CN105348294B - Photochromic monomer, its preparation method, amphipathic nature polyalcohol, its preparation method and vesica and its application - Google Patents
Photochromic monomer, its preparation method, amphipathic nature polyalcohol, its preparation method and vesica and its application Download PDFInfo
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- CN105348294B CN105348294B CN201510783035.1A CN201510783035A CN105348294B CN 105348294 B CN105348294 B CN 105348294B CN 201510783035 A CN201510783035 A CN 201510783035A CN 105348294 B CN105348294 B CN 105348294B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F261/00—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00
- C08F261/10—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00 on to polymers of unsaturated ketones
Abstract
The invention provides a kind of photochromic monomer and preparation method thereof, and present invention also provides by the amphipathic nature polyalcohol of photochromic monomer as hydrophobic segment and preparation method thereof, present invention also provides the vesica by the amphipathic nature polyalcohol self assembly.Because photochromic Primitive Element Distribution is in the hydrophobic duplicature of vesica, and photochromic primitive as polymer hydrophobic segment its reversible open loop closed loop occurs under the light stimulation effect of extraneous wavelength selectivity, so as to realize the reversible permeability of regulation vesica and the structure of vesica will not change.
Description
Technical field
The present invention relates to cell technology field, more particularly to photochromic monomer, its preparation method, amphipathic nature polyalcohol,
Its preparation method and vesica and its application.
Background technology
Cell is the elementary cell for forming life.Cell is the various organelles and cell by cell membrane and its internal package
Matter matrix forms.Cell needs Growth and Differentiation, is also required to complete the induced AC of various signals between cell, and each cell is mutually assisted
Tune completes some complicated life process jointly, and all these controllable mass transfers of inside and outside generation for being required for cell membrane.
Assemble and formed it is well known that cell membrane is the phospholipid molecule being made up of the head of hydrophobic alkyl chain and polar hydrophilic, and it is hydrophobic
Alkyl chain mutually pile up to form hydrophobic duplicature, so the water-soluble substances inside and outside film can not pass freely through cell membrane.For
Effective transmission of material inside and outside cell membrane is realized, biological evolution has gone out a set of effective mass transfer mechanism, i.e., can not led to
Various channel designs are embedded on saturating cell membrane, are typically made up of the channel protein of various topological structures.So, cell is just
The relatively independent functional space of cell interior is not only ensure that, in turn ensures that material-signal transmission of intraor extracellular.
The various artificial self-assembled nanometer knots of scientists development can be excited and guide by exploring the 26S Proteasome Structure and Function of biosystem
Structure, wherein using liposome vesicle and polymer vesicle as most typically example.Both vesicas have one by hydrophobic duplicature bag
The hydrophilic inner chamber to be formed is wrapped up in, more and more is used for constructing drug delivery nano-carrier, nano-reactor and artificial cell device
Deng.Obviously, all these applications effectively exchange closely related, i.e. permeability properties of vesica all with material inside and outside vesica
It is most important.However, compared with liposome vesicle, the more stable polymer vesicle of structure is but faced with serious membrane permeability and asked
Topic, if small molecule organic compound, ion even water are all difficult infiltration.
At present, the infiltrative method of polymer vesicle is improved, is mainly included：Channel protein is merged into duplicature；
Introducing stimulates sensitive polymer (such as pH, CO2, glucose responding polymer)；The polymer of oppositely charged assembles jointly；
The self assembly of bar-shaped-embedding-flexible-chain polymer of spiral and the post-modification method of vesica film.Or the above method needs additional one
A little chemical substances, there is complicated manufacturing process, otherwise permeability can not be regulated and controled well；Importantly, these
Method generally all suffers from reducing Vesicle stability or even destroys the risk of imitated vesicle structure.Therefore, applicant once reports one kind
It is stable with infiltrative new method that vesica can be improved simultaneously, i.e., by situ in polymer vesicle duplicature, that photodissociation occurs is anti-
Should, the primary amine group of the polar hydrophilic of amidation process can occur for release, so as to make film while permeability of the membrane is improved
Interior generation chemical crosslink reaction, Vesicle stability are maintained.But the above method causes vesica to ooze because photodissociation hair should be irreversible
Permeability can only change from hyposmosis to Thief zone, can not further regulate and control in turn.Thus, this application provides a kind of reversible
Regulation and control vesica permeability and the method for maintaining structural stability.
