CN104844796B - A kind of preparation method of the star-like polyglutamic acid with porphyrin as core - Google Patents
A kind of preparation method of the star-like polyglutamic acid with porphyrin as core Download PDFInfo
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Abstract
The invention belongs to optical dynamic treatment technology, the preparation method of specifically a kind of star-like poly- polyglutamic acid with porphyrin as core.It is an object of the invention to effectively improve the existing curative effect in photodynamic therapy, there is provided, to the high molecular preparation method of star-like polyglutamic acid that porphyrin is core, synthetic method is easy and effective, directly triggers Amino Porphyrins for a kind of optical dynamic therapy that can effectively strengthenBenzyl L glutamic acid N carbonyl acid anhydrides ring-opening polymerisations, then debenzylation, operating method are easy, are expected to be applied to industrialized production.
Description
Technical field
The invention belongs to optical dynamic treatment technology, the preparation of specifically a kind of star-like polyglutamic acid with porphyrin as core
Method.
Background technology
In recent years, Porphyrin and its derivative is because there is good photosensitive property to be widely used in medicament slow release and tumour
Photokinesis therapy field；But, because Porphyrin and its derivative molecular hydrophobicity is strong, in aqueous solution, between big plane of a loop
Hydrophobic effect result in the stronger aggregation tendency of sensitising agent, and this not only brings difficulty to isolating and purifying for sensitising agent, and typically
Produce the light power effect of the sensitising agent of aggregation poor, so as to have impact on its spectrochemical property and effect in vivo；Photosensitive
Polypeptide is introduced on agent molecule, electric charge on sensitising agent band can be made, strengthen its water solubility, by polymer functionalization, synthesized various
The macromolecule of topological structure, copolymerization, blending or the method such as hyperbranched can overcome these defects；Therefore design and synthesize with porphyrin
For the polymer and dendrimer of core are paid close attention to by more and more researchers, meanwhile, it is interior with Porphyrin and its derivative
Core, can effectively prevent the self-quenching of porphyrin kernel, therefore be expected to efficiently by the polymer due to outside topological structure
The photosensitive drug of high concentration is delivered to lesions position.
Polyaminoacid is the polymer with ordered structure synthesized with amino acid monomer that a class copies natural macromolecular,
This kind of polymer has the advantages that many upwards in cancer target：A. synthesize and modify all fairly simple, can obtain what composition determined
Compound；B. some polypeptides specifically can be combined with the acceptor in tumor tissues, and sensitising agent is transported into target cell as carrier；
C. compared with protein targeting device, sensitising agent-polypeptide conjugates molecular mass is smaller, can effectively pass through tissue, with tumour
The target position of cell optionally combine and by it is interior swallow it is intracellular；D. polypeptide coupling can change the hydrophilic-hydrophobic balance of sensitising agent,
Regulation intake in vivo and the drug metabolism characteristic such as transport；Polyaminoacid has wide potential application in terms of biotechnology
The aspect such as prospect, such as organizational project, pharmaceutical carrier, used as medicine/gene therapy vector material, more preferably situation is from this
The carrier that a little materials are obtained can selectivity by cell membrane, this require on the one hand these carriers can have it is sufficiently small
Size (such as nanoscale), on the other hand requires them by the modification of the functionalization on some surfaces to realize selective effect
Really, artificial synthesized method is used, then easily material can be modified, to meet the requirement in different use fields.
Are birdsed of the same feather flock together into the advantage of compound by polyaminoacid for this patent and the light power performance of porphyrin is combined, and being prepared for one kind can
The new polymers of light power curative effect is effectively improved, even to this day, there are an achievements in research of many correlations, and main research
Concentrate on polylysine sill and polyglutamic acid sill.
