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Cleavable polymer drug conjugates

A technology of drug conjugates and polymers, applied in the field of diseases

Pending Publication Date: 2019-03-15
RS研究教育咨询医学工业贸易股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the disadvantage of these systems is that the cleavable linker between the drug and the polymer cleaves in the bloodstream and releases the drug molecule before it reaches its target tissue

Method used

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  • Cleavable polymer drug conjugates
  • Cleavable polymer drug conjugates
  • Cleavable polymer drug conjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0208] Example 1: Preparation of a Glycine-Phenylalanine-Leucine-Glycine (GFLG) Cleavable Linker with Methacrylate Functionality

[0209] The GFGL-MA linker was prepared according to the literature method described in K. Ulbrich et al., Journal of Controlled Release, 64, 2000, 63-79.

Embodiment 2

[0210]Embodiment 2: the preparation of docetaxel-GFGL-methacrylate (MA) monomer

[0211] According to the literature method described in Ghandehari et al., Mol. Pharm., 2011, 8(4), 1090-1099, docetaxel (DTX) was coupled to the GFGL-MA linker to obtain DTX-GFLG-MA.

[0212] Docetaxel (0.335 g, 4.1 mmol), 4-(dimethylamino)pyridine (DMAP, 0.049 g, 4.0 mmol) and MA-GFLG-OH (0.188 g, 4.0 mmol) were dried under vacuum. The reaction mixture was dissolved in anhydrous N,N-dimethylformamide (DMF, 5 mL) under nitrogen, cooled with an ice bath (salt / ice) at <0 °C, and diisopropylcarbadiene was added dropwise Imine (DIPC, 76 μL, 4.89 mmol).

[0213] The reaction mixture was then stirred for 1 hour, then the ice bath was removed, the mixture was allowed to warm to room temperature, stirred overnight, and was analyzed by thin layer chromatography (TLC, eluent dichloromethane (DCM):methanol (MeOH) (95:5 )) Progress is monitored for disappearance of starting material and formation of MA-GFL...

Embodiment 3

[0214] Example 3: Preparation of polymer-drug conjugates comprising docetaxel and PEG in the side chain

[0215] Polyethylene glycol methyl ether methacrylate (PEGMEMA) (Mn: 300) and DTX-GFGL-MA were polymerized in the presence of AIBN as an initiator and DMF as a solvent to obtain PEGMEMA-DTX.

[0216]

[0217] Scheme 1: Schematic representation of the copolymerization of PEGMEMA and DTX-GFLG-MA monomers.

[0218] In the above figure, (*) indicates the AIBN fragment as the terminal group of the polymer-drug conjugate.

[0219] By changing the ratio of PEGMEMA, PEGMEMA-DTX conjugates with different molecular weights can be obtained.

[0220] In order to demonstrate that the present invention is applicable to PEGMEMA-DTX conjugates of various molecular weights, the inventors prepared 50 kDa and 85 kDa PEGMEMA-DTX polymer-drug conjugates and performed pharmacokinetic tests on them.

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Abstract

This invention relates to polymer drug conjugates comprising a (meth)acrylate based polymer backbone with at least two types of side chains wherein one of the side chains is a PEG chain and the otherside chain comprises at least one therapeutic agent covalently bonded to a cleavable linker, methods of preparing said polymer-drug conjugates and their use for treatment of diseases such as cancer.

Description

[0001] The present invention relates to polymer drug conjugates of formula I, methods of preparing said polymer-drug conjugates and their use for the treatment of diseases such as cancer. Background technique [0002] Chemotherapeutic agents used to treat cancer are mostly cytotoxic. In addition to the target area, these agents may accumulate in body tissues, which in turn leads to reduced therapeutic benefit and undesired distribution of the drug throughout healthy body tissues. The uncontrolled distribution of these agents throughout the body causes serious side effects to the patient. [0003] Due to the distribution of chemotherapeutic agents throughout the body including healthy tissues, the amount of chemotherapeutic agents reaching tumor tissue is very low despite the high overall toxicity caused by a given dose. This situation results in a low therapeutic benefit for the patient. In addition, chemotherapeutic agents have low solubility, which makes them difficult to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/32A61P35/00C08F222/10
CPCA61K47/58A61K45/06A61K47/32C08F220/603C08F222/1063C08F220/286A61P35/00A61K31/35A61K31/519A61K47/10A61K47/183A61K47/60A61K31/09A61K47/65A61K31/337A61K31/506A61K31/4706
Inventor R·桑雅尔A·桑雅尔M·阿斯兰B·萨默波路O·高克M·卡拉希维S·卡加
Owner RS研究教育咨询医学工业贸易股份有限公司
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