CN105968268B - A kind of polymer and preparation method thereof and application as the sensitive medicament-carried material of temperature - Google Patents
A kind of polymer and preparation method thereof and application as the sensitive medicament-carried material of temperature Download PDFInfo
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- CN105968268B CN105968268B CN201610344721.3A CN201610344721A CN105968268B CN 105968268 B CN105968268 B CN 105968268B CN 201610344721 A CN201610344721 A CN 201610344721A CN 105968268 B CN105968268 B CN 105968268B
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- 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
- C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
- C08F283/04—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G on to polycarbonamides, polyesteramides or polyimides
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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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
Abstract
The present invention provides a kind of polymer and preparation method thereof and the application as the sensitive medicament-carried material of temperature, belongs to temperature sensing material field.The polymer is 2- (2- methoxy ethoxy) ethyl methacrylate-polyvinyl alcohol ester NCA-N- N-isopropylacrylamide, and structural formula is as shown in formula I.The present invention also provides a kind of preparation methods of polymer.Application the present invention also provides above-mentioned polymer as the sensitive medicament-carried material of temperature, the LCST and tumor vicinity temperature of the polymer are adapted, polymer in vitro LCST when, NIPAM segment and water occur hydrogen bond action and are dissolved in water, when being higher than LCST in vivo, hydrogen bond action weakens, while the binding force between hydrophobic grouping increases, and is shrunk to nano microgel and hydrophobic drug is wrapped in micella.The polymer link 2- (2- methoxy ethoxy) ethyl methacrylate be it with good biocompatibility and water solubility, using it as medicine carrying material, can be stable there are in the human body fluids such as blood.
Description
Technical field
The invention belongs to temperature sensing material fields, and in particular to a kind of polymer and preparation method thereof and carry as temperature sensitivity
The application of drug material.
Background technique
N-isopropyl acrylamide (NIPAM) is a kind of temperature-sensitive material of current most study, polymer
The minimum critical-temperature (LCST, 32 DEG C) of PNIPAM is closer to human body temperature.In dilute aqueous solution, PNIPAM homopolymer can be
That is, in 1-2 DEG C of very narrow range of temperature the single-stranded phase transition row between molten ball occurs for 32 DEG C of experience, one phase transition
For.The study found that NIPAM, which is grafted in a plane or spherical surface, can obtain many actual applications, such as the biography of drug
Defeated, solute separation, enzymatic carrier and protein absorption etc., are all the temperature sensitivities using NIPAM.
The hot fields studied now are control release behavior of the polymer nanoparticle drug carriers to drug.Traditional administration
Mode (oral or injection) is easy to be the biggish variation of drug concentration generation in blood.If drug concentration is excessively high, can cause
Toxic side effect；If drug concentration is too low, drug using effect will affect.Control release is carried out to drug using nano-carrier,
Be conducive to the effective use of drug, it is often more important that optimal treatment is provided, to be alleviated very big pain by medicine person.
Many anti-tumor drugs (such as taxol (PTX), adriamycin (DOX)) are in clinical use due to its poor water
Dissolubility seriously affects treatment, and the water solubility for improving these drugs can greatly improve the service efficiency of drug, reduce medical treatment at
This.
China is the high-incidence state of second-biggest-in-the-world cancer, and newly-increased cancer patient accounts for the 20% of global cancer patient sum.Every year
Death toll is more than 1,400,000 people.Since the number of patients of increasing environmental pollution cancer will also continue quickly to rise following.Chemistry
Therapy is the method being widely used at present, but tumour cell, which can generate drug resistance by a variety of methods, makes chemotherapy fail.Nanometer
Delivery system is the overriding resistance method being nowadays widely used, small-molecule drug in conjunction with transportation system after can reduce drug
Toxicity promotes target-oriented drug, while reducing drug resistance.By experimental verification, carried by the drug of Material synthesis of Pidolidone
Body can make cell absorb drug in a manner of pinocytosis, increase drug accumulation and be resident, significantly improve anti-drug resistance.With L- paddy ammonia
Transportation system based on acid has the potentiality of drug-resistant type oncotherapy.
Atom transfer radical polymerization (ATRP) is always current research hotspot, it is used for reference is widely used in organic synthesis
Atom transferred free radical addition reaction thinking, using simple organohalogen compounds as initiator, transient metal complex be halogen original
Subcarrier establishes reversible dynamic equilibrium by redox reaction between reactive species and suspend mode kind, to realize to poly-
Close the control of reaction.
ATRP causes system and is made of initiator, catalyst and ligand three parts.
(1) ATRP reaction initiator: can be caused containing the alkyl halide for inducing or being conjugated group on all positions α.At present
The more typical ATRP initiator of the ratio known mainly has α-halogenatedcarbonylcompounds, such as ethyl α bromopropionate, α-chloro-propionicacid ethyl ester；
Alpha-chloro vinylbenzene, α-benzyl bromide etc.；Polyhalide such as carbon tetrachloride, chloroform etc..