The content of the invention
Present invention solves the technical problem that being to provide a kind of vesica, it can realize the reversible regulation and control of permeability and structure is kept
Stability.
In view of this, this application provides a kind of photochromic monomer with formula (I) structure,
Wherein, R is the photochromic group with formula (II) structure；
R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11.
Preferably, the R1For H, R2For NO2, R3For H, n 1.
Present invention also provides the preparation method of the photochromic monomer described in such scheme, comprise the following steps：
By the compound with formula (III) structure and the compound with formula (IV) structure in the presence of catalyst molten
Reacted in agent, obtain photochromic monomer；
Wherein, R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11.
Present invention also provides a kind of amphipathic nature polyalcohol with formula (V) or formula (VI) structure,
In formula (V), R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
M is 7~250；X is 12~150；N is 1~11；
In formula (VI), R1For H or MeO；
R2For NO2Or CN；
R5For OH, NHCH (CH3)2、OCH2CH2PO4CH2CH2N(CH3)3Or N (CH3)2；
R4For H or CH3；
R3For H or CH3；
M is 7~250；X is 12~150；N is 1~11.
Present invention also provides a kind of preparation method of the amphiphilic polymers with formula (V) structure, including：
Photochromic monomer, chain-transferring agent and the initiator with formula (I) structure are reacted in a solvent, obtained with formula
(V) amphiphilic polymers of structure；
The chain-transferring agent is the end group modification hydrophilic polymer of three thioester groups；
In formula (I), R is the photochromic group with formula (II) structure；
R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11；
In formula (V), R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
M is 7~250；X is 12~150；N is 1~11.
Preferably, the chain-transferring agent is the end group modification polyethylene glycol of three thioester groups, polyacrylic acid, poly- (N-
N-isopropylacrylamide), poly- (2- methacryloxyethyls Phosphorylcholine) or poly- (N, N- dimethylamino acrylamide).
Present invention also provides a kind of preparation method of the amphiphilic polymers with formula (VI) structure, including：
Hydrophilic monomer, chain-transferring agent and the initiator with formula (VII) structure are reacted in a solvent, obtained containing hydrophilic
The polymer of segment；
By the polymer containing hydrophilic segment, the photochromic monomer with formula (I) structure and initiator in solvent
Middle reaction, obtain the amphiphilic polymers with formula (VI) structure；
The chain-transferring agent is the small molecule containing three thioester groups；
In formula (I), R is the photochromic group with formula (II) structure；
R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11；
In formula (VI), R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
R4For H or CH3；
R5For OH, NHCH (CH3)2、OCH2CH2PO4CH2CH2N(CH3)3Or N (CH3)2；
M is 7~250；X is 12~150；N is 1~11；
In formula (VII), R4For H or CH3, R5For OH, NHCH (CH3)2、OCH2CH2PO4CH2CH2N(CH3)3Or N (CH3)2。
Present invention also provides a kind of preparation method of vesica, including：
By the polymer prepared by the preparation method described in described in such scheme or such scheme using cosolvent-plus water
Prepared by method, emulsion process or microchannel method, obtain vesica.
Present invention also provides the vesica prepared by the preparation method described in such scheme.
Present invention also provides the vesica described in prepared by the preparation method described in such scheme or such scheme in medicine
Application in the controlled release of thing load and the regulation and control of nano-reactor.
This application provides a kind of amphipathic nature polyalcohol, its hydrophobic segment contained contains can be in extraneous wavelength selectivity
The lower photochromic primitive that reversible open loop-closed loop occurs of light stimulation effect；The polymer self assembles that the application provides are into vesica
Afterwards, above-mentioned photochromic Primitive Element Distribution is in the hydrophobic duplicature of vesica；Under initial situation, these primitives are with hydrophobic closed-loop shaped
Formula is present, and the duplicature of vesica is low to the permeability of water soluble molecules；When the aqueous dispersions to vesica carry out ultraviolet light,
Photochromic primitive in duplicature occurs to be changed by the isomerization of hydrophobic closed loop configuration to hydrophilic open loop structure, and simultaneously
Due to the interaction of hydrogen bond of the electrostatic interaction between hydrophilic open loop structure and main chain side base, the structure of vesica is able to
Keep, do not dissociate.Therefore, ultraviolet light can improve the permeability of vesica and not change vesica integrally-built
Stability.Subsequently, based on the distinctive reversible isomerism property of this kind of photochromic primitive itself, to the vesica obtained by previous step point
Dispersion liquid carries out radiation of visible light so that the structure of hydrophilic open loop is restored to hydrophobic closed loop configuration, so that vesica oozes
Permeability reduces again, realizes the infiltrative controllable regulation and control of vesica, and the overall structure of vesica does not change.
