MGMA), OEGMA, CuBr and part Me6TREN（Or part PMEDTA）Mole
It is 1 than scope：（6~2000）：（3~100）：（3~100）；In DMF and DMSO in the mixed solvent DMF:DMSO volume ratio
For 1：(0.1~5).
6. the preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses according to claim 1, its
It is characterised by：The step（5）In be dissolved in the molar concentration of Dex-P (MGMA)-b-P (OEGMA) in absolute methanol and DMF
Scope is 0.001~1mmolL-1；The volume range of hydrazine hydrate, methanol and DMF is 1:(5~30):(1~15).
7. the preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses according to claim 1, its
It is characterised by：The step（6）Middle Dex-P (MGMA-NH2)-b-P (OEGMA) and DOX molar concentration scope is respectively
0.001~0.5 molL-1With 0.001~1 molL-1, absolute methanol and DMF volume ratio are 1：(0.1~10).
8. the preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses according to claim 1, its
It is characterised by：The step（7）In the concentration range of obtained adriamycin polymerization prodrug amphipathic molecule be 0.01mgL-1
~1000 mgL-1;The proportion of organic solvent and water is 1：(3~1000);The spherical nanoparticle of gained after being dialysed with water
Its sub diameter range is 5~1000nm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710837083.3A CN107596383B (en) | 2017-09-17 | 2017-09-17 | The preparation method of the amphipathic rodlike adriamycin polymeric prodrugs of a kind of pH response |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710837083.3A CN107596383B (en) | 2017-09-17 | 2017-09-17 | The preparation method of the amphipathic rodlike adriamycin polymeric prodrugs of a kind of pH response |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107596383A true CN107596383A (en) | 2018-01-19 |
| CN107596383B CN107596383B (en) | 2019-10-22 |
Family
ID=61060384
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710837083.3A Active CN107596383B (en) | 2017-09-17 | 2017-09-17 | The preparation method of the amphipathic rodlike adriamycin polymeric prodrugs of a kind of pH response |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107596383B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108774301A (en) * | 2018-07-11 | 2018-11-09 | 西南大学 | The preparation method and applications of sour responsive polymer drug of the one kind based on glucan |
| CN109045306A (en) * | 2018-11-07 | 2018-12-21 | 西南大学 | Camptothecine prodrug and preparation method thereof of the one kind based on cellulose |
| CN110124050A (en) * | 2019-05-24 | 2019-08-16 | 西南大学 | The preparation method of charge flip type polymer support based on covalent self assembly strategy |
| CN111494650A (en) * | 2020-04-23 | 2020-08-07 | 广安长明高端产业技术研究院 | Preparation method of amphiphilic polymer nanoparticles based on near-infrared fluorescence imaging and reduction response and product thereof |
| CN113350526A (en) * | 2021-06-28 | 2021-09-07 | 西南大学 | Polysaccharide supramolecular polymer drug carrier based on host-guest effect and preparation method thereof |
| WO2022082937A1 (en) * | 2020-10-21 | 2022-04-28 | 宁波南大光电材料有限公司 | Diester structure monomer and preparation method therefor and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106963733A (en) * | 2017-05-15 | 2017-07-21 | 西南大学 | The preparation method of one class amphiphilic star-like adriamycin polymeric prodrugs |
| CN107033305A (en) * | 2017-05-20 | 2017-08-11 | 西南大学 | A kind of preparation method of the amphipathic vermiform unimolecule prodrug of reproducibility response |
| CN107049946A (en) * | 2017-06-21 | 2017-08-18 | 西南大学 | A kind of preparation method of the amphipathic Linear block polymer of pH stimuli responsives |
-
2017
- 2017-09-17 CN CN201710837083.3A patent/CN107596383B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106963733A (en) * | 2017-05-15 | 2017-07-21 | 西南大学 | The preparation method of one class amphiphilic star-like adriamycin polymeric prodrugs |
| CN107033305A (en) * | 2017-05-20 | 2017-08-11 | 西南大学 | A kind of preparation method of the amphipathic vermiform unimolecule prodrug of reproducibility response |
| CN107049946A (en) * | 2017-06-21 | 2017-08-18 | 西南大学 | A kind of preparation method of the amphipathic Linear block polymer of pH stimuli responsives |
Non-Patent Citations (3)
| Title |
|---|
| SHI X 等: "pH-Responsive unimolecular micelles based on amphiphilic star-like copolymers with high drug loading for effective drug delivery and cellular imaging", 《JOURNAL OF MATERIALS CHEMISTRY B》 * |
| WANG H 等: "Bioinspired phospholipid polymer prodrug as a pH-responsive drug delivery system for cancer therapy", 《POLYMER CHEMISTRY》 * |