Found through the literature search to prior art, Chang-Ming Dong etc. were in 2007《Combinatorial
Chemistry&High Throughput Screening》On " Biomimetic PAMAM-Poly (the Benzyl L- that deliver
Glutamate)Amphiphiles with Multi-Armed Architecture:Synthesis,Physical
Properties and Self-Assembled Nanoparticles " (the spinning life polymethylacrylic acid-block of many arm configurations-
The synthesis of glutamic acid amphiphilic polymers, physical property and self-assembled micelle).This article proposes that the polyethylene glycol closed by one end draws
The ring-opening polymerization of caprolactone is sent out, after group is converted, generation contains end sulfydryl polymer, then with four arms of disulfide bond
Alkynes reacts, so as to prepare the PEG-PCL copolymer containing disulfide bond, but, so far, with porphyrin
For the star-like glutamic acid of core, there is not been reported.
Based on above-mentioned consideration, the content involved by this paper is concentrated mainly on the polyglutamic for light power target cancer cell
The design of acidic group new material, synthesis and performance study.
The content of the invention
It is an object of the invention to effectively improve the existing curative effect in photodynamic therapy, there is provided one kind can effectively strengthen
Optical dynamic therapy is the high molecular preparation method of star-like polyglutamic acid of core to porphyrin, and synthetic method is easy and effective, directly will
Amino Porphyrins trigger β-benzyl-Pidolidone-N- carbonyl acid anhydrides ring-opening polymerisations, then debenzylation, and operating method is easy, is expected to be applicable
In industrialized production.
The present invention is achieved by the following technical solutions, a kind of to improve the star-like poly- with porphyrin as core of optical dynamic therapy
The high molecular preparation method of glutamic acid, is carried out as steps described below：
(1) by p- 5,10,15,20- tetra- (amino) phenyl porphyrin compounds, β-benzyl-L- paddy ammonia is triggered at room temperature
The ring-opening polymerisation of acid-N- carbonyl acid anhydrides prepares the star-like poly- L- benzyl-glutamates ester with porphyrin as core, and polymerization reaction time is 24 small
When.
The room temperature refers to 20 DEG C -30 DEG C.
(amino) the phenyl porphyrins of p- 5,10,15,20- tetra- and β-benzyl-Pidolidone-N- carbonyl anhydride molar ratios
It is 1:20-1:200.
Wherein as a example by the star-like poly- L- benzyl-glutamates ester with porphyrin as core of 10 repeat units of each arm, 5,10,
(amino) the phenyl porphyrins of 15,20- tetra- are 1 with the mol ratio of b- benzyls-Pidolidone-N- carbonyl acid anhydrides:40.
(2) porphyrin is that the synthesis of the star-like polyglutamic acid of core is come to porphyrin as core by hydrobromic acid/acetic acid mixed solvent
Star-like poly- L- benzyl-glutamates ester on benzyl carry out deprotection, in 15 hours reaction time, reaction temperature is at 45 DEG C.
The hydrobromic acid/acetic acid mixed solvent is：Mass fraction containing hydrobromic acid is the glacial acetic acid solution of 40wt%.
The invention has the advantages that：
1) with p- 5 that end group is amido, 10,15,20- tetra- (amino) phenyl porphyrins trigger polymerization as core, by regulation
Rate of charge can adjust the support arm structure of polymer, so as to influence the yield of singlet oxygen.
2) porphyrin for core star-like polyglutamic acid high molecular polymer have very well it is amphipathic, can at low concentrations,
Micella is self-assembly of in water, the secondary structure of the PBLG segments of accurate synthesis can be used to be formed after adjusting the material self assembles
Nano-particle size and shape, meanwhile, the micella of formation under different PH by size tunable the characteristics of.
3) significantly improve singlet oxygen and produce ability.
4) one kind is provided simply to prepare new optical dynamic treatment of tumor cell polymer drug control release carrier
And effective approach.
Brief description of the drawings
Fig. 1 is synthetic route chart of the present invention.
Fig. 2 is that a kind of polymer prepared by the present invention produces singlet oxygen quantum yield figure.
