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Acid-sensitive doxorubicin prodrug based on zwitterion and folic acid targeting and its preparation method and application

A zwitterion and folic acid targeting technology, which can be used in pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc. It can solve the problems of toxic side effects of healthy tissues, poor drug targeting, and poor water solubility

Active Publication Date: 2020-05-22
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Clinically used antineoplastic drugs, such as doxorubicin, paclitaxel, camptothecin, etc., are all low molecular weight compounds. Due to their poor water solubility, fast blood clearance, poor drug targeting, and relatively large toxic and side effects on healthy tissues, Thus limiting the application of these chemotherapeutic small molecule drugs

Method used

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  • Acid-sensitive doxorubicin prodrug based on zwitterion and folic acid targeting and its preparation method and application
  • Acid-sensitive doxorubicin prodrug based on zwitterion and folic acid targeting and its preparation method and application
  • Acid-sensitive doxorubicin prodrug based on zwitterion and folic acid targeting and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Embodiment one: the synthesis of methacrylate polyethylene glycol p-aldehyde benzoate (PEGMA-BZ)

[0083] First, under the condition of inert gas atmosphere, methacrylate polyethylene glycol (PEGMA-OH) and p-aldehyde benzoic acid were used as raw materials to N, N' -Diisopropylcarbodiimide is used as water absorbing agent and 4-dimethylaminopyridine is used as catalyst, and methacrylate polyethylene glycol p-aldehyde benzoate (PEGMA-BZ) is obtained through esterification reaction. The specific synthesis method is as follows: put a 250mL branched round bottom flask with a stirrer in an oven at 120°C for 24 h, take it out, plug it with a glass stopper, connect it to an oil pump through a latex tube, and evacuate the branched round bottom flask to room temperature. , and then into high-purity nitrogen. During aeration, polyethylene glycol methacrylate (10.0 g, 0.02 mol) and p-aldehyde benzoic acid (6.0 g, 0.04 mol) were added, and 100 mL of dried tetrahydrofuran (THF ) ...

Embodiment 2

[0085] Embodiment two: poly (2-methacryloyloxyethyl phosphorylcholine- co -Synthesis of methacrylate polyethylene glycol p-aldehyde benzoate) copolymer

[0086] 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 aeration, (4-cyanopentanoic acid) trithioacetate (CEP) (10 mg, 0.038 mmol), methacrylate polyethylene glycol p-aldehyde benzoate (1.90 g, 3.04 mmol) and 2-methacryloyloxyethylphosphorylcholine (1.12 g, 3.80 mmol); add 16 mL of dimethyl sulfoxide and deionized water to the branched flask (V / V=1: 1) Mix the solution, then pass high-purity nitrogen gas, vacuumize, repeat this three times and then fill with nitrogen gas. Stir until completely dissolved, then transfer to a 70°C oil bath to react for 12 h.

[0087] The reaction was terminated by rapid cooling. A dialysis bag with a molecular...

Embodiment 3

[0088] Embodiment three: poly (2-methacryloyloxyethyl phosphorylcholine- co -Synthesis of methacrylate polyethylene glycol p-aldehyde benzoate) prodrug

[0089] Add P(MPC- co -PEGMA-BZ) (150 mg, 0.0025 mmol), doxorubicin hydrochloride (80 mg, 0.147 mmol) and 0.5 mL of triethylamine, then add 10 mL of the same amount of dimethyl sulfoxide and deionized water ( V / V=1: 1), after ultrasonication for 10 min, transfer to 30°C oil bath for 48 h. After the reaction is over, dialyze with ultrapure water for 72 hours, and use ammonia water to adjust the pH of the dialyzed aqueous solution to alkaline. fracture. Finally, the solution in the dialysis bag was freeze-dried to obtain a dark red polymer-doxorubicin prodrug called P(MPC- co -PEGMA-BZ)- g -DOX. The productive rate is 78.3%, and the proton nuclear magnetic resonance spectrum figure of product is shown in image 3 .

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Abstract

The invention discloses zwitterions-based folic-acid-targeted acid-sensitive adriamycin prodrug and a preparation method and application. Polyamphoteric polymer prodrug FA-P(MPC-co-PEGMA-BZ)-g-DOX hashigh water solubility, stability and biocompatibility. Structure of poly(2-methacyloyl ethyl phosphocholine) is similar to that of cytomembrane, thereby being conducive to transmembrane transport ofpolymer prodrug micelle, endocytosis of the polymer prodrug micelle is promoted, and utilization rate of the prodrug micelle is increased. In subacid environment of a tumor part, Schiff base breaks tomake the polymer prodrug micelle to quickly release adriamycin original drug so as to achieve the objective of inhibiting tumor cell proliferation. Adopted experimental conditions are mild, and the preparation method is simple in operation, easy-to-obtain in raw material, easy to purify and suitable for industrial production. Therefore, the prodrug can be used as irritation-sensitive antitumor prodrug and has great market application prospect in the future.

Description

technical field [0001] The invention belongs to the field of biomedical polymer materials, and in particular relates to an acid-sensitive doxorubicin prodrug targeted by zwitterions and folic acid, a preparation method thereof and an application thereof as a prodrug. Background technique [0002] According to the 2015 Cancer Survey Report in my country, the number of new cancer cases and deaths in China in 2015 were 4.292 million and 2.814 million, which is equivalent to an average of 12,000 new cancer cases and 7,500 cancer deaths per day. In recent years, many scientific researchers have devoted themselves to researching drugs for the treatment of cancer. [0003] At present, the methods of clinical treatment of cancer mainly include surgery, radiotherapy, chemotherapy and [0004] Surgical treatment can only be used for the early and mid-term treatment of solid tumors with definite tumor sites, but has little effect on metastatic tumors and advanced tumors. Radiotherapy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/704A61K47/54A61K47/58A61K47/60A61K47/69A61P35/00C08F283/06C08F230/02C08F8/32
CPCA61K31/704A61K47/545A61K47/58A61K47/60A61K47/6907A61P35/00C08F8/32C08F283/065C08F230/02
Inventor 倪沛红李磊何金林张明祖
Owner SUZHOU UNIV
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