| 曹栋玲: "基于葡聚糖的刺激响应性喜树碱/阿霉素前药用于癌症的组合治疗", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108774301A (en) * | 2018-07-11 | 2018-11-09 | 西南大学 | The preparation method and applications of sour responsive polymer drug of the one kind based on glucan |
| CN109045306A (en) * | 2018-11-07 | 2018-12-21 | 西南大学 | Camptothecine prodrug and preparation method thereof of the one kind based on cellulose |
| CN110124050A (en) * | 2019-05-24 | 2019-08-16 | 西南大学 | The preparation method of charge flip type polymer support based on covalent self assembly strategy |
| CN110124050B (en) * | 2019-05-24 | 2022-05-24 | 西南大学 | Preparation method of charge inversion type polymer carrier based on covalent self-assembly strategy |
| CN111494650A (en) * | 2020-04-23 | 2020-08-07 | 广安长明高端产业技术研究院 | Preparation method of amphiphilic polymer nanoparticles based on near-infrared fluorescence imaging and reduction response and product thereof |
| CN111494650B (en) * | 2020-04-23 | 2022-11-08 | 广安长明高端产业技术研究院 | Preparation method of amphiphilic polymer nanoparticles based on near-infrared fluorescence imaging and reduction response and product thereof |
| WO2022082937A1 (en) * | 2020-10-21 | 2022-04-28 | 宁波南大光电材料有限公司 | Diester structure monomer and preparation method therefor and application thereof |
| CN113350526A (en) * | 2021-06-28 | 2021-09-07 | 西南大学 | Polysaccharide supramolecular polymer drug carrier based on host-guest effect and preparation method thereof |
| CN113350526B (en) * | 2021-06-28 | 2022-03-15 | 西南大学 | Polysaccharide supramolecular polymer drug carrier based on host-guest effect and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107596383B (en) | 2019-10-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107596383A (en) | The preparation method of the amphipathic bar-shaped adriamycin polymeric prodrugs of a kind of pH responses | |
| CN106963733A (en) | The preparation method of one class amphiphilic star-like adriamycin polymeric prodrugs | |
| CN107049946A (en) | A kind of preparation method of the amphipathic Linear block polymer of pH stimuli responsives | |
| CN105381467B (en) | The amphiphilic block polymer of antitumor activity with folate-targeted pH- reduction double-responses and its preparation and application | |
| CN110123750A (en) | The preparation method of the camptothecin polymeric object prodrug of ROS response based on glucan | |
| CN105440229B (en) | A kind of amphipathic copolymer of pH/ temperature Dual Sensitive and its preparation and application | |
| CN107033305A (en) | A kind of preparation method of the amphipathic vermiform unimolecule prodrug of reproducibility response | |
| CN102091025A (en) | Anti-tumor injectable hydrogel as well as preparation method and application thereof | |
| CN108774301A (en) | The preparation method and applications of sour responsive polymer drug of the one kind based on glucan | |
| CN109045306A (en) | Camptothecine prodrug and preparation method thereof of the one kind based on cellulose | |
| CN106913872A (en) | Adriamycin and NO donor nano composite materials and preparation method thereof | |
| CN114099705B (en) | Nanometer medicine based on hydralazine for improving tumor microenvironment and preparation and application thereof | |
| CN113549184A (en) | Polymer carrier with pH and redox dual responses, drug-loaded micelle, preparation method and application | |
| CN107236100A (en) | A kind of linear diblock of pH stimulating responsives polymerize the preparation method of prodrug | |
| CN105169405A (en) | Preparation method of adriamycin polymer drug | |
| CN103977418A (en) | Preparation method of doxorubicin-containing anti-tumor micelles | |
| CN103977417A (en) | Preparation method of amphiphilic drug-loaded nanoparticles | |
| CN103976948A (en) | Polymer medicament containing polyacrylic acid | |
| CN104001182A (en) | Novel antitumor doxorubicin-containing macromolecular drug | |
| CN104414999A (en) | Anti-tumor targeted nanometer drug-loaded microcapsule preparation method | |
| CN104415003A (en) | Polymer nano drug microcapsule containing polypyrrolidone | |
| CN115337266B (en) | Nanometer drug-loaded micelle and preparation method and application thereof | |
| Layek | Functionalized biopolymer-based drug delivery systems: current status and future perspectives | |
| CN103990139A (en) | Preparation method for medicinal high-molecule carrier | |
| CN103977421A (en) | Preparation of high-molecular-based pH-sensitive medicament micelle |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |