CN103613724A - Preparation method for polylactic acid block copolymer micelle capable of slowly releasing medicines - Google Patents
Preparation method for polylactic acid block copolymer micelle capable of slowly releasing medicines Download PDFInfo
- Publication number
- CN103613724A CN103613724A CN201310586182.0A CN201310586182A CN103613724A CN 103613724 A CN103613724 A CN 103613724A CN 201310586182 A CN201310586182 A CN 201310586182A CN 103613724 A CN103613724 A CN 103613724A
- Authority
- CN
- China
- Prior art keywords
- pla
- nitrogen
- preparation
- vacuum
- obtaining
- 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.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a method for preparing a novel mercaptan-response type degradable polylactic acid-based micelle. The preparation method disclosed by the invention comprises the following steps: performing ring opening polymerization by using disulphide glycol as an initiator and performing free radical polymerization after the ring opening polymerization reaction is finished. The prepared triblock copolymer contains a disulfide bond at the centre, has narrow molecular weight distribution, and can be self-assembled into a micelle aggregate non-toxic to cells by taking polylactic acid containing disulphides as a core, and the disulfide bond at the centre is capable of responding to mercaptan by virtue of breakage. The preparation method disclosed by the invention is capable of enhancing the release of capsule-type anticancer medicines, and great in application prospect in the field of cancer therapy.
Description
Technical field
The present invention relates to a kind of preparation method of copolymer micelle, relate in particular to a kind of preparation method of the block copolymer micelle based on poly(lactic acid) of degradable mercaptan response type.
Background technology
Poly(lactic acid) (PLA) is a kind of hydrophobic aliphatic polyester based on hydroxy alkanoic acid, because its good biocompatibility is in a lot of biomedical sector application.But what hinder its application is mainly two aspects: 1, wetting ability: hydrophobic PLA multipolymer can or be used hydrophilic monomer copolymerization with hydrophilic polymer modification, for example, by the amphiphilic block copolymer that contains PLA with hydrophilic polyacrylic methyl esters instrument preparation, this segmented copolymer based on PLA can be self-assembled into the core that contains hydrophobicity PLA and the coacervate micella of hydrophilic shell in the aqueous solution; 2, degradation rate: relatively slow degradation rate can cause the release of capsule type medicine very slow and uncontrolled, the slow rate of release of medicine is mainly that the delay of passing through hydrophobicity PLA core that the slow hydrolysis owing to the ester bond in hydrophobicity contact and PLA skeleton causes is spread, and prior art cannot reach quick, controlled degraded and release.
Stimuli responsive degraded (SRD) is a kind of very promising method building multi-functional nano-carrier field.To outside priming factors, there is the stimuli responsive degraded of response not only can strengthen the rate of release of capsule type biomolecules, and can regulate and control the pattern of self-assembled nano structures.The breaking bonds of stimuli responsive type is embedded in block copolymer micelle, and these keys, being subject to lower can the fracture of some outside stimulus factors (as low pH, light, ultrasonic, reductive agent and enzyme), cause the division of nano material.
Two degradation of thiols are a kind of very promising stimuli responsive degradeds, because disulfide linkage can fracture generate two mercaptan that respond under the stimulation of reduction reaction, a kind of gsh (GSH that can cause the reduction reaction of disulfide linkage, the tripeptides that contains halfcystine) in intracellular concentration than at an extracellular height, in cancer cells, concentration is higher.Based on these features, can develop a kind of platform for building the enhancing/controlled transmission nano-carrier based on disulfide linkage self-assembly coacervate micella.
Summary of the invention
The present invention utilizes the preparation method of polylactic-acid block copolymer micella, has developed the degradable micella based on PLA of a kind of novel mercaptan response type, and this micella has the decomposition of enhancing and release performance.This class micella contains containing of good controllability single center disulfide linkage (ss (ABP)
2) the both sexes triblock copolymer based on PLA.This mercaptan response type segmented copolymer is synthetic by the combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP), and wherein a kind of two mercaptan are as the initiator of ring-opening polymerization.Good controlled ss (ABP)
2can be self-assembled into liquid micella coacervate, in to the response of mercaptan, single disulfide linkage division at micella center, causes ss (ABP)
2be degraded into the HS-ABP with amphoteric substance performance, the degraded that this mercaptan causes can strengthen the release of capsule type medicine.
Concrete grammar is as follows:
(1) ss (PLA-OH) is prepared in ring-opening polymerization
2: the ring-opening polymerization of lactic acid (LA) is carried out at 120 ℃ under the existence of dihydroxy ethyl disulphide (ssDOH) bi-functional initiator in toluene, LA, 60mg (0.2mmol) stannous iso caprylate (Sn (Oct) of 459mg (3mmol) ssDOH, 30g (208mmol)
2) and the toluene of 5mL join in the Shu Lunke bottle of a 20mL, the mixture obtaining circulates 4～6 times to remove deoxidation by freeze-thaw pump circulation method, reaction flask is full of nitrogen, then be immersed in and in the oil bath of 120～130 ℃, start polyreaction and continue 3～5h, cool to room temperature after reaction, the homopolymer obtaining is Precipitation in containing the methyl alcohol of 5ml10%HCl, then by the method for vacuum pump suction filtration, sample separation is out obtained to white solid sample after rear 50 ℃ of vacuum-drying 24h.
(2) ss (PLA-OH) of the esterification of ss (PLA-Br) 2: 4.0g (0.6mmol)
2, 0.6g (6.0mmol) triethyl nitrogen be dissolved in 50ml tetrahydrofuran (THF) (THF), the mixture obtaining is advertised 30min with nitrogen.Bromo-isobutyl bromide is dropwise joined in 15min in above-mentioned solution to then room temperature preservation 12h in the ice-water bath of 0 ℃, the solid obtaining is isolated by the method for vacuum filtration, then in methyl alcohol, precipitate to remove remaining triethyl nitrogen and isobutyl bromide collecting precipitation thing room temperature vacuum-drying 12h.
(3) atom transfer radical polymerization is for ss (PLA-b-POEOMA)
2(ss (ABP)
2): 1.0g (0.15mol) is dried pure ss (PLA-Br)
2, 1.4g (3.0mmol) OEOMA, 31.5 μ L (0.15mmol) PMDETA and 3mL THF in the Shu Lunke of 10mL bottle, mix, freeze-thaw pump circulation method deoxygenation for the mixture obtaining.Reaction flask adds 21.6mg (0.15mmol) cupric bromide after being full of nitrogen, and reaction flask sealing final vacuum purifies then at backflow nitrogen, then immerses in the oil bath of 47 ℃ and starts polymerization, and after reaction 2h, Kaifeng stops polymerization.The Sample Purification on Single process obtaining is as follows: the sample obtaining is dropwise joined in the normal hexane of 350mL of stirring, the pillar of green precipitation polymers by extending oil alkali alumina/THF 3～6 times is to remove the species of cupric, solvent is removed with Rotary Evaporators, then room temperature vacuum-drying 24h further removes residual solvent, obtains pure ss (ABP)
2.
The preparation method of the micella the present invention relates to utilizes a kind of disulfides glycol as the initiator of ring-opening polymerization, after finishing, ring-opening polymerization carries out again radical polymerization, the multipolymer of preparation has narrow molecular weight distribution (Mw/Mn < 1.15), and the poly(lactic acid) that contains disulphide of can take does not have virose micella coacervate as core is self-assembled into cell, the disulfide linkage at center can respond to mercaptan by fracture, and the degraded that this mercaptan causes can strengthen the release of capsule type cancer therapy drug.
Embodiment
In order to strengthen the understanding of the present invention, below in conjunction with example, the present invention is described in further detail.
(1) ss (PLA-OH) is prepared in ring-opening polymerization
2: the ring-opening polymerization of lactic acid (LA) is carried out at 120 ℃ under the existence of dihydroxy ethyl disulphide (ssDOH) bi-functional initiator in toluene, LA, 60mg (0.2mmol) stannous iso caprylate of 459mg (3mmol) ssDOH, 30g (208mmol) (Sn (, Oct)
2) and the toluene of 5mL join in the Shu Lunke bottle of a 20mL, the mixture that obtains is with freeze-thaw pump circulation method circulation 5 times with except deoxidation, reaction flask is full of nitrogen, is then immersed in the oil bath of 120 ℃ and starts polyreaction; After 3.5h, polyreaction stops and cool to room temperature, and the homopolymer obtaining is Precipitation in containing the methyl alcohol of 5ml10%HCI, then by the method for vacuum pump suction filtration, sample separation is out obtained to white solid sample after rear 50 ℃ of vacuum-drying 24h.
(2) ss (PLA-OH) of the esterification of ss (PLA-Br) 2: 4.0g (0.6mmol)
2, 0.6g (6.0mmol) triethyl nitrogen be dissolved in 50ml tetrahydrofuran (THF) (THF), the mixture obtaining is advertised 30min with nitrogen, bromo-isobutyl bromide is dropwise joined in 15min in above-mentioned solution to then room temperature preservation 12h in the ice-water bath of 0 ℃, the solid obtaining is isolated by the method for vacuum filtration, then in methyl alcohol, precipitation is to remove remaining triethyl nitrogen and isobutyl bromide, and collecting precipitation thing is room temperature vacuum-drying 12h then.
