CN108456298A - A kind of amphipathic nature polyalcohol and synthetic method of the modification of solubility unsymmetrical phthalocyanine - Google Patents

A kind of amphipathic nature polyalcohol and synthetic method of the modification of solubility unsymmetrical phthalocyanine Download PDF

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CN108456298A
CN108456298A CN201810454825.9A CN201810454825A CN108456298A CN 108456298 A CN108456298 A CN 108456298A CN 201810454825 A CN201810454825 A CN 201810454825A CN 108456298 A CN108456298 A CN 108456298A
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polymer
phthalocyanine
znpc
monomethyl ether
glycol monomethyl
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CN108456298B (en
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高波
段潜
郭善雷
李东霓
李艳辉
张昊天
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Changchun University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/91—Polymers modified by chemical after-treatment
    • C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
    • 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
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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
    • 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
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    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes

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Abstract

A kind of amphipathic organic polymer modified with unsymmetrical phthalocyanine, is organic polymer material, it is characterised in that：Hydrophilic segment is poly glycol monomethyl ether；Oleophilic moiety is polylactic acid and phthalocyanine, and the two is connected using cystine linkage.The amphipathic molecule can be used for the treatment of cancer, belong to organic polymer field.The asymmetric ZnPc of present invention synthesizing soluble first：Then it utilizes poly glycol monomethyl ether to cause L lactide ring-opening polymerisations and forms block polymer；The two is connected to form amphiphatic polymer using cystine linkage.But it can be self-assembled into as micella when polymer is in aqueous solution, inside can wrap up chemotherapeutics as pharmaceutical carrier；Polymer itself can also make cancer cell by dynamic response, this is optical dynamic therapy；Generally speaking this polymer can be as the combination therapy drug of chemotherapy and optical dynamic therapy.