(2) catalyst and ligand: catalyst is containing complexing composed by the strong ligand such as transistion metal compound and N, O, P
Redox reaction easily occurs for object, central ion, is balanced by establishing quick redox reversible, makes to increase reactive species change
For suspend mode kind.Ligand also becomes complexant, and main function is to form complex compound with transition metal (copper, iron, nickel etc.), is dissolved in it
Solvent adjusts the oxidation-reduction potential of central metal, and when metal ion oxidation state changes, ligancy increases and decreases therewith, establishes former
The dynamic equilibrium of son transfer.
Being unique in that for ATRP has used organic halogen to make initiator, and is turned with transition-metal catalyst or degeneration
The mode of shifting makes chain growth, and free radical, at suspend mode kind, effectively inhibits the biradical termination between free radical to react by reversible passivation,
Its relative molecular weight is can be controlled between 10000~100000, and molecular weight distribution is 1.05~1.70.
Research report " preparation of poly benzyl glutamate and acrylamide copolymer and the tablets in vitro row that Northcentral University Wei comes
For research " a kind of poly benzyl glutamate and acrylamide copolymer are disclosed, which can be used as medicine carrying material use, then
This structure, which is that NIPAM, OEG block are too long as the shortcomings that medicine carrying material, to be easy to keep drug carrier nano micellar particle size excessive.
Summary of the invention
The present invention provide a kind of polymer and preparation method thereof and and as the sensitive medicament-carried material of temperature application, the polymerization
Object has good Thermo-sensitive and pH sensibility, can be used as drug conveying carrier use.
Present invention firstly provides a kind of polymer, which is 2- (2- methoxy ethoxy) ethyl methacrylate-
Polyvinyl alcohol ester NCA-N- N-isopropylacrylamide, structural formula is as shown in formula I:
In formula I, m=14~110, n=65~82, p=80~120, i=2.
The present invention also provides a kind of preparation methods of polymer, this method comprises:
Step 1: Pidolidone and chlorethanol are reacted under condition of ice bath, obtain Pidolidone chloroethene alcohol ester；
Step 2: it is being full of N2Under conditions of, the Pidolidone chloroethene alcohol ester and triphosgene that step 1 is obtained are in tetrahydro
It is reacted in tetrahydrofuran solution, generates glutamic acid chloroethene alcohol ester NCA；
Step 3: using triethylamine as initiator, it is poly- to cause the Pidolidone chloroethene alcohol ester NCA progress open loop that step 2 obtains
It closes, obtains polyglutamic acid chloroethene alcohol ester；
Step 4: in Cu (I) X organic ligand catalyst system, polyglutamic acid chloroethene alcohol ester and 2- that step 3 is obtained
(2- methoxy ethoxy) ethyl methacrylate and NIPAM reaction, obtain 2- (2- methoxy ethoxy) methacrylic acid second
Ester-polyvinyl alcohol ester NCA-N- N-isopropylacrylamide.
Preferably, the molar ratio of Pidolidone and chlorethanol is 1:(0.8~1 in the step 1).
Preferably, the reaction temperature of the step 2 is 50~60 DEG C, and the reaction time is 2~2.5h.
Preferably, the molar ratio of Pidolidone chloroethene alcohol ester and triphosgene is 1:(1~1.2 in the step 2).
Preferably, the reaction temperature of the step 3 is 20~25 DEG C, and the reaction time is 48~72h.Preferably, institute
Stating the molar ratio of triethylamine and Pidolidone chloroethene alcohol ester NCA in step 3 is (1~2): 1.
Preferably, the reaction temperature of the step 4 is 55~60 DEG C, and the reaction time is 2~3h.
Preferably, Cu (I) X is CuCl in the step 4, and organic ligand is 3- hexamethyl amino-ethyl amine.
Application the present invention also provides above-mentioned polymer as the sensitive medicament-carried material of temperature.
Beneficial effects of the present invention
Present invention firstly provides a kind of polymer, and structural formula is as shown in formula I, skeleton symbol are as follows: OEG-PGLC-NIPAM, formula
In: OEG is 2- (2- methoxy ethoxy) ethyl methacrylate, and PGLC is polyvinyl alcohol ester NCA, and NIPAM is N- isopropyl
Acrylamide；2- (2- methoxy ethoxy) ethyl methacrylate-polyvinyl alcohol ester NCA-N- isopropyl acrylamide
Amine (OEG-PGLC-NIPAM) is a kind of Thermo-sensitive cancer target high molecular polymer, and NIPAM is a kind of temperature sensing polymer,
Lowest critical solution temperature is about 32 DEG C, meets the needs of Human Physiology temperature by adjusting the quantity of the NIPAM linked.