(3) atom transfer radical polymerization is for ss (PLA-b-POEOMA)
2(ss (ABP)
2): 1.0g (0.15mol) is dried pure ss (PLA-Br)
2, 1.4g (3.0mmol) OEOMA, 31.5 μ L (0.15mmol) PMDETA and 3mL THF in the Shu Lunke of 10mL bottle, mix, freeze-thaw pump circulation method deoxygenation for the mixture obtaining, reaction flask adds 21.6mg (0.15mmol) cupric bromide after being full of nitrogen, reaction flask sealing final vacuum purifies and then backflow nitrogen, then immerse the abundant middle beginning polymerization of oil of 47 ℃, after reaction 2h, Kaifeng stops polymerization.The Sample Purification on Single process obtaining is as follows: the sample obtaining is dropwise joined in the normal hexane of 350mL of stirring, the pillar of green precipitation polymers by extending oil alkali alumina/THF three times is to remove the species of cupric, solvent is removed with Rotary Evaporators, then room temperature vacuum-drying 24h further removes residual solvent, obtains pure ss (ABP)
2.
Claims (2)
1. a preparation method for polylactic-acid block copolymer micella that can slow releasing pharmaceutical, its step is as follows:
(1) ss (PLA-OH) is prepared in ring-opening polymerization
2:
The ring-opening polymerization of lactic acid (LA) is carried out at 120 ℃ under the existence of dihydroxy ethyl disulphide (ssDOH) bi-functional initiator in toluene, LA, 60mg (0.2mmol) stannous iso caprylate (Sn (Oct) of 459mg (3mmol) ssDOH, 30g (208mmol)
2) and the toluene of 5mL join in the Shu Lunke bottle of a 20mL, freeze-thaw pump circulation method circulation 4～6 times for the mixture obtaining, reaction flask is full of nitrogen, be immersed in and in the oil bath of 120～130 ℃, start polyreaction and continue 3～5h, cool to room temperature after reaction, the homopolymer obtaining is Precipitation in containing the methyl alcohol of 5ml10%HCl, then by the method for vacuum pump suction filtration, sample separation is out obtained to white solid sample after rear 50 ℃ of vacuum-drying 24h;
(2) esterification of ss (PLA-Br) 2:
The ss (PLA-OH) of 4.0g (0.6mmol)
2, 0.6g (6.0mmol) triethyl nitrogen be dissolved in 50ml tetrahydrofuran (THF) (THF), the mixture obtaining is advertised 30min with nitrogen, bromo-isobutyl bromide is dropwise joined in 15min in above-mentioned solution to then room temperature preservation 12h in the ice-water bath of 0 ℃, the solid obtaining is isolated by the method for vacuum filtration, then in methyl alcohol, precipitate to remove remaining triethyl nitrogen and isobutyl bromide collecting precipitation thing room temperature vacuum-drying 12h;
(3) atom transfer radical polymerization is for ss (PLA-b-POEOMA)
2(ss (ABP)
2):
1.0g (0.15mol) is dried pure ss (PLA-Br)
2, 1.4g (3.0mmol) OEOMA, the THF of 31.5 μ L (0.15mmol) PMDETA and 3mL mixes in the Shu Lunke of 10mL bottle, freeze-thaw pump circulation method deoxygenation for the mixture obtaining, reaction flask adds 21.6mg (0.15mmol) cupric bromide after being full of nitrogen, nitrogen again refluxes after reaction flask sealing final vacuum purifies, immerse in the oil bath of 47 ℃ and start polymerization, after reaction 2h, Kaifeng stops polymerization, the sample obtaining is dropwise joined in the normal hexane of 350mL of stirring, the pillar of green precipitation polymers by extending oil alkali alumina/THF 3～6 times, solvent is removed with Rotary Evaporators, room temperature vacuum-drying 24h again, obtain pure ss (ABP)
2.
