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Amphiphilic copolymer-maytansine covalent drug conjugates, preparation method and application

A technology of amphiphilic copolymers and maytansinoids, which is applied in the field of preparation of amphiphilic copolymers-maytansinoids covalently coupled drugs, which can solve the problem of high cost of synthetic process products and drug loading capacity. Low, heterogeneity and other issues, to achieve good market prospects and clinical application value, low preparation cost, reduce the effect of damage

Inactive Publication Date: 2018-04-17
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although several ADC drugs have initially achieved some clinical applications, the antibody-conjugated maytansinoids shown above have some limitations: i) the drug loading is extremely low, and a large amount of antibody protein is required for clinical use; ii) the formation of ADC drugs require multi-step organic reactions, and the cumbersome synthesis process leads to high product costs; iii) due to the poor specificity of the chemical reactions used in the preparation process, the product preparation is highly heterogeneous; iv) using The chemical bond coupled with the drug is exposed to the water phase, resulting in instability during circulation in the body, causing the safety hazard of early release of the drug; v) After the drug is conjugated to the antibody, it is easy to cause the antibody to be immunogenic, so that the antibody can be quickly removed from the blood circulation clear in

Method used

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  • Amphiphilic copolymer-maytansine covalent drug conjugates, preparation method and application
  • Amphiphilic copolymer-maytansine covalent drug conjugates, preparation method and application
  • Amphiphilic copolymer-maytansine covalent drug conjugates, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] The synthesis of methoxypolyethylene glycol-polylactic acid-maleimide-maytansinoid coupling drug I-1, the synthetic route is as follows figure 1 shown.

[0070] Add mPEG(2K)-PLA(2K)-MAL (purchased from Advanced Polymer Materials, Canada, m=28, n=45, 110.7mg, 0.027mmol) and DM1 (20mg, 0.027mmol) into a 100mL round bottom flask, and use 3 mL of anhydrous DMF (dimethylformamide) was dissolved. At 37°C, the reaction was carried out under magnetic stirring for 20 hours. After the reaction was completed, DMF was removed by rotary evaporation, and the solid was dissolved in dichloromethane, and purified by column chromatography (DCM:MeOH=20:1) to obtain product I-1 (80.2 mg, yield 61%).

[0071] Product I-1 1 The H NMR nuclear magnetic data is as follows:

[0072] 1 H NMR (400MHz, CDCl 3 ): δ0.80(s,3H),1.24(s,1H),1.26(s,3H),1.52(s,3H),1.55-1.57(d,84H,J=6.8),1.64(s,3H ),2.85(s,3H),3.01-3.02(d,1H,J=4.80),3.06-3.14(t,2H),3.20-3.21(d,3H,J=2.0),3.36(s,3H) ,3.38(s,3H),3.46-3...

Embodiment 2

[0074] The synthesis of methoxypolyethylene glycol-polylactic acid-maleimide-maytansinoid coupling drug I-2, the synthetic route is as follows figure 2 shown.

[0075] Add mPEG(2K)-PLA(4.2K)-MAL (purchased from Advanced Polymer Materials, Canada, m=58, n=45, 300mg, 0.048mmol) and DM1 (35.1mg, 0.048mmol) into a 100mL round bottom flask, Dissolve with 3 mL of anhydrous DMF (dimethylformamide). At 37°C, the reaction was carried out under magnetic stirring for 20 hours. After the reaction was completed, DMF was removed by rotary evaporation, and the solid was dissolved in dichloromethane, and purified by column chromatography (DCM:MeOH=40:1) to obtain product I-2 (227.8 mg, yield 68%).

[0076] Product I-2 1 The H NMR nuclear magnetic data is as follows:

[0077] 1 H NMR (400MHz, CDCl 3 ): δ0.80(s,3H),1.23(s,1H),1.26(s,4H),1.52(s,3H),1.55-1.59(m,174H),1.64(s,3H),2.85( s,3H),3.02-3.04(d,1H,J=9.60),3.07-3.12(t,2H),3.19-3.21(t,3H),3.36(s,3H),3.38(s,3H), 3.46-3.49 (m,2H),3.51...

Embodiment 3

[0079] Dissolve 5 mg each of the conjugates I-1 and conjugates I-2 prepared in Example 1 and Example 2 in 2 mL of acetone, and slowly inject them into 20 mL of water to obtain nano drug. The acetone solution was removed by rotary evaporation under reduced pressure to obtain nanomedicine.

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Abstract

The invention discloses amphiphilic copolymer-maytansine covalent drug conjugates, a preparation method and an application thereof. The structure of the amphiphilic copolymer-maytansine covalent drugconjugates is R-X-may, wherein X is a connection piece, R is derived from amphiphilic polymers and may is a maytansine base. A drug precursor and nano-micelle loaded with an anti-tumor drug can be obtained through simple chemical reactions, and release of a maytansine drug in blood can be significantly reduced, so that the drug conjugates are expected to greatly reduce damage to normal tissue andorgans. The drug conjugates are low in preparation cost, high in stability and good in safety, meet the clinical medication requirement, meet large-scale industrial production and have good market prospects and clinical application value.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a preparation method and application of an amphiphilic copolymer-maytansinoid covalently coupled drug. Background technique [0002] Maytansine is a natural alkaloid that was first isolated from Maytans ovale by Kupchan et al. in 1972. It exists in Maytans and its relatives in the genus Maytans. Maytansine acts on microtubules and tubulin, blocks the formation of spindles during cell mitosis by inhibiting the depolymerization of cellular microtubules, and has a strong ability to inhibit tumor cell proliferation. DM1 (chemical name is N 2’ -Deacetyl-N 2 '–(3-Mercapto-1-oxopropyl)-maytansine) is a synthetic derivative of maytansine. In vitro experiments, maytansinoid derivatives showed nearly a hundred times higher cytotoxicity than conventional chemotherapy drugs such as powerful anticancer drugs vinblastine (Issell B F, Crooke S T.Maytansine....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K31/5365C08G63/91A61P35/00
CPCA61K31/5365C08G63/912
Inventor 王杭祥谢轲谢海洋周琳郑树森
Owner ZHEJIANG UNIV
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