2- (2- methoxy ethoxy) ethyl methacrylate has good water solubility, can be mentioned by being connected on polyaminoacid
Biocompatibility is risen, convenient for the transport of pharmaceutical carrier in blood.
The present invention also provides a kind of preparation methods of polymer, and the preparation method raw material is simple and easy to get, simple synthetic method,
Polymerization activity is controllable.
Application the present invention also provides above-mentioned polymer as the sensitive medicament-carried material of temperature, the LCST and tumour of the polymer
Neighbouring temperature is adapted, polymer in vitro LCST when, NIPAM segment and water occur hydrogen bond action and are dissolved in water, high in vivo
When LCST, hydrogen bond action weakens, while the binding force between hydrophobic grouping increases, and is shrunk to nano microgel for hydrophobic medicine
Object is wrapped in micella.2- (2- methoxy ethoxy) ethyl methacrylate of polymer link is it with good biological
Compatibility and water solubility, using it as medicine carrying material, can be stable there are in the human body fluids such as blood.
Detailed description of the invention:
The GPC figure that Fig. 1 is the PLGL that embodiment 1-3 is prepared；
Fig. 2 is PLGL, OEG-PGLC-NIPAM's that embodiment 1 is prepared1H NMR spectra；
Fig. 3 is the infrared absorption spectrum of PLGL, OEG-PGLC-NIPAM that embodiment 1 is prepared；
Fig. 4 is the CMC spectrogram for the OEG-PGLC-NIPAM that embodiment 1 is prepared；
Fig. 5 is the adriamycin that the OEG-PGLC-NIPAM that embodiment 4 obtains contains simulation physiological environment progress after adriamycin
Cumulative in vitro release profiles；
Fig. 6 is that the transmitted electron of surface topography of the OEG-PGLC-NIPAM under different amplification in embodiment 4 is aobvious
Micro mirror photo；
Fig. 7 is that the transmitted electron of surface topography of the OEG-PGLC-NIPAM under different amplification in embodiment 4 is aobvious
Micro mirror photo.
Specific embodiment
Present invention firstly provides a kind of polymer, which is 2- (2- methoxy ethoxy) ethyl methacrylate-
Polyvinyl alcohol ester NCA-N- N-isopropylacrylamide, skeleton symbol are as follows: OEG-PGLC-NIPAM, in formula: OEG is 2- (2- methoxyl group
Ethyoxyl) ethyl methacrylate, PGLC is that polyvinyl alcohol ester NCA, NIPAM are n-isopropyl acrylamide, and structural formula is such as
Shown in formula I:
In formula I, m=14~110, n=65~82, p=80~120, i=2.
According to the present invention, the 2- (2- methoxy ethoxy) ethyl methacrylate-polyvinyl alcohol ester NCA-N- is different
Propylacrylamide (OEG-PGLC-NIPAM) is a kind of Thermo-sensitive cancer target high molecular polymer, and NIPAM is a kind of temperature sensitive
Property polymer, lowest critical solution temperature is about 32 DEG C, meets Human Physiology by adjusting the quantity of NIPAM of link
The needs of temperature.2- (2- methoxy ethoxy) ethyl methacrylate has good water solubility, poly- by being connected to
Biocompatibility can be promoted on amino acid, convenient for the transport of pharmaceutical carrier in blood.
The present invention also provides a kind of preparation methods of polymer, this method comprises:
Step 1: Pidolidone and chlorethanol are reacted under condition of ice bath, obtain Pidolidone chloroethene alcohol ester；
Step 2: it is being full of N2Under conditions of, the Pidolidone chloroethene alcohol ester and triphosgene that step 1 is obtained are in tetrahydro
It is reacted in tetrahydrofuran solution, generates glutamic acid chloroethene alcohol ester NCA；
Step 3: with triethylamine (TEA) for initiator, cause the Pidolidone chloroethene alcohol ester NCA that step 2 obtains and carry out
Ring-opening polymerisation obtains polyglutamic acid chloroethene alcohol ester (PLGL)；
Step 4: in Cu (I) X organic ligand catalyst system, polyglutamic acid chloroethene alcohol ester and 2- that step 3 is obtained
(2- methoxy ethoxy) ethyl methacrylate and NIPAM reaction, obtain 2- (2- methoxy ethoxy) methacrylic acid second
Ester-polyvinyl alcohol ester NCA-N- N-isopropylacrylamide.
According to the present invention, Pidolidone and chlorethanol are added in there-necked flask, measures the concentrated sulfuric acid, divides and is added dropwise in there-necked flask
It is clarified to solution, weighs sodium bicarbonate, water is put into beaker, reaction solution is poured slowly under ice bath environment, it is stirring while adding,
It is sealed with preservative film, is put into refrigerator overnight, recrystallization three times, is cleaned with organic solution.It is preferred that first being washed once with ethyl alcohol, then use
Ether is washed once, be put into drier drain it is spare.The Pidolidone and chlorethanol molar ratio is preferably 1:(0.8~1).
It is anti-that Pidolidone chloroethene alcohol ester, triphosgene and solvent is added in there-necked flask vacuum nitrogen gas according to the present invention
It answers, selected solvent is preferably THF, and the reaction temperature is preferably 50~60 DEG C, and the reaction time is 2~2.5 hours, uses petroleum
Ether sedimentation reaction liquid to upper liquid is clarified, and solid is filtered to take, and is dissolved with ethyl acetate and ice water, upper liquid is taken after liquid separation, then use
It is dry that it is put into anhydrous magnesium sulfate after washing, drains solvent and obtains Pidolidone chloroethene alcohol ester NCA.The Pidolidone chlorethanol
Ester and triphosgene molar ratio are preferably 1:(1~1.2).
According to the present invention, Pidolidone chloroethene alcohol ester NCA, triethylamine and solvent are added after reactor is substituted gas 3 times, uses
Triethylamine causes open loop and obtains polyglutamic acid chloroethene alcohol ester, and the reaction temperature is preferably room temperature, and the reaction time is preferably 48
~72 hours, reaction dissolvent was preferably DMF, and the NCA and triethylamine molar ratio are preferably 1:(1~2).
According to the present invention, catalyst, polyglutamic acid chloroethene alcohol ester, organic ligand, 2- (2- methoxyl group are added in the reactor
Ethyoxyl) ethyl methacrylate, n-isopropyl acrylamide (NIPAM) and solvent reaction, the reaction temperature be preferably 55
~60 DEG C, the reaction time is 2~3h, obtains 2- (2- methoxy ethoxy) ethyl methacrylate-polyvinyl alcohol ester NCA-N-
N-isopropylacrylamide.The solvent is preferably the mixed solvent of DMF and methanol, and catalyst is preferably CuCl, and organic ligand is
3- hexamethyl amino-ethyl amine.The polyglutamic acid chloroethene alcohol ester, organic ligand, catalyst, 2- (2- methoxy ethoxy)
Ethyl methacrylate and monomer n-isopropyl acrylamide (NIPAM) molar ratio are preferably 1:1:1:(60~120): (80~
120)。
Application the present invention also provides above-mentioned polymer as the sensitive medicament-carried material of temperature, the LCST of the polymer and people's
Body temperature is adapted, polymer in vitro LCST when, NIPAM segment and water occur hydrogen bond action and are dissolved in water, are higher than in vivo
When LCST, hydrogen bond action weakens, while the binding force between hydrophobic grouping increases, and is shrunk to nano microgel for hydrophobic drug
It is wrapped in micella.2- (2- methoxy ethoxy) ethyl methacrylate of polymer link is it with good biological phase
Capacitive and water solubility, using it as medicine carrying material, can be stable there are in the human body fluids such as blood.
The present invention will be further described in detail combined with specific embodiments below, and involved raw material is in embodiment
It is commercially available.
Embodiment 1
Pidolidone 40g is weighed, chlorethanol 60ml is measured, is added in there-necked flask, paddle stirring is stirred.Measure the concentrated sulfuric acid
(98%) 16ml divides and is added dropwise in there-necked flask and (clarifies to solution).60g sodium bicarbonate is weighed, 200ml water is put into 1000ml beaker
In, reaction solution is poured slowly under ice bath environment, it is stirring while adding, it is sealed with preservative film, is put into refrigerator overnight, recrystallization three
It is secondary, it is first washed once with ethyl alcohol, then washed once with ether, is put into drier and drains spare, obtain glutamic acid chloroethene alcohol ester.
Stirrer is added in attachment device, bakes bottle three times, vacuumizes three times, inflated with nitrogen is three times.Glutamic acid chloroethene alcohol ester is added
5g, THF80ml are stirred at 55 DEG C, and triphosgene 7.61g is added, and (it is recommended that in three times plus for the first time more than second, second more
In third time), react 2h.It is clarified with petroleum ether sedimentation reaction liquid to the upper liquid of 250ml ice, solid is stayed in filtering.With 80ml ice
Ethyl acetate and 5ml ice water dissolved solid.Upper liquid is stayed in liquid separation, and saturated sodium bicarbonate aqueous solution is washed once, and ice water washes one
It is secondary.With the dry upper liquid of anhydrous magnesium sulfate, filtering drains solvent, obtains pale yellow oily liquid i.e. product glutamic acid chloroethene alcohol ester
NCA。
Add stirrer in reaction flask, 0.471gNCA is added, is dissolved with DMF, substitutes gas three times.25 μ l triethylamines are added,
React at room temperature 72h.Obtain polyglutamic acid chloroethene alcohol ester NCA (PLGL).