2. the preparation method of copolymer micelle as claimed in claim 1, is characterized in that: described in step (1), the temperature of oil bath is 120 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310586182.0A CN103613724A (en) | 2013-11-15 | 2013-11-15 | Preparation method for polylactic acid block copolymer micelle capable of slowly releasing medicines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310586182.0A CN103613724A (en) | 2013-11-15 | 2013-11-15 | Preparation method for polylactic acid block copolymer micelle capable of slowly releasing medicines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103613724A true CN103613724A (en) | 2014-03-05 |
Family
ID=50164451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310586182.0A Pending CN103613724A (en) | 2013-11-15 | 2013-11-15 | Preparation method for polylactic acid block copolymer micelle capable of slowly releasing medicines |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103613724A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111318172A (en) * | 2018-12-17 | 2020-06-23 | 中国石油化工股份有限公司 | Preparation method of polymer-modified graphene filtering membrane |
-
2013
- 2013-11-15 CN CN201310586182.0A patent/CN103613724A/en active Pending
Non-Patent Citations (4)
| Title |
|---|
| ALEXANDER CUNNINGHAM,ET AL.: "New design of thiol-responsive degradable polylactide-based block copolymer micelles", 《MACROMOLECULAR RAPID COMMUNICATIONS》 * |
| ARAM OMER SAEED,ET AL.: "One-pot controlled synthesis of biodegradable and biocompatible co-polymer micelles", 《JOURNAL OF MATERIALS CHEMISTRY》 * |
| BEHNOUSH KHORSAND SOURKOHI,ET AL.: "Biodegradable block copolymer micelles with thiol-responsive sheddable coronas", 《BIOMACROMOLECULES》 * |
| JUNG KWON OH: "Polylactide(PLA)-based amphiphilic block copolymers:synthesis self-assembly, and biomedical applications", 《SOFT MATTER》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111318172A (en) * | 2018-12-17 | 2020-06-23 | 中国石油化工股份有限公司 | Preparation method of polymer-modified graphene filtering membrane |
| CN111318172B (en) * | 2018-12-17 | 2022-01-25 | 中国石油化工股份有限公司 | Preparation method of polymer-modified graphene filtering membrane |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bhuchar et al. | Degradable thermoresponsive nanogels for protein encapsulation and controlled release | |
| CN107550921B (en) | Nanoparticle-polymer injectable composite hydrogel double-drug-loading system and preparation method thereof | |
| CN103554508B (en) | Acid-sensitive amphipathic star-block copolymers, its preparation method and application | |
| CN105251013B (en) | One kind having degradable water-soluble antitumor polymeric prodrugs of redox response and preparation method thereof | |
| CN102633959B (en) | PH-responsive comb-like copolymer and preparation and application thereof | |
| CN104231155B (en) | Cholesterol modifies amphipathic pH response brush copolymer and preparation and micella thereof | |
| Ebara | Biomaterials nanoarchitectonics | |
| CN103251561B (en) | Double-sensitive disintegrating nano-sized vesica medicine carrier preparation and preparation method thereof | |
| EP1800694A1 (en) | Controlled release gels | |
| CN106188555B (en) | A kind of tumour intelligently targeting and environment double responsiveness siRNA delivery system and preparation method and application | |
| Pradeepkumar et al. | Deep eutectic solvent-mediated FA-g-β-alanine-co-PCL drug carrier for sustainable and site-specific drug delivery | |
| CN105030672B (en) | A kind of preparation method of the stereocomplex PLA copolymer carrier micelle of temperature-responsive | |
| CN106279581B (en) | pH response/membrane adhesion amphiphilic block copolymer and preparation method thereof | |
| Cao et al. | Controlled cross-linking strategy for formation of hydrogels, microgels and nanogels | |
| CN104262638A (en) | Hyaluronic acid-cystamine-polylactic acid-glycollic acid graft polymer and preparation method thereof | |
| CN108926531A (en) | A kind of reduction and the nano-micelle of pH dual responsiveness and the preparation method and application thereof | |
| Kang et al. | Small intestine-and colon-specific smart oral drug delivery system with controlled release characteristic | |
| JP2015040276A (en) | Hydrogelling agent formed by combining biodegradable polymer and clay mineral | |
| CN103694379B (en) | A kind of have di-block copolymer of light and pH response characteristic and preparation method thereof | |
| CN101880265A (en) | Acid-sensitive polymeric micelle pharmaceutical composition and preparation method thereof | |
| CN103613724A (en) | Preparation method for polylactic acid block copolymer micelle capable of slowly releasing medicines | |
| CN103980502B (en) | A kind of polymer vesicle as pharmaceutical carrier and its preparation method and application | |
| CN108676156B (en) | Reduction response type ABC type block polymer and preparation method and application thereof | |
| Kim et al. | Calcium carbonate-mineralized polymer nanoparticles for pH-responsive robust nanocarriers of docetaxel | |
| CN107163255B (en) | Redox and pH dual-response random-graft type drug carrier and method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140305 |