Brief description of the drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum of photochromic monomer prepared by the embodiment of the present invention 1；
Fig. 2 is the nuclear-magnetism carbon spectrum of photochromic monomer prepared by the embodiment of the present invention 1；
Fig. 3 is electrospray ionization mass spectrum prepared by the embodiment of the present invention 1；
Fig. 4 is that the nuclear-magnetism of amphipathic nature polyalcohol prepared by the embodiment of the present invention 2 characterizes；
Fig. 5 is gel permeation chromatography (GPC) phenogram of amphipathic nature polyalcohol prepared by the embodiment of the present invention 3；
Fig. 6 is the TEM photos before vesica illumination prepared by the embodiment of the present invention 4；
Fig. 7 be vesica prepared by the embodiment of the present invention 5 during ultraviolet lighting scattered light intensity and particle diameter with exposure time
Change curve；
Fig. 8 is TEM photo of the vesica of the invention prepared after ultraviolet lighting；
Fig. 9 be the embodiment of the present invention prepare vesica before and after ultraviolet lighting particle diameter distribution result curve figure；
Figure 10 be after ultraviolet lighting the vesica for preparing of the present invention during visible ray photograph scattered light intensity with particle diameter with spoke
According to the change curve of time；
Figure 11 is TEM photo of the vesica of the invention prepared after UV-Visible irradiates；
Figure 12 is the releasing curve diagram of vesica coumarin-102 before and after ultraviolet lighting prepared by the present invention；
Figure 13 is vesica 5-dFu before and after ultraviolet lighting prepared by present invention releasing curve diagram；
Figure 14 is vesica 5-dFu in alternately ultraviolet-visible illumination prepared by present invention releasing curve diagram；
The microreactor for the vesica that Figure 15 is prepared for present invention osmotic adjustment photo after ultraviolet lighting；
Figure 16 is the microreactor of vesica prepared by the present invention without permeability test result photo during ultraviolet lighting；
Figure 17 is the TEM photos of SP-2 vesicas prepared by the present invention.
Embodiment
For a further understanding of the present invention, the preferred embodiment of the invention is described with reference to embodiment, still
It should be appreciated that these descriptions are simply further explanation the features and advantages of the present invention, rather than to the claims in the present invention
Limitation.
The embodiment of the invention discloses a kind of photochromic monomer with formula (I) structure,
Wherein, R is the photochromic group with formula (II) structure；
R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11.
This application provides a kind of photochromic monomer, and what it be able to can occur under the illumination condition that wavelength selects closes
Ring-open loop isomerization transformation, so as to form it into the vesica that polymer is assembled into, it is capable of the permeability of reversible regulation and control vesica, and
The overall structure of vesica is not changed.
According to the present invention, R is that it has in following structure and the photochromic group linked by amino-formate bond
It is a kind of：
Present invention also provides the preparation method of the photochromic monomer, comprise the following steps：
By the compound with formula (III) structure and the compound with formula (IV) structure in the presence of catalyst molten
Reacted in agent, obtain photochromic monomer；
Wherein, R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11.
Herein described photochromic monomer is hydroxyl and formula (IV) structure in the compound by formula (III) structure
The NCO of compound reacts what is obtained.
During above-mentioned preparation photochromic monomer, the solvent is preferably dichloromethane, and the catalyst is preferred
For dibutyl tin laurate.
According to the present invention, after synthesizing photochromic monomer, as the hydrophobic segment of polymer, and by its with containing
The compound polymerization of hydrophilic segment, obtains a kind of amphipathic nature polyalcohol with formula (V) or formula (VI) structure,
In formula (V), R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
M is 7~250；X is 12~150；N is 1~11；
In formula (VI), R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
R4For H or CH3；
R5For OH, NHCH (CH3)2、OCH2CH2PO4CH2CH2N(CH3)3Or N (CH3)2；
M is 7~250；X is 12~150；N is 1~11.
