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Hyaluronic acid derivatized maytansinoid prodrug, its preparation method and its application in the preparation of tumor targeting therapy drugs

A technology of hyaluronic acid and maytansine, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve problems such as damage and interstitial lung disease, tissue damage, patient pain, etc., and achieve the preservation of anti-tumor activity, Maintain medicinal properties and avoid harsh effects of reaction conditions

Active Publication Date: 2019-02-19
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are obvious deficiencies in these treatment methods: during the treatment process, it will cause irreversible damage to the normal tissues of the body, produce serious toxic and side effects, and bring great pain to patients.
Trastuzumab-maytansine antibody conjugate (T-DM1) has been approved by the FDA for the treatment of advanced HER2-positive breast cancer in 2013, but in addition to production and cost issues, T-DM1 may also cause some Adverse effects such as nausea, musculoskeletal pain, hepatotoxicity, cardiac damage, and interstitial lung disease

Method used

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  • Hyaluronic acid derivatized maytansinoid prodrug, its preparation method and its application in the preparation of tumor targeting therapy drugs
  • Hyaluronic acid derivatized maytansinoid prodrug, its preparation method and its application in the preparation of tumor targeting therapy drugs
  • Hyaluronic acid derivatized maytansinoid prodrug, its preparation method and its application in the preparation of tumor targeting therapy drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Synthesis of hyaluronic acid derivatized maytansine prodrug (HA-SS-DM1) ( M nHA =35 kDa, DM1% =20 wt.%)

[0038] First, aminodithiopyridine hydrochloride (PDA·HCl) (34.7 mg, 0.156 mmol) was added to hyaluronic acid (HA) (400 mg, 1.04 mmol carboxyl) aqueous solution (20 mL) at room temperature and the whole solution was The pH was adjusted to 6.5, and 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM) (57.51 mg, 0.208mmol) was added thereto at 35 After stirring and reacting at ℃ for 24 hours, it was dialyzed and freeze-dried to obtain hyaluronic acid-dithiopyridine (HA-SS-Py). The product yield was 85%. NMR results showed that its structure was hyaluronic acid-dithiopyridine (HA-SS-Py), and the degree of substitution (DS) of the dithiopyridine functional group (-SS-Py) was 6%. NMR see image 3 , 1 H NMR (D 2 O): Hyaluronic acid (HA): δ (ppm) 1.86-2.01, 3.28-4.02, and 4.21-4.75; Dithiopyridine functional group (-SS-Py): δ (ppm) 2.90 (...

Embodiment 2

[0040] Example 2 Synthesis of hyaluronic acid derivatized maytansine prodrug (HA-SS-DM1) ( M nHA =35 kDa, DM1%=26 wt.%)

[0041] First, aminodithiopyridine hydrochloride (PDA•HCl) (53 mg, 0.24 mmol) was added to hyaluronic acid (HA) (400 mg, 1.04 mmol carboxyl) aqueous solution (20 mL) at room temperature and the whole solution The pH was adjusted to 6.5, and 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM) (86.3 mg, 0.316mmol) was added thereto at 35 After stirring and reacting at ℃ for 24 hours, it was dialyzed and freeze-dried to obtain hyaluronic acid-dithiopyridine (HA-SS-Py). The product yield was 85%. NMR results showed that its structure was hyaluronic acid-dithiopyridine (HA-SS-Py), and the degree of substitution (DS) of the dithiopyridine functional group (-SS-Py) was 8.5%.

[0042] Under nitrogen protection, HA-SS-Py (100 mg, 40.6 micromole dithiopyridine functional group) dissolved in 8 mL of secondary water was sequentially added to a 10...

Embodiment 3

[0043] Example 3 Synthesis of hyaluronic acid derivatized maytansine prodrug (HA-SS-DM1) ( M nHA =35 kDa, DM1% =30 wt.%)

[0044] First, under nitrogen protection, add aminodithiopyridine hydrochloride (PDA•HCl) (70 mg, 0.312 mmol) to hyaluronic acid (HA) (400 mg, 1.04 mmol carboxyl) aqueous solution (20 mL) The pH of the solution was adjusted to 6.5, then 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM) (115.01 mg, 0.416 mmol) was added thereto, After stirring and reacting at 35°C for 24 hours, it was dialyzed and freeze-dried to obtain hyaluronic acid-dithiopyridine (HA-SS-Py). The product yield was 85%. NMR results showed that its structure was hyaluronic acid-dithiopyridine (HA-SS-Py), and the degree of substitution (DS) of the dithiopyridine functional group (-SS-Py) was 11%.

[0045] Under nitrogen protection, add HA-SS-Py (100 mg, 54.2 micromole dithiopyridine functional group) dissolved in 8 mL of secondary water into a 100 mL three-necked fl...

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Abstract

The invention discloses a hyaluronic acid derivatized maytansine prodrug, its preparation method and its application in the preparation of tumor targeting therapy drugs, including hyaluronic acid main chain and maytansine side chain; said maytansine The hyaluronic acid and the hyaluronic acid are connected by a disulfide bond, and the molecular weight of the hyaluronic acid is 7-500 kDA; the content of the maytansine in the hyaluronic acid-derived maytansine prodrug is 10%-50%. The hyaluronic acid derivatized maytansinoid prodrug of the present invention has amphiphilicity and can self-assemble in aqueous solution to form nano-drugs. The outer hydrophilic layer is composed of hyaluronic acid, and the inner hydrophobic layer is composed of hydrophobic drug maytansine. constitute. It can greatly improve the maximum drug resistance of anticancer drugs; and it has active targeting ability without additional modification of targeting molecules, has a high enrichment rate in tumor sites, and has high cytotoxicity to tumor cells. Tumor growth can be well inhibited during the in vivo treatment of tumor nude mice.

Description

technical field [0001] The invention belongs to the field of medical materials, and relates to a polymer prodrug of an anticancer drug and its application; in particular, it relates to a hyaluronic acid derivatized maytansinoid prodrug, its preparation method and its use in the preparation of tumor targeting therapy drugs Applications. Background technique [0002] Malignant cancer has become a major killer threatening human health, and its morbidity and mortality are increasing year by year. Current tumor treatment methods mainly include surgical resection, radiation therapy and chemotherapy. There are obvious deficiencies in these treatment methods: the treatment process will cause irreversible damage to the normal tissue of the body, produce serious toxic and side effects, and bring great pain to the patient. In the past few decades, polymer prodrugs have been developed from being proposed to a nano-drug that is widely recognized by scientists as an effective drug deliv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/61A61K31/537A61K9/19A61P35/00C08B37/08
CPCA61K9/19A61K31/537C08B37/0072
Inventor 钟志远程茹钟平
Owner SUZHOU UNIV
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