Cationic polymer for co-loading drugs and genes and application of cationic polymer

Abstract

The invention discloses a cationic polymer for co-loading drugs and genes and application of the cationic polymer. A constructed cationic PCL-ss-P (GHA-co-PEGMA) polymer is rich in side chains, so that the polymer has good biocompatibility and water solubility; in addition, a shell layer is rich in hydroxy groups, which can promote transmembrane transport of a drug / gene complex and improve the transcription and expression of the genes in cells. Under the condition of higher glutathione, cracking of a main chain in the drug / gene complex is caused, and the release of drugs in polymeric micellesis caused, thereby achieving the purpose of inhibiting tumor cell proliferation. The release of the drugs and the transcription and expression of the genes can be combined to treat the lung cancer, and the drug resistance of anti-cancer drugs in the cells is effectively overcome. The cationic polymer for the co-loading drugs and genes and the application of the cationic polymer have the advantagesthat the used experimental conditions are milder, the structure of the cationic polymer is easy to control, the operation is simple, the raw materials are easy to obtain, purification is easy, and the cationic polymer is suitable for industrial production; therefore, the cationic polymer can be used as a common carrier of the anti-cancer drug and cancer suppressor genes, and has a larger market application prospect in the future.

Description

technical field

[0001] The invention belongs to the field of biomedical macromolecular materials, and in particular relates to a preparation method of a cationic polymer with reduction responsiveness and its application of co-carrying drugs and gene combinations to treat lung cancer. Background technique

[0002] Malignant tumors are a large class of diseases that seriously threaten human health. According to the 2018 Global Cancer Database (GLOBOCAN 2018 database) compiled and released by the International Agency for Research on Cancer (IARC), the annual incidence and mortality of lung cancer ranks first in the world. two. However, the incidence and mortality of lung cancer in my country continue to rise every year, and how to effectively treat cancer is an urgent problem to be solved. Currently, the commonly used treatment methods are drug chemotherapy, surgery, immunotherapy and gene therapy.

[0003] The core of gene therapy is gene delivery, which enters cells for gen...

Examples

Embodiment 1

[0070] Example 1: Synthesis of 4-cyano-4-(dithiobenzoyloxy)valeric acid-dithiodiethanol ester

[0071] First, under an inert gas atmosphere, using 4-cyano-4-(dithiobenzoyloxy)valeric acid (4-CPDB) and dithiodiethanol as raw materials, the N,N ’-Diisopropylcarbodiimide (DIC) is used as water-absorbing agent and 4-dimethylaminopyridine (DMAP) as catalyst, and 4-CPDB- ss -OH double head reagent.

[0072] The specific synthesis method is as follows: During the ventilation process, dithiodiethanol (5.46 g, 35.4 mmol), dithiodiethanol (5.46 g, 35.4 mmol), and N,N ’-Diisopropylcarbodiimide (DIC, 0.88 g, 7.0 mmol), 4-dimethylaminopyridine (DMAP, 0.214 g, 1.75 mmol), and 10 mL of dried dichloromethane (CH 2 Cl 2 ); Then use a constant pressure funnel to contain 10mL CH 2 Cl 2A solution of 4-CPDB (1.0 g, 3.5 mmol) was added dropwise into a round bottom flask. After being completely sealed, the reaction bottle and constant pressure funnel were transferred to a low temperature and...

Embodiment 2

[0074] Embodiment two: polyester chain transfer agent 4-CPDB- ss -Synthesis of PCL

[0075] Place the 50 mL branched flask equipped with a stirring bar in an oven at 120 °C to dry for at least 12 h, take it out, connect the branched flask to the double-row tube, evacuate it to room temperature with an oil pump, repeat the pumping and inflation three times, and finally fill it with nitrogen. Add 4-CPDB- ss -OH (51.3 mg, 0.122 mmol), use the toluene azeotropic method to remove the residual moisture in the initiator; after the toluene distillation is completed, add ε-CL monomer (698 mg, 4.84 mmol) and stannous octoate (Sn( Oct) 2 , 24.6 mg, 0.061 mmol). After being filled with nitrogen and completely sealed, it was transferred to an oil bath at 110 °C and continued to stir for 6 h. After the reaction was completed, the reaction flask was cooled to room temperature, and a small amount of CH was added. 2 Cl 2 Dissolve the crude product, add 2-3 drops of glacial acetic acid, s...

