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Hyaluronic acid-g-folic acid amphiphilic polymer and application thereof

A technology of amphiphilic polymers and hyaluronic acid, which is applied in the direction of drug combinations, organic active ingredients, medical preparations of non-active ingredients, etc., can solve the problem of poor biocompatibility and biodegradability, and limit single target To address issues such as the efficacy of nano-drugs and the impact of nano-drug structure and size, to achieve the effects of prolonging blood circulation time, improving bioavailability, and overcoming the complexity of design and preparation

Active Publication Date: 2019-10-11
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this can increase the curative effect to a certain extent, on the one hand, the receptors on the cell surface are in a dynamic change process and the receptor-ligand binding is saturated, which limits the curative effect of single-targeted nano-drugs; on the other hand, it will increase Preparation cost, and may affect the structural size of nanomedicine
[0003] In addition, most of the existing nanomedicines are complex in design, poor in biocompatibility and biodegradability

Method used

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  • Hyaluronic acid-g-folic acid amphiphilic polymer and application thereof
  • Hyaluronic acid-g-folic acid amphiphilic polymer and application thereof
  • Hyaluronic acid-g-folic acid amphiphilic polymer and application thereof

Examples

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Effect test

Embodiment 1

[0040] Example 1 Synthetic polymer hyaluronic acid-folic acid (HA- g -FA) ( M nHA = 35 kDa, DS = 8.5%)

[0041] figure 1 For the example polymer HA- g -Synthetic route map of FA. To a solution of folic acid (FA, 175 mg, 0.40 mmol) in anhydrous dimethylsulfoxide (DMSO, 5 mL) was added 1.5 mL of N,N'-dicyclohexylcarbodiimide (DCC, 163 mg) under a nitrogen atmosphere. , 0.79 mmol) in DMSO, stirred at 30°C for 12 hours, then added 1 mL 4-dimethylaminopyridine (DMAP, 97 mg, 0.79 mmol) and 4 mL hyaluronic acid (HA, 200 mg, 0.53 mmol - CH 2 OH) in anhydrous DMSO solution at 30°C for 24 hours. After the reaction, hyaluronic acid-g-folate (HA-g-FA) polymer was obtained by suction filtration, dialysis, and freeze-drying, with a yield of 93%. NMR see figure 2 , 1 H NMR (D 2 O: DMSO- d 6 ): Hyaluronic acid (HA): δ (ppm) 1.86–2.01, 3.28–4.02, 4.21–4.75; Folic acid (FA): δ (ppm) 6.64, 7.63, 8.61. NMR results show that its structure is hyaluronic acid- g -Folic acid (HA- g ...

Embodiment 2

[0042] Example two Synthetic polymer HA- g -FA ( M nHA = 35 kDa, DS = 6.4%)

[0043] Under a nitrogen atmosphere, 1 mL of LDCC (109 mg, 0.53 mmol) in anhydrous DMSO (3 mL) was added to a solution of folic acid (FA, 116 mg, 0.26 mmol) in anhydrous DMSO, stirred at 30°C for 12 hours, and then Add 1 mL DMAP (64 mg, 0.53 mmol) and 4 mL hyaluronic acid (HA, 200 mg, 0.53 mmol) sequentially 2 OH) in DMSO and reacted at 30°C for 24 hours. After the reaction, hyaluronic acid- g - Folic acid (HA-g-FA) polymer in 93% yield. NMR results show that its structure is HA- g -FA, wherein the degree of substitution (DS) of FA is 6.4%.

Embodiment 3

[0044] Example three synthetic polymer HA- g -FA ( M nHA = 35 kDa, DS = 11.1%)

[0045] Under a nitrogen atmosphere, 2 mL of LDCC (218 mg, 1.06 mmol) in anhydrous DMSO (6 mL) was added to a solution of folic acid (FA, 232 mg, 0.52 mmol) in anhydrous DMSO, stirred at 30°C for 12 hours, and then Add 1 mL DMAP (128 mg, 1.06 mmol) and 4 mL hyaluronic acid (HA, 200 mg, 0.53 mmol -CH 2 OH) in anhydrous DMSO solution at 30°C for 24 hours. After the reaction, hyaluronic acid- g -Folic acid (HA- g -FA) polymer in 93% yield. NMR results show that its structure is HA- g -FA, wherein the degree of substitution (DS) of folic acid is 11.1%.

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Abstract

The invention discloses a hyaluronic acid-g-folic acid amphiphilic polymer and application thereof. By a main chain namely hydrophilic hyaluronic acid and a side chain namely hydrophobic folic acid, efficient and stable loading of a micromolecular anticancer drug can be realized, and the blood circulation time of the drug is prolonged; high gathering amount at a tumor part is realized and reaches12.0%ID / g, and after reaching tumor tissues, a dual-targeted nano drug is closely combined with the tumor cell surface and effectively enters tumor cells under the action of receptor mediated endocytosis to realize quick release of the drug in the tumor cells, so that an efficient therapeutic effect is achieved. The polymer is high in biocompatibility and degradability and can be excreted conveniently; defects of low drug loading efficiency, small gathering amount at the tumor parts, low cell endocytosis efficiency, low release speed in cells and the like are overcome. In addition, a preparation method is simple, raw material sources are rich, and the nano drug is excellent in lyophilization redispersibility and beneficial to large-scale production and application.

Description

technical field [0001] The invention belongs to the technical field of polymer nanomedicine, and relates to a biocompatible and biodegradable polymer material based on pure natural substances and its application, in particular to a hyaluronic acid amphiphilic polymer grafted with folic acid, As well as the dual-targeted anti-tumor nano-medicine and its application prepared therefrom. Background technique [0002] Polymer nanoparticles as anticancer drug carriers have significant advantages in cancer therapy, however, the distribution of existing polymer nanomedicines in tumors is generally 1-5% ID / g, resulting in poor bioavailability of drugs. Researchers bond targeting molecules on the surface of nanomedicines to guide nanomedicines to specifically bind target cells and mediate their endocytosis, expecting to achieve active targeted therapy, thereby improving efficacy and reducing systemic toxicity. Although this can increase the curative effect to a certain extent, on the...

Claims

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Application Information

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IPC IPC(8): C08B37/08A61K9/19A61K31/704A61K47/22A61K47/36A61P35/00
CPCA61K9/19A61K31/704A61K47/22A61K47/36A61P35/00C08B37/0072
Inventor 孙欢利鄢雨钟志远
Owner SUZHOU UNIV
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