The present invention devise a kind of hydrophobic segment contain can extraneous wavelength selectivity light stimulation effect under occur can
The Amphipathilic block polymer of the photochromic primitive of inverse open loop-closed loop.
In herein described amphipathic nature polyalcohol, m is preferably that 30~100, x is preferably 30~120.
Present invention also provides a kind of preparation method of the amphiphilic polymers with formula (V) structure, including：
Photochromic monomer, chain-transferring agent and the initiator with formula (I) structure are reacted in a solvent, obtained with formula
(V) amphiphilic polymers of structure；
The chain-transferring agent is the end group modification hydrophilic polymer of three thioester groups；
In formula (I), R is the photochromic group with formula (II) structure；
R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11；
In formula (V), R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
M is 7~250；X is 12~150；N is 1~11.
During the application prepares amphipathic nature polyalcohol, it polymerize (RAFT) means using reversible addion-fragmentation chain transfer
Polymer is synthesized.The hydrophilic polymer of hydrophilic segment in amphipathic nature polyalcohol three thioester groups by end group modification carries
For the polyethylene glycol of three thioester groups, polyacrylic acid, NIPA, poly- (2- preferably by end group modification
Methacryloxyethyl Phosphorylcholine) it is or poly- (N, N- dimethylamino acrylamide), three more preferably using end group modification
The polyethylene glycol (PEG-CTA) of thioester group is used as Macromolecular chain transfer agent, and wherein PEG chain segment is hydrophilic segment, its segment
Length can be selected arbitrarily, and the polymer of hydrophobic segment can effectively be changed by changing polymerization parameter and condition.
Present invention also provides a kind of preparation method of the amphiphilic polymers with formula (VI) structure, including：
Hydrophilic monomer, chain-transferring agent and the initiator with formula (VII) structure are reacted in a solvent, obtained containing hydrophilic
The polymer of segment；
By the polymer containing hydrophilic segment, the photochromic monomer with formula (I) structure and initiator in solvent
Middle reaction, obtain the amphiphilic polymers with formula (VI) structure；
The chain-transferring agent is the small molecule containing three thioester groups；
In formula (I), R is the photochromic group with formula (II) structure；
R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11；
In formula (VI), R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
R4For H or CH3；
R5For OH, NHCH (CH3)2、OCH2CH2PO4CH2CH2N(CH3)3Or N (CH3)2；
M is 7~250；X is 12~150；N is 1~11；
In formula (VII), R4For H or CH3, R5For OH, NHCH (CH3)2、OCH2CH2PO4CH2CH2N(CH3)3Or N (CH3)2。
In above process, the segment that the first step polymerize obtained polymer is hydrophilic segment, and its chain length can appoint
Meaning selection；Second step is polymerized to the synthesis of amphipathic nature polyalcohol, and the wherein degree of polymerization of hydrophobic segment can be by changing polymerization ginseng
Number and polymerizing condition effectively change.
Herein described initiator is preferably azodiisobutyronitrile, and the solvent is preferably dioxane, the chain tra nsfer
Agent is preferably trithiocarbonate.
This application provides a kind of preparation method of vesica, including：
Polymer prepared by preparation method described in such scheme is used into cosolvent-water feeding method, emulsion process or miniflow
Prepared by passage method, obtain vesica.
It is above-mentioned prepare vesica during, the cosolvent-water feeding method is specially：
Polymer is completely dissolved in cosolvent, pure water is added in whipping process, then using dialysis or vacuum distillation
Mode remove organic solvent, obtain vesica.
In said process, the cosolvent is preferably acetone, dioxane or tetrahydrofuran.Using cosolvent-water feeding method
The size of the vesica of preparation is tens to hundreds of nano-scales, preferably 20~600 nanometers.
Double emulsion or the microchannel method is method well known to those skilled in the art, is no longer carried out herein specifically
It is bright；A few to tens of microns, preferably 2~100 microns of big vesica have been obtained using double emulsion or microchannel method vegetation.