Embodiment 3

[0076] Embodiment three: polycaprolactone- ss -Poly(glycidyl methacrylate- co - Synthesis of Polyethylene Glycol Methacrylate) Copolymer

[0077] Dry the 50 mL round-bottomed flask and glass stopper with a stirring bar in an oven at 120 °C for 24 h, take it out, plug it with a glass stopper, and connect it to an oil pump through a latex tube. into high-purity nitrogen. During the aeration process, 4-CPDB- ss -PCL (100 mg, 0.020 mmol), azobisisobutyronitrile (AIBN, 3.2 mg, 0.020 mmol), polyethylene glycol methacrylate (PEGMA, 136.6 mg, 0.29 mmol), and glycidyl methacrylate (GMA, 282 mg, 1.98 mmol); under nitrogen atmosphere, add 8 mL of N,N - Dimethylformamide, evacuated, filled with nitrogen after repeating this three times. Stir until completely dissolved, then transfer to a 70 °C oil bath for 12 h. The reaction was terminated by rapid cooling. A dialysis bag with a molecular weight cut-off of 12,000-14,000 Da was used to dialyze the solution of the polymerization re...

technical field

[0001] The invention belongs to the field of biomedical macromolecular materials, and in particular relates to a preparation method of a cationic polymer with reduction responsiveness and its application of co-carrying drugs and gene combinations to treat lung cancer. Background technique

[0002] Malignant tumors are a large class of diseases that seriously threaten human health. According to the 2018 Global Cancer Database (GLOBOCAN 2018 database) compiled and released by the International Agency for Research on Cancer (IARC), the annual incidence and mortality of lung cancer ranks first in the world. two. However, the incidence and mortality of lung cancer in my country continue to rise every year, and how to effectively treat cancer is an urgent problem to be solved. Currently, the commonly used treatment methods are drug chemotherapy, surgery, immunotherapy and gene therapy.

[0003] The core of gene therapy is gene delivery, which enters cells for gen...

Examples

Embodiment 1

[0070] Example 1: Synthesis of 4-cyano-4-(dithiobenzoyloxy)valeric acid-dithiodiethanol ester

[0071] First, under an inert gas atmosphere, using 4-cyano-4-(dithiobenzoyloxy)valeric acid (4-CPDB) and dithiodiethanol as raw materials, the N,N ’-Diisopropylcarbodiimide (DIC) is used as water-absorbing agent and 4-dimethylaminopyridine (DMAP) as catalyst, and 4-CPDB- ss -OH double head reagent.

[0072] The specific synthesis method is as follows: During the ventilation process, dithiodiethanol (5.46 g, 35.4 mmol), dithiodiethanol (5.46 g, 35.4 mmol), and N,N ’-Diisopropylcarbodiimide (DIC, 0.88 g, 7.0 mmol), 4-dimethylaminopyridine (DMAP, 0.214 g, 1.75 mmol), and 10 mL of dried dichloromethane (CH 2 Cl 2 ); Then use a constant pressure funnel to contain 10mL CH 2 Cl 2A solution of 4-CPDB (1.0 g, 3.5 mmol) was added dropwise into a round bottom flask. After being completely sealed, the reaction bottle and constant pressure funnel were transferred to a low temperature and...

Embodiment 2

[0074] Embodiment two: polyester chain transfer agent 4-CPDB- ss -Synthesis of PCL

[0075] Place the 50 mL branched flask equipped with a stirring bar in an oven at 120 °C to dry for at least 12 h, take it out, connect the branched flask to the double-row tube, evacuate it to room temperature with an oil pump, repeat the pumping and inflation three times, and finally fill it with nitrogen. Add 4-CPDB- ss -OH (51.3 mg, 0.122 mmol), use the toluene azeotropic method to remove the residual moisture in the initiator; after the toluene distillation is completed, add ε-CL monomer (698 mg, 4.84 mmol) and stannous octoate (Sn( Oct) 2 , 24.6 mg, 0.061 mmol). After being filled with nitrogen and completely sealed, it was transferred to an oil bath at 110 °C and continued to stir for 6 h. After the reaction was completed, the reaction flask was cooled to room temperature, and a small amount of CH was added. 2 Cl 2 Dissolve the crude product, add 2-3 drops of glacial acetic acid, s...

Embodiment 3

[0076] Embodiment three: polycaprolactone- ss -Poly(glycidyl methacrylate- co - Synthesis of Polyethylene Glycol Methacrylate) Copolymer

[0077] Dry the 50 mL round-bottomed flask and glass stopper with a stirring bar in an oven at 120 °C for 24 h, take it out, plug it with a glass stopper, and connect it to an oil pump through a latex tube. into high-purity nitrogen. During the aeration process, 4-CPDB- ss -PCL (100 mg, 0.020 mmol), azobisisobutyronitrile (AIBN, 3.2 mg, 0.020 mmol), polyethylene glycol methacrylate (PEGMA, 136.6 mg, 0.29 mmol), and glycidyl methacrylate (GMA, 282 mg, 1.98 mmol); under nitrogen atmosphere, add 8 mL of N,N - Dimethylformamide, evacuated, filled with nitrogen after repeating this three times. Stir until completely dissolved, then transfer to a 70 °C oil bath for 12 h. The reaction was terminated by rapid cooling. A dialysis bag with a molecular weight cut-off of 12,000-14,000 Da was used to dialyze the solution of the polymerization re...

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