Description

A kind of amphipathic nature polyalcohol and synthetic method of the modification of solubility unsymmetrical phthalocyanine
Technical field
The invention belongs to Material Field, more particularly to a kind of amphipathic nature polyalcohol modified by soluble unsymmetrical phthalocyanine and Synthetic method, the amphipathic nature polyalcohol can be self-assembled into aqueous solution as micella particle.
Technical background
As cancer becomes one of the biggest threat of people's life and health safety, the means of effective treating cancer have been found Emphasis through being studied as people.At present compared to traditional chemotherapy means, optical dynamic therapy has bio-toxicity low, by people Close attention.It is always the emphasis of people's research in quick dose of Photodynamic Therapy as important component part.Phthalocyanine As the outstanding person in second generation photosensitizer, it is constantly subjected to the favor of people, but due to its deliquescent problem, so that it Purposes be restricted, thus we expect to make the phthalocyanine that a kind of dissolubility is easy to well modification, in order to this light Quick dose is modified.In this patent, devise a kind of improving phthalocyanine to the means for carrying out increasing carbochain on Phthalocyanine ring Dissolubility, so that it is conducive to the further modification to it.Phthalocyanine in this patent is a kind of unsymmetrical phthalocyanine of solubility, Phthalocyanine is combined to form amphiphilic with block copolymer polyethylene glycol monomethyl ether-polylactic acid using the cystine linkage with passive targeting Property polymer, may further be self-assembly of micella, can also load chemotherapeutics synergistic treatment with itself treating cancer Cancer.
Invention content
The present invention is modified phthalocyanine presoma using the method for increasing carbochain, then forms splendid not right of dissolubility Claim phthalocyanine, combined using cystine linkage and block copolymer polyethylene glycol monomethyl ether-polylactic acid (mPEG-b-PLA), is formed amphipathic Phthalocyanine polymer can be self-assembly of micella particle.
In implementation, synthesized using 4- decyloxies phthalic nitrile and 4- [2- (2- bromine oxethyls-pyrans)] phthalic nitrile Soluble unsymmetrical phthalocyanine, structure are：
In embodiment, using poly glycol monomethyl ether as initiator, alcoholic extract hydroxyl group can draw under the conditions of anhydrous and oxygen-free It sends out lactide and carries out ring-opening polymerisation, obtain block polymer mPEG-b-PLA, the degree of polymerization controls between 100-140, structure For：
In embodiment, mPEG-b-PLA is combined to form amphiphilic organic polymer using cystine linkage with unsymmetrical phthalocyanine Object, structure are：
Advantageous effect
Technical solutions according to the invention compared with prior art, can obtain following advantageous effect：The present invention provides A kind of amphipathic nature polyalcohol and preparation method thereof of solubility unsymmetrical phthalocyanine modification, this amphiphilic modified by unsymmetrical phthalocyanine Property polymer, biocompatibility is good, bio-toxicity is low, and micella ability can be formed due to having, and can be used for chemotherapeutics Carrier enhances the therapeutic effect of cancer, and while making its functional further enhancing, toxic side effect is smaller than chemotherapy drug Very much.
Description of the drawings
Fig. 1 is the synthetic route chart of ZnPC-OH
Fig. 2 is the synthetic route chart of ZnPC-S-S-COOH
Fig. 3 is the synthetic route chart of mPEG-b-PLA
Fig. 4 is the synthetic route chart of mPEG-b-PLA-S-S-ZnPC
Fig. 5 is the nucleus magnetic hydrogen spectrum figure of mPEG-b-PLA-S-S-ZnPC
Fig. 6 is the scanning electron microscope (SEM) photograph of micella mPEG-b-PLA-S-S-ZnPC
Specific implementation method
The soluble unsymmetrical phthalocyanine Amphipathilic block polymer polyethylene glycol monomethyl ether-polylactic acid (mPEG-b- of the present invention PLA-S-S-ZnPC) having has aqueous solution different affinity, therefore can be self-assembly of nano-micelle particle, this is poly- Close object the advantages of be to be not restricted to the optical dynamic therapy of itself, can also combined chemotherapy drug such as adriamycin synergistic treatment cancer Disease.
The synthesis of three decyloxy Phthalocyanine Zincs (ZnPC-OH) of 3- ethyoxyl hydroxyls -10,17,24-
The synthetic route of three decyloxy Phthalocyanine Zincs (ZnPC-OH) of 3- ethyoxyl hydroxyls -10,17,24- is shown in Fig. 1.It learns from else's experience high-temperature process 4- decyloxies phthalic nitrile (0.568g, 2mmol) and 4- [2- (2- ethyoxyls pyrans)] is added in the single necked round bottom flask of postcooling Phthalic nitrile (0.182g, 0.67mmol), is then added 10ml n-amyl alcohols, and reaction for 24 hours, removes protecting group, is using purification Blue-green product 42mg, yield 5.8% can be obtained.Elemental Analysis:C,69.35；H,7.19；N,10.02.
The synthesis of ZnPC-S-S-COOH
The synthetic route of ZnPC-S-S-COOH is shown in Fig. 2.By ZnPC-OH (110.6mg, 0.1mmol) and 3,3'- dithio dipropyls Sour (168mg, 0.8mmol) is added in 5mL DCM, 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCC) Under effect.It is stirred at room temperature overnight.DCM extractions and water washing are recycled, after evaporation removes DCM, crude product is carried by separation After pure, ZnPc-S-S-COOH, 45mg, yield 34.7% are obtained.Elemental Analysis:C,64.72；H,6.83；N, 8.63。
The synthesis of block copolymer polyethylene glycol monomethyl ether-polylactic acid (mPEG-b-PLA)
The synthetic route of block copolymer mPEG-b-PLA is shown in Fig. 3.In N2Under conditions of, 30ml toluene is added in flask, then 1g mPEG-5000 and 1.73gL- lactides are added in two mouth flask, 50 μ L stannous octoates is stirring evenly and then adding into, is placed in 10h is reacted in oil bath.White solid is settled to obtain after terminating, vacuum drying obtains bi-block copolymer 2.7g.With polystyrene For marker, obtained polymer is analyzed with gel permeation chromatography, obtains polyethylene glycol monomethyl ether-polylactic acid Number-average molecular weight is 1.65 ten thousand.
The synthesis of mPEG-b-PLA-S-S-ZnPC
The synthetic route of mPEG-b-PLA-S-S-ZnPC as shown in figure 4, by ZnPC-S-S-COOH (60mg, 0.046mmol), MPEG-b-PLA (450mg, 0.03mmol) is added to 20ml dichloromethane, then in 4-dimethylaminopyridine (DMAP) and two rings Under the action of hexyl carbodiimide (DCC), it is stirred at room temperature overnight.After removing impurity therein, obtained most using dialysis Whole product 198mg, yield 41%.Using polystyrene as marker, with gel permeation chromatography to obtained polymer into Row analysis, the number-average molecular weight for obtaining polylactic acid are 1.8 ten thousand.In chemical potential 7.5~9.5ppm phases from the nucleus magnetic hydrogen spectrum figure of Fig. 5 The corresponding displacement for proton hydrogen on phthalocyanine ring, corresponds to the proton peak of PLA repetitive unit methylene at 5.16ppm, at 3.64ppm Corresponding mPEG component methene protons peak, to prove out with strong point purpose product.It can be with from the scanning electron microscopic picture of Fig. 6 Find out that the formation of micella particle tends to be spherical, this is consistent with initial design philosophy.
The explanation of above example is only the preferred embodiments of the invention and its core concept, it is noted that for this For the those of ordinary skill of technical field, without departing from the principle of the present invention, the present invention can also be carried out several Improvement and modification, these improvement and modification are also fallen within the protection scope of the claims of the present invention.