Solvent is made in DMF and methanol mixing (V/V=1:1), and CuCl makees catalyst, and 190.5mgPLGL, 0.1897g2- is added
(2- methoxy ethoxy) ethyl methacrylate and 0.904gNIPAM, 60 DEG C of reaction temperature, reaction time 6h obtains OEG-
PGLC-NIPAM。
The GPC that a in Fig. 1 is the PLGL that embodiment 1 is prepared schemes, and the number-average molecular weight Mn of PLGL-1 is in figure
1200g/mol, polydispersity PDI are 1.29；Scheme the peak in a to be in unimodal symmetrical and gradually move to high molecular weight direction
It is dynamic, illustrate there is no the generation of other by-products in each reaction process, it was demonstrated that the success of each step reaction.
Fig. 2 is PLGL (a), the OEG-PGLC-NIPAM (b) that embodiment 1 obtains1H NMR spectra, PLGL passes through in figure
Triethylamine (TEA) causes the NCA open loop of Pidolidone chloroethene alcohol ester.Pass through analysis1H NMR spectra, it may be clearly seen that
The ownership at each peak.Nuclear magnetic resonance peak-to-peak signal at 4.76ppm (a) is hydrogen (- C (O) CH (CH on polyaminoacid main chain2–)
NH-, 1H)；Nuclear magnetic resonance peak-to-peak signal at 2.30ppm and 2.02ppm (b) is hydrogen (- C (O) CH (CH on methyl2) NH-,
2H)；Nuclear magnetic resonance peak-to-peak signal at 2.75ppm (c) is the hydrogen (- CH on the carbon connected with carbon phase on ester group2-C(O)-O-,
2H)；Nuclear magnetic resonance peak-to-peak signal at 4.32ppm (d) is hydrogen (- C (O)-O-CH on the carbon being connected with oxygen on ester group2-,
2H)；The nuclear magnetic resonance peak-to-peak signal at the place (e) is the hydrogen (- CH on the carbon being connected with chlorine atom at 3.68ppm2- Cl, 2H).
OEG-PGLC-NIPAM forms random block copolymer by graft N IPAM and OEG.Pass through analysis1H NMR
Spectrogram, the nuclear magnetic resonance peak-to-peak signal at 1.30ppm (k) are hydrogen (- C (O) NH (CH on random block NIPAM main chain2–)
CH2, 2H)；Nuclear magnetic resonance peak-to-peak signal at 3.89ppm (f) is hydrogen (- C (O) NH (CH on methyl2–)CH2, 1H)；?
The nuclear magnetic resonance peak-to-peak signal at the place 1.35ppm (g) is hydrogen (- C (O)-C-CH on graft N IPAM methyl3-,3H)；In 1.82ppm
(j) the nuclear magnetic resonance peak-to-peak signal at place is hydrogen (- C (the O)-C-CH being grafted on OEG on methyl3-,3H)；The place (i) at 4.68ppm
Nuclear magnetic resonance peak-to-peak signal be hydrogen (- O-O-CH on the carbon being connected with chlorine atom2, 2H).These characteristic peaks show polymer
OEG-PGLC-NIPAM block copolymerization success.
Fig. 3 be embodiment 1 obtain PLGL (a), OEG-PGLC-NIPAM (b) infrared absorption spectrum, with KBr tabletting,
Wave number is 500~3750cm-1In range, the C=O stretching vibration being saturated in ester bond in figure belongs to 1683cm-1Place, it can be seen that
The peak intensity is very big, it was demonstrated that a large amount of ester bond structure units exist；1631cm-1, 1550cm-1Respectively amide group (N-H
Bending vibration) characteristic absorption peak, 629cm-1 be chloro C-Cl stretching vibration absworption peak；By infrared spectrum curve it is found that polymerization
Object has amide feature structure (C=O, the 1655cm of NIPAM-1；N-H,1560cm-1), it is compared with PLGL chemical structural formula,
It knows PNIPAM and POEG and is successfully grafted, generate stable block copolymer.