Specific embodiment
Embodiments of the invention are elaborated below：The present embodiment is carried out under premised on technical solution of the present invention
Implement, give detailed implementation method and specific operating process, but protection scope of the present invention is not limited to following implementations
Example.
The synthetic route of the embodiment of the present invention is as shown in Figure 1.
Embodiment 1：The preparation method of the star-like glutamic acid (10 repeat units of each arm) with porphyrin as core
P- 5,10,15,20- tetra- (amino) phenyl porphyrins are initiator (50.6mg, 0.075mmol), β-benzyl-L- paddy
During propylhomoserin-N- carbonyls acid anhydrides (394mg, 3mmol) is respectively placed in through fully dry two different test tubes, sealed with turned welt plug,
Vacuum line operation vacuumizes logical nitrogen back and forth after three times, with dried N, N '-dimethyl formamide (2mL) dissolving β-benzyl-
Pidolidone-N- carbonyl acid anhydrides, until completely dissolved with two test tubes of transfer syringe needle UNICOM, p- 5 is passed through by the component of dissolving,
In 10,15,20- tetra- (amino) phenyl porphyrins, reacted 24 hours under 25 DEG C of oil baths；After the completion of reaction, rotary evaporation removes big
Partial solvent, products therefrom is dissolved with THF (5mL), the precipitation in absolute ether (50mL), after abandoning supernatant, first in room temperature
Under dried in water pump, then dried in rifle is vacuum dried at 40 DEG C, finally obtain crude product, monomer conversion is
83.4%.
300mg crude products are taken, is placed in 50mL round-bottomed flasks, 0.7mL hydrobromic acids are dissolved in 14mL ice vinegar in beaker
The glacial acetic acid solution that mass fraction containing hydrobromic acid is 40wt% is obtained in acid, round-bottomed flask is subsequently poured into, round-bottomed flask is placed in
45 DEG C of oil baths a, coreaction 15 hours is precipitated after the completion of reaction in 150mL absolute ethers, is sufficiently stirred for rear static, is discarded
Clear liquid, sediment is washed 4 times with absolute ether, finally obtains shallow green powder, yield 86.54%.
Embodiment 2：The preparation method of the star-like glutamic acid (30 repeat units of each arm) with porphyrin as core
P- 5,10,15,20- tetra- (amino) phenyl porphyrins are initiator (17.0mg, 0.025mmol), β-benzyl-L- paddy
During propylhomoserin-N- carbonyls acid anhydrides (394mg, 3mmol) is respectively placed in through fully dry two different test tubes, sealed with turned welt plug,
Vacuum line operation vacuumizes logical nitrogen back and forth after three times, with dried N, N '-dimethyl formamide (2mL) dissolving β-benzyl-
Pidolidone-N- carbonyl acid anhydrides, until completely dissolved with two test tubes of transfer syringe needle UNICOM, p- 5 is passed through by the component of dissolving,
In 10,15,20- tetra- (amino) phenyl porphyrins, reacted 24 hours under 25 DEG C of oil baths, after the completion of reaction, rotary evaporation removes big
Partial solvent, products therefrom is dissolved with THF (5mL), the precipitation in absolute ether (50mL), after abandoning supernatant, first in water pump
Middle drying, then dried in rifle is vacuum dried, crude product is finally obtained, monomer conversion is 83.4%.
300mg crude products are taken, is placed in 50mL round-bottomed flasks.0.7mL hydrobromic acids are dissolved in 14mL ice vinegar in beaker
The glacial acetic acid solution that mass fraction containing hydrobromic acid is 40wt% is obtained in acid, round-bottomed flask is subsequently poured into.Round-bottomed flask is placed in
45 DEG C of oil baths a, coreaction 15 hours is precipitated after the completion of reaction in 150mL absolute ethers, is sufficiently stirred for rear static, is discarded
Clear liquid.Sediment is washed 4 times with absolute ether, finally obtains shallow green powder, yield 86.54%.