Claims (3)

1. a kind of amphipathic organic high molecular polymer modified with unsymmetrical phthalocyanine, it is characterised in that：Hydrophilic segment is poly- second Glycol monomethyl ether；Oleophilic moiety is polylactic acid and phthalocyanine, and the two is connected using cystine linkage, forms amphiphilic polymer.It is simultaneous Have optical dynamic therapy and the effect as chemotherapeutics carrier, the poison to organism can be reduced when itself is as optical dynamic therapy Property, therapeutic effect can also be enhanced by loading chemotherapeutics come combination therapy.
2. amphipathic organic high molecular polymer preparation method according to claim 1, which is characterized in that use solvent-thermal method 3- ethyoxyl hydroxyls -10,17 are prepared, tri- decyloxy Phthalocyanine Zincs of 24-, by esterification and 3, the reaction of 3 ＇-dithiodipropionic acids generates The carboxyl phthalocyanine (ZnPC-S-S-COOH) that end is modified by disulphide；The poly- breast of block polymer synthesis poly glycol monomethyl ether- ZnPC-S-S-COOH, is grafted on polymer using ester bond and finally obtains amphiphilic organic high score by sour (mPEG-b-PLA) Sub- polymer.
3. amphiphilic organic high molecular polymer according to claim 2, itself can be as the material of optical dynamic therapy Material, also can be used as pharmaceutical carrier, more worth it is to be noted that its own is with passive target to enhance the effect for the treatment of cancer Tropism reduces bio-toxicity.
CN201810454825.9A 2018-05-15 2018-05-15 Soluble asymmetric phthalocyanine modified amphiphilic polymer and synthesis method thereof Expired - Fee Related CN108456298B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110960686A (en) * 2019-12-26 2020-04-07 中国医学科学院生物医学工程研究所 Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy
CN111040180A (en) * 2020-01-15 2020-04-21 重庆大学 Biological cascade reaction type photodynamic integrated biopolymer and preparation method and application thereof
CN111303167A (en) * 2020-03-30 2020-06-19 Tcl华星光电技术有限公司 Color development material, optical filter and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103435639A (en) * 2013-08-26 2013-12-11 福州大学 Axial nucleoside asymmetrically-modified silicon phthalocyanine and preparation method and application thereof
CN105348458A (en) * 2015-08-03 2016-02-24 长春理工大学 Methoxy polyethylene glycol-poly-N-isopropyl acrylamide-metal tetramino phthalocyanine and preparation method therefor
JP6347684B2 (en) * 2014-07-07 2018-06-27 京セラ株式会社 Thermosetting resin composition for semiconductor bonding and semiconductor device

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103435639A (en) * 2013-08-26 2013-12-11 福州大学 Axial nucleoside asymmetrically-modified silicon phthalocyanine and preparation method and application thereof
JP6347684B2 (en) * 2014-07-07 2018-06-27 京セラ株式会社 Thermosetting resin composition for semiconductor bonding and semiconductor device
CN105348458A (en) * 2015-08-03 2016-02-24 长春理工大学 Methoxy polyethylene glycol-poly-N-isopropyl acrylamide-metal tetramino phthalocyanine and preparation method therefor

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110960686A (en) * 2019-12-26 2020-04-07 中国医学科学院生物医学工程研究所 Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy
CN111040180A (en) * 2020-01-15 2020-04-21 重庆大学 Biological cascade reaction type photodynamic integrated biopolymer and preparation method and application thereof
CN111040180B (en) * 2020-01-15 2021-12-07 重庆大学 Biological cascade reaction type photodynamic integrated biopolymer and preparation method and application thereof
CN111303167A (en) * 2020-03-30 2020-06-19 Tcl华星光电技术有限公司 Color development material, optical filter and preparation method thereof

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