Fig. 4 is the CMC spectrogram for the OEG-PGLC-NIPAM that embodiment 1 obtains, and is visited using the pyrene of isoconcentration as hydrophobic fluorescent
Needle uses the CMC of each block polymer of fluorescence spectrophotometry.Experimental method are as follows: prepare serial equivalent using centrifuge tube
The acetone soln (6 × 10mol/L 30uL) of pyrene, then (25 DEG C) vacuum drying of room temperature allow acetone to volatilize completely.It is each to draw 3mL
A series of aqueous solutions of polymers of preconfigured concentration is added in the above-mentioned centrifuge tube containing pyrene, by this solution in room temperature
It is placed for 24 hours under (25 DEG C), pyrene is allowed to reach dissolution equilibrium in water phase.Then using under fluorescence spectrophotometer measurement various concentration
Polymer and pyrene emission spectrum.Instrument parameter sets excitation wavelength as 332nm, and bandwidth and transmitted bandwidth is excited all to be scheduled on
0.5nm collects the emission spectrum between 240nm to 900nm.According to the emission spectrum of pyrene, recognized in the peak intensity angle value of I=335nm
For the function for being polymer concentration.Make polymer concentration to the scatter plot of peak intensity, it is corresponding when fluorescence intensity mutates
Polymer concentration is defined as the CMC of polymer.
From Fig. 4 it can be clearly seen that as polymer concentration increases, total fluorescence intensity has a mutation
Point, catastrophe point show that the formation of micella and pyrene enter hydrophobic micelle inner core.Polymer corresponding to the fluorescence intensity of catastrophe point
Concentration is defined as the CMC of the polymer.
According to calculation shows that, with the increase of OEG-PGLC-NIPAM block copolymer hydrophobic segment ratio, micelle forma-tion
CMC it is lower, this is because the active force between hydrophobic section is bigger, dissolubility in water with the increase of hydrophobic segment
It is just smaller, it is easier to form micella.Micella has extremely low CMC, shows that micella can also remain steady in extremely dilute aqueous medium
Fixed structure, for example in the blood of human body, it is also able to maintain micellar conformation, this is load dewatering medicament and extends it in blood
Circulation time provide objective foundation.
Embodiment 2
Pidolidone 40g is weighed, chlorethanol 60ml is measured, is added in there-necked flask, paddle stirring is stirred.Measure the concentrated sulfuric acid
(98%) 16ml divides and is added dropwise in there-necked flask and (clarifies to solution).60g sodium bicarbonate is weighed, 200ml water is put into 1000ml beaker
In, reaction solution is poured slowly under ice bath environment, it is stirring while adding, it is sealed with preservative film, is put into refrigerator overnight, recrystallization three
It is secondary, it is first washed once with ethyl alcohol, then washed once with ether, is put into drier and drains spare, obtain glutamic acid chloroethene alcohol ester.
Stirrer is added in attachment device, bakes bottle three times, vacuumizes three times, inflated with nitrogen is three times.Glutamic acid chloroethene alcohol ester is added
5g, THF80ml are stirred at 55 DEG C, and triphosgene 7.61g is added, and (it is recommended that in three times plus for the first time more than second, second more
In third time), react 2h.It is clarified with petroleum ether sedimentation reaction liquid to the upper liquid of 250ml ice, solid is stayed in filtering.With 80ml ice
Ethyl acetate and 5ml ice water dissolved solid.Upper liquid is stayed in liquid separation, and saturated sodium bicarbonate aqueous solution is washed once, and ice water washes one
It is secondary.With the dry upper liquid of anhydrous magnesium sulfate, filtering drains solvent, obtains pale yellow oily liquid i.e. product glutamic acid chloroethene alcohol ester
NCA。
Add stirrer in reaction flask, 0.471gNCA is added, is dissolved with DMF, substitutes gas three times.50 μ l triethylamines are added,
React at room temperature 72h.Obtain polyglutamic acid chloroethene alcohol ester NCA (PLGL).
Solvent is made in DMF and methanol mixing (V/V=1:1), and CuCl makees catalyst, and 130mgPLGL, 0.1897g2- (2- is added
Methoxy ethoxy) ethyl methacrylate and 1.13gNIPAM, 60 DEG C of reaction temperature, reaction time 6h obtains OEG-PGLC-
NIPAM。
The GPC that b in Fig. 1 is the PLGL that embodiment 2 is prepared schemes, and the number-average molecular weight Mn of PLGL-2 is in figure
2500g/mol, polydispersity PDI are 1.54；Scheme the peak in b to be in unimodal symmetrical and gradually move to high molecular weight direction
It is dynamic, illustrate there is no the generation of other by-products in each reaction process, it was demonstrated that the success of each step reaction.
Embodiment 3
Pidolidone 40g is weighed, chlorethanol 60ml is measured, is added in there-necked flask, paddle stirring is stirred.Measure the concentrated sulfuric acid
(98%) 16ml divides and is added dropwise in there-necked flask and (clarifies to solution).60g sodium bicarbonate is weighed, 200ml water is put into 1000ml beaker
In, reaction solution is poured slowly under ice bath environment, it is stirring while adding, it is sealed with preservative film, is put into refrigerator overnight, recrystallization three
It is secondary, it is first washed once with ethyl alcohol, then washed once with ether, is put into drier and drains spare, obtain glutamic acid chloroethene alcohol ester.