The application provide firstly a kind of photochromic monomer, then be synthesized by a kind of amphipathic nature polyalcohol, then
Amphipathic nature polyalcohol is self-assembled into vesica, and makes photochromic Primitive Element Distribution in the hydrophobic duplicature of vesica, initial situation
Under, these primitives exist with hydrophobic closed loop, and the duplicature of vesica is low to the permeability of water soluble molecules；When to vesica
When aqueous dispersions carry out ultraviolet light (wavelength is less than 420nm) irradiation, the photochromic primitive in duplicature occurs to be closed by hydrophobic
The isomerization of ring structure to hydrophilic open loop structure changes, and simultaneously because electrostatic interaction between hydrophilic open loop structure
And the interaction of hydrogen bond of main chain side base, the structure of vesica are maintained, not dissociated, therefore, ultraviolet light
The permeability of vesica can be improved and do not change the integrally-built stability of vesica；Subsequently, based on this kind of photochromic primitive sheet
The distinctive reversible isomerism property of body, radiation of visible light (wavelength is more than 450nm) is carried out to the vesica dispersion liquid obtained by previous step
The structure of hydrophilic open loop can be caused to be restored to hydrophobic closed loop configuration, so that the permeability of vesica reduces again.
From said process, reversible regulation and control vesica permeability process can be very easily by changing extraneous light irradiation ripple
Long selection is realized, and can be repeated still effective many times.Based on this layout strategy, realize the hydrophilic of vesica load and
The space-time controlled sequenceization release of hydrophobic molecule, the regulation and control of vesica reactor.
According to the above-mentioned performance of vesica, this application provides controlled release of the vesica in drug loading to react with nanometer
Application in the regulation and control of device.
For a further understanding of the present invention, with reference to embodiment to photochromic monomer provided by the invention, amphipathic
The preparation method of polymer and the application of vesica are described in detail, and protection scope of the present invention is not limited by following examples
System.
Raw material employed in following examples is to be prepared or be commercially available according to prior art.
Embodiment 1
The photochromic molecules precursor of the ethoxy functionalization as shown in formula (VII) of 1 molar equivalent is dissolved in into 30mL to do
In dry dichloromethane, 0.5% DBTL is added as catalyst, by 1.5 molar equivalents such as formula under the conditions of 25~50 DEG C
(VIII) isocyanatoethyl shown in adds, and 7~24h of stirring reaction, reaction uses saturated aqueous common salt water after terminating
Wash and add anhydrous MgSO twice4Dry, decompression rotary evaporation removes solvent, and eluent post is used as using dichloromethane-ethyl acetate
Chromatography purifies to obtain corresponding product, is designated as M1 monomers, and its yield is 75~92%.The structure of M1 monomers passes through nuclear-magnetism hydrogen
Spectrum, nuclear-magnetism carbon spectrum are characterized with high resolution mass spec, are as a result shown as shown in Figures 1 to 3.
In above formula, R1For H, R2For NO2, R3For H, n 1.
Embodiment 2
PEG-CTA chain-transferring agents shown in 1.2g M1 monomers, 0.3g formulas (Ⅸ) and 5.0mg AIBN initiators are dissolved in
4mL dioxane, it is then added in the tube sealing containing magnetic stir bar, fully tube sealing after degassing, is placed in 70 DEG C of oil bath, polymerize
Terminating reaction after reacting 7~12 hours, and be deposited in absolute ether, precipitation three times, dry, and obtains polymer by vacuum drying oven
P1, Fig. 4 are that the nuclear-magnetism of polymer P 1 characterizes.
Wherein, R1For H, R2For NO2, R3For H, x 19, n 1, m 45.
Embodiment 3
By hydrophilic monomer, 0.1g CTA chain-transferring agents and 4.0mg AIBN as shown in formula (Ⅹ) of the 2g as shown in formula (VII)
Initiator is dissolved in 5mL dioxane, is then added in the tube sealing containing magnetic stir bar, fully tube sealing after degassing, is placed in 70 DEG C
In oil bath, polymerisation terminating reaction after 5~10 hours, and be deposited in absolute ether, precipitation three times, dry by vacuum drying oven,
Obtain the polymer of first segment；Then 1.8g hydrophilic segments, 1.5g photochromic monomer M1 and 5.0mg AIBN is taken to trigger
Agent is dissolved in 4mL dioxane, is then added in the tube sealing containing magnetic stir bar, fully tube sealing after degassing, is placed in 70 DEG C of oil bath
In, terminating reaction after polymerisation 7-12 hours, and be deposited in absolute ether, precipitation three times, dry, and obtains two by vacuum drying oven
The subject polymer of block, Fig. 5 be amphipathic nature polyalcohol gel permeation chromatography (GPC) figure, 4) curve represent synthesis first
The gel permeation chromatography curve of individual segmented polymer, 5) the gel permeation chromatography curve of the amphiphilic polymers of Curves compilation.
