CN108456298B

CN108456298B - Soluble asymmetric phthalocyanine modified amphiphilic polymer and synthesis method thereof

Info

Publication number: CN108456298B
Application number: CN201810454825.9A
Authority: CN
Inventors: 高波; 段潜; 郭善雷; 李东霓; 李艳辉; 张昊天
Original assignee: Changchun University of Science and Technology
Current assignee: Changchun University of Science and Technology
Priority date: 2018-05-15
Filing date: 2018-05-15
Publication date: 2020-06-05
Anticipated expiration: 2038-05-15
Also published as: CN108456298A

Abstract

An amphiphilic organic polymer modified by asymmetric phthalocyanine, which is an organic polymer material, is characterized in that: the hydrophilic moiety is polyethylene glycol monomethyl ether; the lipophilic part is polylactic acid and phthalocyanine which are connected by a disulfide bond. The amphiphilic molecule can be used for treating cancers, and belongs to the field of organic polymers. The invention firstly synthesizes soluble asymmetric zinc phthalocyanine: then initiating the ring-opening polymerization of L-lactide by utilizing the polyethylene glycol monomethyl ether to form a block polymer; the two are connected by disulfide bonds to form an amphiphilic polymer. When the polymer is in an aqueous solution, the polymer can be self-assembled into a micelle, and the inside of the micelle can be wrapped with chemotherapeutic drugs to be used as drug carriers; the polymer itself may also respond passively to cancer cells, which is a photodynamic therapy; the polymer can be used as a combined treatment drug of chemotherapy and photodynamic therapy.

Description

Soluble asymmetric phthalocyanine modified amphiphilic polymer and synthesis method thereof

Technical Field

The invention belongs to the field of materials, and particularly relates to an amphiphilic polymer modified by soluble asymmetric phthalocyanine and a synthesis method thereof.

Technical Field

As cancer becomes one of the greatest threats to the health and safety of human life, the search for effective cancer treatment means has become a major research focus. Compared with the traditional chemotherapy means, the photodynamic therapy has low biological toxicity at present and is strongly concerned by people. Photosensitizers have been the focus of research as an important component of photodynamic therapy. The phthalocyanine is a very outstanding second-generation photosensitizer, but because of its solubility, and its limited use, it is desirable to modify a phthalocyanine with good solubility and easy modification to facilitate the modification of the photosensitizer. In this patent, a means of extending the carbon chain on the phthalocyanine molecule ring is designed to improve the solubility of the phthalocyanine, making it advantageous for its further modification. The phthalocyanine in the patent is a soluble asymmetric phthalocyanine, and the phthalocyanine and a segmented copolymer polyethylene glycol monomethyl ether-polylactic acid are combined to form an amphiphilic polymer by utilizing a disulfide bond with passive targeting, so that the phthalocyanine can be further self-assembled to form micelles, and the phthalocyanine can be used for self-treating cancers and can also be used for loading chemotherapeutic drugs to treat the cancers in a synergistic manner.

Disclosure of Invention

The method utilizes a method for increasing a carbon chain to modify a phthalocyanine precursor, then asymmetric phthalocyanine with excellent solubility is formed, and a disulfide bond is combined with a block copolymer polyethylene glycol monomethyl ether-polylactic acid (mPEG-b-PLA) to form an amphiphilic phthalocyanine polymer which can be self-assembled to form micelle particles.

In the implementation method, 4-decyloxyphthalitrile and 4- [2- (2-bromoethoxy-pyran) ] phthalonitrile are used for synthesizing soluble asymmetric phthalocyanine, and the structure of the soluble asymmetric phthalocyanine is as follows:

in the embodiment, polyethylene glycol monomethyl ether is used as an initiator, the hydroxyl group of the polyethylene glycol monomethyl ether can initiate lactide to carry out ring-opening polymerization under anhydrous and oxygen-free conditions to obtain a block polymer mPEG-b-PLA, the polymerization degree is controlled between 100-140, and the structure is as follows:

in an embodiment, mPEG-b-PLA and asymmetric phthalocyanine are combined by a disulfide bond to form an amphiphilic organic polymer, which has the structure:

advantageous effects

Compared with the prior art, the technical scheme of the invention can obtain the following beneficial effects: the amphiphilic polymer modified by the asymmetric phthalocyanine has good biocompatibility and low biological toxicity, and can be used as a chemotherapeutic drug carrier to enhance the treatment effect of cancer due to the capability of forming micelles, so that the functionality of the amphiphilic polymer is further enhanced, and the toxic and side effects of the amphiphilic polymer are much smaller than those of a pure chemotherapeutic drug.

Drawings

FIG. 1 is a scheme showing the synthesis scheme of ZnPC-OH

FIG. 2 is a scheme showing the synthesis scheme of ZnPC-S-S-COOH

FIG. 3 is a synthetic route scheme for mPEG-b-PLA

FIG. 4 is a scheme showing the synthesis scheme of mPEG-b-PLA-S-S-ZnPC

FIG. 5 is nuclear magnetic hydrogen spectrum of mPEG-b-PLA-S-S-ZnPC

FIG. 6 is a scanning electron microscope image of micelle mPEG-b-PLA-S-S-ZnPC

Detailed description of the invention

The soluble asymmetric phthalocyanine amphiphilic block polymer polyethylene glycol monomethyl ether-polylactic acid (mPEG-b-PLA-S-S-ZnPC) has different affinities for aqueous solution, so that nano micelle particles can be formed by self-assembly.

