Hyaluronic acid-g-folate amphiphilic polymer and its application

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 solve the problems of nano-drug efficacy and nano-drug structure size, etc., to prolong the circulation time in the body, overcome the poor selectivity of tumor cells, and facilitate long-term stable storage

Active Publication Date: 2021-08-27
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-folate amphiphilic polymer and its application
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  • Hyaluronic acid-g-folate amphiphilic polymer and its application

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, 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 -FA), the degree of substitution...

Embodiment 2

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

[0043] Under nitrogen atmosphere, add 1 mL of DCC (109 mg, 0.53 mmol) in anhydrous DMSO (3 mL) solution of folic acid (FA, 116 mg, 0.26 mmol), stir at 30°C for 12 hours, 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 DCC (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 present invention discloses hyaluronic acid- g ‑Folic acid amphiphilic polymer and its application, the main chain is hydrophilic hyaluronic acid, and the side chain is hydrophobic folic acid, which can efficiently and stably load small molecule anticancer drugs and prolong the blood circulation time of drugs; The enrichment amount is high, reaching 12.0%ID / g. After reaching the tumor tissue, the dual-targeted nanomedicine tightly binds to the surface of tumor cells and effectively enters the tumor cells through receptor-mediated endocytosis, and then realizes The drug is released quickly, resulting in a highly effective therapeutic effect. The polymer of the present invention has good biocompatibility and degradability, and is convenient to be excreted from the body; it overcomes the shortcomings of low drug delivery efficiency, less accumulation in tumor sites, low cell endocytosis efficiency, and slow intracellular release; and the method is simple to prepare , the source of raw materials is abundant, and the obtained nanomedicine has excellent freeze-drying redispersibility, which is conducive 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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Patent Type & Authority Patents(China)
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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