Hyaluronic acid derived maytansine prodrug, preparation method thereof and application of maytansine prodrug in preparation of tumor target treatment medicines

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, toxic and side effects, tissue damage, etc., and achieve preservation of anti-tumor activity, Good biological activity and the effect of maintaining medicinal properties

Active Publication Date: 2016-11-23
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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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) ha

Method used

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  • Hyaluronic acid derived maytansine prodrug, preparation method thereof and application of maytansine prodrug in preparation of tumor target treatment medicines
  • Hyaluronic acid derived maytansine prodrug, preparation method thereof and application of maytansine prodrug in preparation of tumor target treatment medicines
  • Hyaluronic acid derived maytansine prodrug, preparation method thereof and application of maytansine prodrug in preparation of tumor target treatment medicines

Examples

Experimental program
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Example Embodiment

[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 an aqueous solution of hyaluronic acid (HA) (400 mg, 1.04 mmol carboxyl) (20 mL) at room temperature and the entire solution The pH was adjusted to 6.5, and 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM) (57.51 mg, 0.208 mmol) was added thereto at 35 After stirring at °C for 24 hours, dialysis and lyophilization were performed 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), in which the degree of substitution (DS) of the dithiopyridine functional group (-SS-Py) was 6%. see NMR 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)...

Example Embodiment

[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 an aqueous solution of hyaluronic acid (HA) (400 mg, 1.04 mmol carboxyl) (20 mL) at room temperature and the entire solution was added The pH was adjusted to 6.5, and 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM) (86.3 mg, 0.316 mmol) was added thereto at 35 After stirring at °C for 24 hours, dialysis and lyophilization were performed 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), in which 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 μmol dithiopyridine functional group) dissolved in 8 mL of secondary water was added t...

Example Embodiment

[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, in an aqueous solution of hyaluronic acid (HA) (400 mg, 1.04 mmol carboxyl) (20 mL) was added aminodithiopyridine hydrochloride (PDA•HCl) (70 mg, 0.312 mmol) and the entire The pH of the solution was adjusted to 6.5, and then 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DTMMM) (115.01 mg, 0.416 mmol) was added thereto, After stirring the reaction at 35°C for 24 hours, dialysis and lyophilization were performed 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), in which 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 micromoles of dithiopyridine functional group) dissolved in 8 m...

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Abstract

The invention discloses a hyaluronic acid derived maytansine prodrug, a preparation method thereof and application of maytansine prodrug in preparation of tumor target treatment medicines. The maytansine prodrug comprises a hyaluronic acid main chain and a maytansine side chain, wherein maytansine and hyaluronic acid are connected by a disulfide bond, and the hyaluronic acid has a molecular weight of 7-500kDA; and the maytansine content in the hyaluronic acid derived maytansine prodrug is 10-50 percent. The hyaluronic acid derived maytansine prodrug is amphipathic, and can be self-assembled in an aqueous solution to form a nano-drug, the outer hydrophilic layer is formed by hyaluronic acid, and the inner hydrophobic layer is formed by the hydrophobic drug maytansine, so that the maximum tolerated dose of an anti-cancer drug can be improved to a great extent. Furthermore, the hyaluronic acid derived maytansine prodrug has a positive target capability without extra modifying target molecules, has a high enrichment ratio on a tumor part, has high cytotoxicity to tumor cells and canwell inhibit tumor growth in the in-vivo treatment process for a tumor-bearing naked mouse.

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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IPC IPC(8): A61K47/48A61K31/537A61K9/19A61P35/00C08B37/08
CPCA61K9/19A61K31/537C08B37/0072
Inventor 钟志远程茹钟平
Owner SUZHOU UNIV
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