Synthesis of 3-ethoxyhydroxy-10, 17, 24-tridecyloxy zinc phthalocyanine (ZnPC-OH)

The synthetic route of 3-ethoxyhydroxy-10, 17, 24-tridecyloxy zinc phthalocyanine (ZnPC-OH) is shown in figure 1. Taking a single-neck round-bottom flask cooled after high-temperature treatment, adding 4-decyloxyphthalitrile (0.568g, 2mmol) and 4- [2- (2-ethoxypyran) ] phthalodinitrile (0.182g,0.67mmol), then adding 10ml of n-amyl alcohol, reacting for 24h, removing a protecting group, and purifying to obtain a blue-green product of 42mg with the yield of 5.8%. Elementary Analysis C, 69.35; h, 7.19; and N, 10.02.

Synthesis of ZnPC-S-S-COOH

The synthetic route of ZnPC-S-S-COOH is shown in figure 2. ZnPC-OH (110.6mg, 0.1mmol) and 3,3' -dithiodipropionic acid (168mg, 0.8mmol) were added to 5mL of DCM under the action of 4-Dimethylaminopyridine (DMAP) and Dicyclohexylcarbodiimide (DCC). Stir at room temperature overnight. And performing DCM extraction and water washing, evaporating to remove DCM, and separating and purifying the crude product to obtain ZnPc-S-S-COOH, 45mg and the yield of 34.7%. Elementary Analysis C, 64.72; h, 6.83; and N, 8.63.

Synthesis of block copolymer polyethylene glycol monomethyl ether-polylactic acid (mPEG-b-PLA)

The synthetic route of the block copolymer mPEG-b-PLA is shown in FIG. 3. In N₂Under the condition of (1), 30ml of toluene is added into a flask, 1g of mPEG-5000 and 1.73g of L-lactide are added into a two-neck flask, and after being uniformly stirred, 50 mu L of stannous octoate is added and placed in an oil bath for reaction for 10 hours. After completion, a white solid was precipitated and dried in vacuo to give 2.7g of a diblock polymer. The obtained polymer was analyzed by gel permeation chromatography using polystyrene as a standard reference substance, and the number average molecular weight of the polyethylene glycol monomethyl ether-polylactic acid was 1.65 ten thousand.

Synthesis of mPEG-b-PLA-S-S-ZnPC

The synthetic route of mPEG-b-PLA-S-S-ZnPC is shown in FIG. 4, ZnPC-S-S-COOH (60mg, 0.046mmol), mPEG-b-PLA (450mg, 0.03mmol) was added to 20ml of dichloromethane, and then stirred overnight at room temperature under the action of 4-Dimethylaminopyridine (DMAP) and Dicyclohexylcarbodiimide (DCC). After removal of impurities, dialysis was performed to obtain 198mg of the final product in 41% yield. The obtained polymer was analyzed by gel permeation chromatography using polystyrene as a standard reference substance to obtain polylactic acid having a number average molecular weight of 1.8 ten thousand. The nuclear magnetic hydrogen spectrum diagram in figure 5 shows that the chemical position of 7.5-9.5 ppm corresponds to the shift of proton hydrogen on phthalocyanine ring, 5.16ppm corresponds to the proton peak of PLA repeating unit methylene, and 3.64ppm corresponds to the proton peak of mPEG component methylene, so that the product with good advantages and purposes is proved. It can be seen from the sem picture of fig. 6 that the micelle particle formation tends to be spherical, which is consistent with the original design concept.

The above examples are only illustrative of the preferred embodiments of the present invention and the core idea thereof, it should be noted that a person skilled in the art could make several improvements and modifications to the present invention without departing from the principle of the present invention, and these improvements and modifications also fall into the protection scope of the claims of the present invention.

Claims

1. An amphiphilic organic high molecular polymer modified by asymmetric phthalocyanine, which is characterized in that: the hydrophilic moiety is polyethylene glycol monomethyl ether; the lipophilic part is polylactic acid and phthalocyanine which are connected by a disulfide bond to form an amphiphilic polymer; the compound preparation has the functions of photodynamic therapy and serving as a chemotherapeutic drug carrier, can reduce the toxicity to organisms when being used as the photodynamic therapy, and can also enhance the treatment effect by carrying chemotherapeutic drugs to carry out combined treatment.

2. The method for synthesizing amphiphilic organic high molecular polymer modified by asymmetric phthalocyanine according to claim 1, characterized in that 3-ethoxy hydroxyl-10, 17, 24-tridecyloxy phthalocyanine zinc is prepared by solvothermal method, and carboxyl phthalocyanine with disulfide-modified end is generated by esterification and 3,3' -dithiodipropionic acid ZnPC-S-S-COOH; synthesizing a block polymer polyethylene glycol monomethyl ether-polylactic acid mPEG-b-PLA, and grafting ZnPC-S-S-COOH to the polymer by utilizing ester bonds to finally obtain the amphiphilic organic high molecular polymer modified by the asymmetric phthalocyanine.

3. The amphiphilic organic high molecular polymer modified by asymmetric phthalocyanine according to claim 1 can be used as a photodynamic therapy material and a drug carrier to enhance the effect of cancer therapy, and more particularly, the amphiphilic organic high molecular polymer has passive targeting to reduce biological toxicity.