Embodiment 3：The preparation method of the star-like glutamic acid (50 repeat units of each arm) with porphyrin as core
P- 5,10,15,20- tetra- (amino) phenyl porphyrins are initiator (10.1mg, 0.015mmol), β-benzyl-L- paddy
During propylhomoserin-N- carbonyls acid anhydrides (394mg, 3mmol) is respectively placed in through fully dry two different test tubes, sealed with turned welt plug,
Vacuum line operation vacuumizes logical nitrogen back and forth after three times, with dried N, N '-dimethyl formamide (2mL) dissolving β-benzyl-
Pidolidone-N- carbonyl acid anhydrides, until completely dissolved with two test tubes of transfer syringe needle UNICOM, p- 5 is passed through by the component of dissolving,
In 10,15,20- tetra- (amino) phenyl porphyrins, reacted 24 hours under 25 DEG C of oil baths.After the completion of reaction, rotary evaporation removes big
Partial solvent, products therefrom is dissolved with THF (5mL), the precipitation in absolute ether (50mL), after abandoning supernatant, first in room temperature
Under dried in water pump, then dried in rifle is vacuum dried at 40 DEG C, finally obtain crude product, monomer conversion is
83.4%.
300mg crude products are taken, is placed in 50mL round-bottomed flasks, 0.7mL hydrobromic acids are dissolved in 14mL ice vinegar in beaker
The glacial acetic acid solution that mass fraction containing hydrobromic acid is 40wt% is obtained in acid, round-bottomed flask is subsequently poured into, round-bottomed flask is placed in
45 DEG C of oil baths a, coreaction 15 hours is precipitated after the completion of reaction in 150mL absolute ethers.It is sufficiently stirred for rear static, discards
Clear liquid, sediment is washed 4 times with absolute ether, finally obtains shallow green powder, yield 86.54%.
Experimental example
Star-like glutamic acid with porphyrin as core produces singlet oxygen ability
The oxygen of triplet state is converted into the oxygen of singlet, single line as the porphyrin of polymer core under the exciting of visible ray
State oxygen and its active, can destroy cell tissue, cause cell death, and this feature of porphyrin is its optical dynamic therapy in tumour
In be widely used；The height of singlet oxygen yield is in the potential ability for determining porphyrin to a certain degree as sensitising agent
Size, 1,3- diphenyl isobenzofuran (DPBF) is a kind of excellent singlet oxygen agent for capturing, can quickly and singlet oxygen
Reacting is destroyed its conjugated structure, and generation colourless product does not have fluorescence property, thus can be by detecting 1,3- hexichol
Base isobenzofuran (DPBF) relative consumption to measure indirectly the ability that porphyrin produces singlet oxygen, therefore we use 1,3-
Diphenyl isobenzofuran (DPBF) determines tetraphenyl porphin by sepectrophotofluorometer respectively as singlet oxygen agent for capturing
Two kinds of different materials of quinoline and the polyglutamic acid with porphyrin as core ability that singlet oxygen is produced under the conditions of specific wavelength illumination, obtains
Fig. 2.
In figure it can be seen that, micromolecular compound p-hydroxybenzene porphyrin in illumination 2 minutes, under the fluorescence intensity of DPBF
Drop is slow, illustrates to produce substantial amounts of singlet oxygen during this period, and with the rapid association reactions of DPBF so that the fluorescence intensity of DPBF
It is greatly reduced；And the polyglutamic acid with porphyrin as core, with the increase of light application time, the fluorescence intensity of DPBF is reduced quickly, thus
Can be by the generation ability of the control singlet oxygen of light application time；Meanwhile, with tetraphenylporphyrin as reference material, compared for both single
The size of line state quantum yield finds that the polyglutamic acid singlet yield with porphyrin as core is as many as twice of tetraphenylporphyrin, because
This polyglutamic acid with porphyrin as core is a kind of new biomaterial that can be used for optical dynamic therapy cancer.
