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7-ethyl-10-hydroxycamptothecine-polymer conjugated drug and preparation method of drug nano-preparation

A technology of hydroxycamptothecin and nano-formulation, which is applied in the directions of drug combination, drug delivery, pharmaceutical formulation, etc., can solve the problems of low bioavailability, low conversion rate, loss of activity, etc., and achieve high safety and reduce inactivation. , the effect of slowing drug release

Active Publication Date: 2017-05-10
ZHEJIANG UNIV
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AI Technical Summary

Problems solved by technology

But this medicine of clinical application has very big defect: i) irinotecan is converted into the SN38 that has anticancer effect in vivo and needs the enzymolysis of carboxylesterase, but its transformation rate in vivo is less than 8%, causes bioavailability Very low; ii) irinotecan is still easily hydrolyzed in the blood circulation, resulting in loss of activity; iii) the metabolite SN38 of irinotecan remains in the intestinal tract, causing relatively large side effects such as bloody diarrhea, which limits the increase in drug dosage

Method used

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  • 7-ethyl-10-hydroxycamptothecine-polymer conjugated drug and preparation method of drug nano-preparation
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  • 7-ethyl-10-hydroxycamptothecine-polymer conjugated drug and preparation method of drug nano-preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 Synthesis of SN38-polylactic acid coupled prodrug 1 ( figure 1 )

[0053] Add mPLA(600)-SA (207mg, 0.26mmol) and SN38 (100mg, 0.26mmol) into a 100mL round bottom flask, dissolve in 10mL of anhydrous dichloromethane, and add EDC (59mg, 0.38mmol). Stir at 50°C for 4 hours, remove the reaction solvent, and wash with 5% citric acid, saturated sodium bicarbonate, and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was collected and the solvent was removed under reduced pressure. Product 1 (102 mg, 34%) was obtained after separation and purification by column chromatography (DCM:MeOH=120:1).

[0054] Prodrug 1 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0055] 1 H NMR (400MHz, CDCl 3 ): δ1.00-1.01(t,3H),1.38-1.42(t,3H),1.58(s,24H),1.88-1.92(q,2H),2.89-2.92(t,2H),2.98-3.03 (m,2H),3.13-3.19(q,2H),3.38(s,3H),3.53-3.56(t,2H),3.61-3.64(t,2H),3.68-3.70(t,2H),4.25 -4.33...

Embodiment 2

[0056] Example 2 Synthesis of SN38-polylactic acid coupled prodrug 2 ( figure 2 )

[0057] Add mPLA(1200)-SA (357mg, 0.26mmol) and SN38 (100mg, 0.26mmol) into a 100mL round bottom flask, dissolve in 13mL of anhydrous dichloromethane, and add EDC (59mg, 0.38mmol). Stir at 50°C for 4 hours, remove the reaction solvent, and wash with 5% citric acid, saturated sodium bicarbonate, and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was collected and the solvent was removed under reduced pressure. Product 2 (185 mg, 41%) was obtained after separation and purification by column chromatography (DCM:MeOH=120:1).

[0058] Prodrug 2 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0059] 1 HNMR (400MHz, CDCl 3 ):δ1.02-1.06(t,3H),1.38-1.42(t,3H),1.57-1.61(m,51H),1.88-1.92(q,2H),2.89-2.94(m,2H),2.98 -3.07(m,2H),3.13-3.18(q,2H),3.38(s,3H),3.54-3.56(q,2H),3.63-3.65(q,2H),3.68-3.70(t,2H) ,4.25-...

Embodiment 3

[0060] Example 3 Synthesis of SN38-polylactic acid coupled prodrug 3 ( image 3 )

[0061] Add mPLA(2600)-SA (591 mg, 0.20 mmol) and SN38 (79 mg, 0.20 mmol) into a 100 mL round bottom flask, dissolve in 15 mL of anhydrous dichloromethane, and add EDC (47 mg, 0.30 mmol). Stir at 50°C for 4 hours, remove the reaction solvent, and wash with 5% citric acid, saturated sodium bicarbonate, and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was collected and the solvent was removed under reduced pressure. Product 3 (320 mg, 48%) was obtained after separation and purification by column chromatography (DCM:MeOH=120:1).

[0062] Prodrug 3 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0063] 1 HNMR (400MHz, CDCl 3 ):δ1.02-1.06(t,3H),1.38-1.42(t,3H),1.53-1.61(m,108H),1.86-1.92(m,2H),2.89-2.92(m,2H),2.98 -3.03(m,2H),3.13-3.19(q,2H),3.38(s,3H),3.53-3.56(q,2H),3.63-3.65(t,2H),3.68-3.70(t,2H) ...

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Abstract

The invention discloses a 7-ethyl-10-hydroxycamptothecine (SN38) conjugated polymer, a preparation method, a nano-preparation of the conjugated polymer and an anti-tumor application. C-10 position or C-20 position hydroxy of a 7-ethyl-10-hydroxycamptothecine compound is conjugated with different molecular weight terminal carboxyl group polymers through covalent bonds to obtain an SN38 series conjugated prodrug, and then amphiphilic polymer materials and the SN38 prodrug are prepared into a nano-drug. The nano-drug solves the problem of poor water solubility of SN38, and slow release of the SN38 is achieved in vitro. Besides, the particle diameter of the nano-drug is mainly distributed within the range of 20-50nm, high permeability and EPR (enhanced permeation and retention) effects of nano-particles through solid tumors are achieved, and passive targeting functions of the nano-particles are enhanced. The nano-drug has good effects in vitro and vivo and accordingly has a good application prospect.

Description

technical field [0001] The invention relates to the prodrug of 7-ethyl-10-hydroxycamptothecin coupled polylactic acid or polylactic acid-glycolic acid copolymer, the preparation of the prodrug, the construction of its nanometer preparation and its antitumor effect in vivo and in vitro. Background technique [0002] 7-Ethyl-10-hydroxycamptothecin (SN38) is a derivative of camptothecin, which has a strong activity of inhibiting tumor cell proliferation. Mainly through the combination with topoisomerase I and DNA complex (TOPcc), thereby inhibiting the unwinding of DNA and the proliferation of tumor cells. Since SN38 molecules are insoluble in water and pharmaceutically acceptable solvents (such as Tween 80, polyoxyethylene castor oil, etc.), it cannot be directly used in clinical practice through intravenous injection. In addition, once SN38 enters the blood circulation system, it is easily hydrolyzed and combined with serum albumin to lose its activity. The US FDA approved ...

Claims

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Application Information

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IPC IPC(8): A61K47/59A61K9/14A61K31/4745A61P35/00C08G63/91
CPCA61K9/0002A61K9/146A61K31/4745C08G63/912
Inventor 王杭祥
Owner ZHEJIANG UNIV
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