Stirrer is added in attachment device, bakes bottle three times, vacuumizes three times, inflated with nitrogen is three times.Glutamic acid chloroethene alcohol ester is added
5g, THF80ml are stirred at 55 DEG C, and triphosgene 7.61g is added, and (it is recommended that in three times plus for the first time more than second, second more
In third time), react 2h.It is clarified with petroleum ether sedimentation reaction liquid to the upper liquid of 250ml ice, solid is stayed in filtering.With 80ml ice
Ethyl acetate and 5ml ice water dissolved solid.Upper liquid is stayed in liquid separation, and saturated sodium bicarbonate aqueous solution is washed once, and ice water washes one
It is secondary.With the dry upper liquid of anhydrous magnesium sulfate, filtering drains solvent, obtains pale yellow oily liquid i.e. product glutamic acid chloroethene alcohol ester
NCA。
Add stirrer in reaction flask, 0.471gNCA is added, is dissolved with DMF, substitutes gas three times.75 μ l triethylamines are added,
React at room temperature 72h.Obtain polyglutamic acid chloroethene alcohol ester NCA (PLGL).
Solvent is made in DMF and methanol mixing (V/V=1:1), and CuCl makees catalyst, and 130mgPLGL, 0.3097g2- (2- is added
Methoxy ethoxy) ethyl methacrylate and 0.904gNIPAM, 60 DEG C of reaction temperature, reaction time 6h obtains OEG-
PGLC-NIPAM。
The GPC that c in Fig. 1 is the PLGL that embodiment 3 is prepared schemes, and the number-average molecular weight Mn of PLGL-3 is in figure
3400g/mol, polydispersity PDI are 1.76.Scheme the peak in c to be in unimodal symmetrical and gradually move to high molecular weight direction
It is dynamic, illustrate there is no the generation of other by-products in each reaction process, it was demonstrated that the success of each step reaction.
Embodiment 4
Pidolidone 40g is weighed, chlorethanol 60ml is measured, is added in there-necked flask, paddle stirring is stirred.Measure the concentrated sulfuric acid
(98%) 16ml divides and is added dropwise in there-necked flask and (clarifies to solution).60g sodium bicarbonate is weighed, 200ml water is put into 1000ml beaker
In, reaction solution is poured slowly under ice bath environment, it is stirring while adding, it is sealed with preservative film, is put into refrigerator overnight, recrystallization three
It is secondary, it is first washed once with ethyl alcohol, then washed once with ether, is put into drier and drains spare, obtain glutamic acid chloroethene alcohol ester.
Stirrer is added in attachment device, bakes bottle three times, vacuumizes three times, inflated with nitrogen is three times.Glutamic acid chloroethene alcohol ester is added
5g, THF80ml are stirred at 55 DEG C, and triphosgene 7.61g is added, and (it is recommended that in three times plus for the first time more than second, second more
In third time), react 2h.It is clarified with petroleum ether sedimentation reaction liquid to the upper liquid of 250ml ice, solid is stayed in filtering.With 80ml ice
Ethyl acetate and 5ml ice water dissolved solid.Upper liquid is stayed in liquid separation, and saturated sodium bicarbonate aqueous solution is washed once, and ice water washes one
It is secondary.With the dry upper liquid of anhydrous magnesium sulfate, filtering drains solvent, obtains pale yellow oily liquid i.e. product glutamic acid chloroethene alcohol ester
NCA。
Add stirrer in reaction flask, 0.471gNCA is added, is dissolved with DMF, substitutes gas three times.100 μ l, tri- second is added
Amine reacts at room temperature 72h.Obtain polyglutamic acid chloroethene alcohol ester NCA (PLGL).
Solvent is made in DMF and methanol mixing (V/V=1:1), and CuCl makees catalyst, and 130mgPLGL, 0.3097g2- (2- is added
Methoxy ethoxy) ethyl methacrylate and 1.13gNIPAM, 60 DEG C of reaction temperature, reaction time 6h obtains OEG-PGLC-
NIPAM。
Fig. 5 is the adriamycin that the OEG-PGLC-NIPAM that embodiment 4 obtains contains simulation physiological environment progress after adriamycin
Cumulative in vitro release profiles；Choose the ring that the phosphate buffer solution (PBS) that pH is 5.6,6.8,7.4 simulates cell interior respectively
The environment in border, the environment of tumor locus and normal human tissue.Fig. 5 illustrates: the buffering that the pH for simulating normal tissue is 7.4 is molten
Liquid, by the release of 72h, the adriamycin cumulative release amount being calculated is 37% or so, with the continuous reduction of pH, adriamycin
Burst size gradually increasing, pH be 5.6 when, cumulative release amount has had reached 78% or so, and this phenomenon illustrates medicine
Object is more easy release under more acid environment.The reason of causing this phenomenon may be since Poly-L-glutamic acid exists
Degree of ionization under acid condition decreases, and so as to cause passively releasing for adriamycin, there is the cumulative release of adriamycin
Increased.Adriamycin releasing result demonstrates release of the composite material under different physiological environments not under different acidic conditions
Together, the release under more acid environment, can not only reduce the toxic side effect of drug, but also drug can be made to concentrate on swelling
Tumor position reaches preferable antitumous effect.