Wherein, R1For H, R2For NO2, R3For H, R4For H, R5For N (CH3)2, x 20, n 1, m 45.
Embodiment 4
It is whole according to vesica osmotic adjustment under incentive condition and vesica with ultraviolet/visible light that self assembly prepares vesica (step 1)
Maintenance (the step 2) of body structure：
(1) 10mg P1 polymer is dissolved in 2mL tetrahydrofuran cosolvent, with 2mL/h speed under the conditions of being stirred at room temperature
Degree adds 18mL ultra-pure waters thereto, and the shape emulsion that turns white of gained is positioned in bag filter, dialyses in water, after dialysing 12 hours
Eliminate organic solvent, so as to obtain diameter about 450nm vesica (SP polymersomes), as Fig. 6 TEM intuitively
Characterization result, as shown in Figure 6, the thickness in the intermediate layer of vesica is about 20nm, and the size of whole vesica is about 450nm, and size is divided
Cloth is more homogeneous；
(2) it is 365nm ultraviolet lights by wavelength by vesica aqueous dispersions, is then detected.Such as Fig. 7 ultraviolet light
Dynamic light scattering result according to during shows the change of the scattered light intensity and particle diameter in During Illumination, in figure ● curve is scattered
For irradiation by force with the scattering strength curve of ultraviolet light irradiation, ■ curves are vesica corresponding with scattering strength during ultraviolet light
The change curve of particle diameter；Fig. 8 is TEM photo of the vesica after ultraviolet lighting；It can be seen from Fig. 7 and Fig. 8, illumination post-consumer polymer capsule
The overall structure of bubble still keeps fine.Before and after ultraviolet lighting, particle diameter distribution result such as Fig. 9 dynamic light scattering datas of vesica
Shown, ■ curves are the grading curve of original vesica in figure, ● particle diameter distribution is bent after curve is ultraviolet light 10min
Line.
(3) the polymer vesicle aqueous dispersions obtained by previous step irradiate by wavelength for visible ray (such as 520nm), Ran Houjin
Row detection, as shown in Figure 10, Figure 10 are the change curve of the scattered light intensity and particle diameter in During Illumination, in figure ● curve is scattered
For irradiation by force with the scattering strength curve of visible light exposure, ■ curves are vesica corresponding with scattering strength during radiation of visible light
The change curve of particle diameter；Figure 11 is TEM picture of the vesica after infrared light takes, from Figure 10 and Figure 11, the overall knot of vesica
Structure is after infrared radiation still without generation significant change.
The hydrophilic/hydrophobic drug loading and controlled release of application examples 1SP vesicas
Before the self assembly of polymer P 1, by water soluble molecules (such as medicine deoxyribose -5 FU 5 fluorouracil, 5-dFu)
It is dissolved in ultra-pure water, the insoluble molecule of water (such as model drug coumarin-102) is dissolved in organic solvent together with P1, then with real
Method self assembly in example 1 is applied, has been loaded hydrophilic and dewatering medicament vesica simultaneously, is prepared for the pharmaceutical carrier of vesica.
With reference to described in embodiment 1, ultraviolet lighting stimulation is carried out to vesica under physiological ph conditions.As shown in figure 12, scheme
12 releasing curve diagrams of vesica coumarin-102s before and after ultraviolet lighting prepared for the present invention, in figure ● curve is ultraviolet lighting
During cumarin release caused by fluorescence intensity decline, ■ curves be without illumination feelings control group cumarin fluorescence
Strength Changes, Figure 13 are vesica 5-dFu before and after ultraviolet lighting releasing curve diagram prepared by the present invention, in figure ● curve is purple
5-dFu discharges process after outer illumination, and ■ curves are to discharge process without the 5-dFu of the control group of illumination feelings；As a result show：
The dewatering medicament in hydrophobic duplicature is contained as During Illumination gradually discharges, and the release that hydrophilic drugs also can be light-operated.