Claims (7)
1. the preparation method of a kind of star-like polyglutamic acid with porphyrin as core, it is characterised in that：With the amino porphin that end group is amino
Quinoline triggers β-benzyl-Pidolidone-N- carbonyl acid anhydrides ring-opening polymerisations, then debenzylation, obtains described star-like poly- with porphyrin as core
Glutamic acid.
2. the preparation method of a kind of star-like polyglutamic acid with porphyrin as core as claimed in claim 1, it is characterised in that：It is described
End group is 5,10,15,20- tetra- (4- aminophenyls) porphyrins for the Amino Porphyrins of amino, by changing 5,10,15,20- tetra- (4-
Aminophenyl) porphyrin and β-benzyl-Pidolidone-N- carbonyl acid anhydrides the ratio between the amount of material, can adjust with porphyrin as core
The support arm structure of star-like polyglutamic acid.
3. the preparation method of a kind of star-like polyglutamic acid with porphyrin as core as claimed in claim 1, it is characterised in that specific
Step is as follows：
(1) by 5,10,15,20- tetra- (4- aminophenyls) porphyrins trigger β-benzyl-Pidolidone-N- carbonyl acid anhydrides at room temperature
Ring-opening polymerisation prepares the star-like poly- L- benzyl-glutamates ester with porphyrin as core, and polymerization reaction time is 24 hours；
(2) porphyrin is that the synthesis of the star-like polyglutamic acid of core is come to the star with porphyrin as core by hydrobromic acid/acetic acid mixed solvent
Benzyl on the poly- L- benzyl-glutamates ester of type carries out deprotection, and in 15 hours reaction time, reaction temperature is at 45 DEG C.
4. the preparation method of a kind of star-like polyglutamic acid with porphyrin as core as claimed in claim 3, it is characterised in that：Step
Room temperature described in 1 refers to 20 DEG C -30 DEG C；(4- aminophenyls) porphyrins of the 5,10,15,20- tetra- and β-benzyl-Pidolidone-N-
Carbonyl anhydride molar ratio is 1:20-1:200.
5. the preparation method of a kind of star-like polyglutamic acid with porphyrin as core as claimed in claim 3, it is characterised in that：Step
In 2, the hydrobromic acid/acetic acid mixed solvent is：Mass fraction containing hydrobromic acid is the glacial acetic acid solution of 40wt%.
6. the preparation method of a kind of star-like polyglutamic acid with porphyrin as core as claimed in claim 3, it is characterised in that described
By 5,10,15,20- tetra- (4- aminophenyls) porphyrins, at room temperature trigger β-benzyl-Pidolidone-N- carbonyl acid anhydrides open loops
The star-like poly- L- benzyl-glutamates ester concrete technology step that polymerization is prepared with porphyrin as core is as follows：
5,10,15,20- tetra- (4- aminophenyls) porphyrins are initiator, and β-benzyl-Pidolidone-N- carbonyl acid anhydrides is respectively placed in
In through fully dry two different test tubes, sealed with turned welt plug, vacuum line operation vacuumizes logical nitrogen back and forth after three times, with dry
The DMF dissolving β-benzyl-Pidolidone-N- carbonyl acid anhydrides of dry mistake, is joined with transfer syringe needle until completely dissolved
Lead to two test tubes, the component of dissolving is passed through in 5,10,15,20- tetra- (4- aminophenyls) porphyrins, 24 are reacted under room temperature oil bath
Hour；After the completion of reaction, rotary evaporation removes most of solvent, and products therefrom is dissolved with THF, is precipitated in absolute ether, abandons
After removing supernatant, first dried in water pump, then dried in rifle is vacuum dried.
7. the star-like polyglutamic acid with porphyrin as core that prepared by preparation method as claimed in claim 1 swells preparing optical dynamic therapy
Purposes in oncocyte polymer drug control release carrier.
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