Fig. 6 is the saturating of surface topography of the OEG-PGLC-NIPAM at different amplification (figure a, b, c) in embodiment 4
Penetrate electron micrograph；Fig. 7 is surface of the OEG-PGLC-NIPAM at different amplification (figure a and b) in embodiment 4
The transmission electron microscope photo of pattern.As can be seen from Figures 6 and 7: nanoparticle is rounded and relatively regular, almost without hair
Raw the phenomenon that reuniting.Show not interact between polymer nano-particle, be separated from each other.Material after being loaded
Partial size substantially in 75 ± 15nm, polydispersity index (PDI) is 1.051, and it is good to indicate that the system has by lesser partial size and PDI
Good stability carries out endocytosis convenient for cell, is acted in the cell convenient for drug, thus by drug delivery to cell
In vivo.And drug concentration in high-permeability and retention effect raising tumour can be relied on.By electron microscope it can also be seen that: OEG-
PGLC-NIPAM forms spherical micelle in the solution, and the partial size of medicine carrying material is smaller, and the nanometer medicine-carried system of preparation has very
Good stability and preferable dispersibility, can not only prevent drug from acting on cell membrane or being inhaled in vivo by albumen
It is attached, and due to the elecrtonegativity of system, may make it in the cell has lower toxicity, improves the safety of system
Intracellular action time can be tied up to extension body simultaneously, to have the function that assemble drug in privileged site.
Claims (6)
1. a kind of polymer, which is characterized in that the polymer is 2- (2- methoxy ethoxy) ethyl methacrylate-polychlorostyrene second
Alcohol ester NCA-N- N-isopropylacrylamide, structural formula is as shown in formula I:
In formula I, m=14~110, n=65~82, p=80~120, i=2；
The preparation method of the polymer includes:
Step 1: Pidolidone and chlorethanol are reacted under condition of ice bath, obtain Pidolidone chloroethene alcohol ester；The step 1
The molar ratio of middle Pidolidone and chlorethanol is 1:(0.8~1)；
Step 2: it is being full of N2Under conditions of, the Pidolidone chloroethene alcohol ester and triphosgene that step 1 is obtained are molten in tetrahydrofuran
It is reacted in liquid, generates glutamic acid chloroethene alcohol ester NCA；The molar ratio of Pidolidone chloroethene alcohol ester and triphosgene is in the step 2
1:(1~1.2)；
Step 3: using triethylamine as initiator, causing the Pidolidone chloroethene alcohol ester NCA that step 2 obtains and carry out ring-opening polymerisation,
Obtain polyglutamic acid chloroethene alcohol ester；The molar ratio of triethylamine and Pidolidone chloroethene alcohol ester NCA are (1~2) in the step 3:
1；
Step 4: in Cu (I) X organic ligand catalyst system, polyglutamic acid chloroethene alcohol ester and 2- (2- first that step 3 is obtained
Oxygroup ethyoxyl) ethyl methacrylate and NIPAM reaction, it is poly- to obtain 2- (2- methoxy ethoxy) ethyl methacrylate-
Chloroethene alcohol ester NCA-N- N-isopropylacrylamide；The polyglutamic acid chloroethene alcohol ester, 2- (2- methoxy ethoxy) methyl-prop
Olefin(e) acid ethyl ester and monomer n-isopropyl acrylamide NIPAM molar ratio are 1:(60~120): (80~120).
2. a kind of polymer according to claim 1, which is characterized in that the reaction temperature of the step 2 is 50~60
DEG C, the reaction time is 2~2.5h.
3. a kind of polymer according to claim 1, which is characterized in that the reaction temperature of the step 3 is 20~25
DEG C, the reaction time is 48~72h.
4. a kind of polymer according to claim 1, which is characterized in that the reaction temperature of the step 4 is 55~60
DEG C, the reaction time is 2~3h.
5. a kind of polymer according to claim 1, which is characterized in that Cu (I) X is CuCl in the step 4, organic
Ligand is 3- hexamethyl amino-ethyl amine.
6. application of the above-mentioned polymer according to claim 1 as the sensitive medicament-carried material of temperature.
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| Polypeptide diblock copolymers: Syntheses and properties of poly(N-isopropylacrylamide)-b-polylysine;Cheng-Jyun Huang;《Macromolecules》;20080609;第41卷(第19期);7041,7048,7050 * |
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