Further, using the reversible modulating properties of permeability of gained vesica, shone by alternate UV-Visible
Penetrate, as shown in figure 14, Figure 14 is vesica 5-dFu in alternately ultraviolet-visible illumination prepared by present invention releasing curve diagram, by
Figure 14 understands that vesica prepared by the application can successfully realize the pattern of staged controlled release.This mechanisms for drug release pair
Huge potential application will be had in the treatment of future clinical disease, there is provided a kind of regulation and control of the insoluble drug release of brand-new sequencing
Pattern.
The microreactor regulation and control of application examples 2SP vesicas
For the ease of the direct infiltrative change of observation vesica of fluorescence co-focusing, using the polymer of designed synthesis,
It is prepared for the big vesica of tens micron-scales by microchannel method, and can be with cysteine substrate in vesica internal package
The dye molecule BQCy of reaction generation fluorescence, is thus prepared for microreactor.
With reference to described in embodiment 1, carrying out ultraviolet lighting stimulation to vesica, and using fluorescence instruction amino acid substrate with
BQCy reacts in microreactor；As shown in Figure 15 and Figure 16, the results showed that：After ultraviolet lighting, water soluble molecules cysteine can
Entered with passing through the membrane structure of vesica inside vesica, reacted with BQCy, and generate fluorescence-causing substance；And control group
(loaded BQCy, cysteine is equally added outside vesica, but without photo-irradiation treatment) does not have chemical reaction substantially.
The appearance and size regulation and control of application examples 3SP vesicas
The assembling result of polymer prepared by the application also has much relations with polymer composition structure, from different polymerizations
The block copolymer of degree, the imitated vesicle structure of different sizes can be obtained.When such as using the P2 polymer that the degree of polymerization is 27,
Under conditions of other parameters are constant, diameter about 70nm vesica (SP-2 vesicas, as shown in figure 17) is obtained.This is more to prepare later
The nanometer assembling of kind different-shape size provides a kind of realistic plan.
The explanation of above example is only intended to help the method and its core concept for understanding the present invention.It should be pointed out that pair
For those skilled in the art, under the premise without departing from the principles of the invention, the present invention can also be carried out
Some improvement and modification, these are improved and modification is also fallen into the protection domain of the claims in the present invention.
The foregoing description of the disclosed embodiments, professional and technical personnel in the field are enable to realize or using the present invention.
A variety of modifications to these embodiments will be apparent for those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, it is of the invention
The embodiments shown herein is not intended to be limited to, and is to fit to and principles disclosed herein and features of novelty phase one
The most wide scope caused.
Claims (8)
1. one kind has the photochromic monomer of formula (I) structure,
Wherein, R is the photochromic group with formula (II) structure；
R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11.
2. photochromic monomer according to claim 1, it is characterised in that the R1For H, R2For NO2, R3For H, n 1.
3. the preparation method of the photochromic monomer described in claim 1, comprises the following steps：
By the compound with formula (III) structure and the compound with formula (IV) structure in the presence of catalyst in a solvent
Reaction, obtains photochromic monomer；
The solvent is dichloromethane, and the catalyst is dibutyl tin laurate；
Wherein, R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11.
4. one kind has the amphipathic nature polyalcohol of formula (V) structure,
In formula (V), R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
M is 7~250；X is 12~150；N is 1~11.
5. one kind has the preparation method of the amphiphilic polymers of formula (V) structure, including：
Photochromic monomer, chain-transferring agent and the initiator with formula (I) structure are reacted in a solvent, obtained with formula (V)
The amphiphilic polymers of structure；
The chain-transferring agent is the hydrophilic polymer with formula (IX) structure；
In formula (I), R is the photochromic group with formula (II) structure；
R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
N is 1~11；
In formula (V), R1For H or MeO；
R2For NO2Or CN；
R3For H or CH3；
M is 7~250；X is 12~150；N is 1~11.
6. a kind of preparation method of vesica, including：
By the polymer prepared by the polymer described in claim 4 or the preparation method described in claim 5 using cosolvent-
Prepared by water feeding method, obtain vesica.
7. the vesica prepared by preparation method described in claim 6.
8. vesica described in prepared by the preparation method described in claim 6 or claim 7 is in the realizing controlled-release of drug loading
Put the application in the regulation and control with nano-reactor.
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