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Construction of paclitaxel-oleic acid small-molecular prodrug self-assembled nanoparticles

A technology of self-assembled nanoparticles and paclitaxel, which is applied in the direction of drug combination, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problem that PTX-DHA does not show advantages in curative effect, paclitaxel breaks, drug is easy to Leakage and other problems, to reduce adverse reactions, the preparation method is simple and easy, easy to modify the effect of the surface

Active Publication Date: 2016-08-10
SHENYANG PHARMA UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although nanotechnology has greatly improved the druggability of paclitaxel, these new nanoformulations also have some drawbacks, including: carrier-related toxicity, low drug loading (generally less than 10%), poor stability, and easy drug leakage during storage , crystallization, etc.
However, the latest clinical results show that compared with the existing chemotherapy drugs, the efficacy of PTX-DHA does not show advantages
Analyzing the structure of PTX-DHA, we found that paclitaxel and docosahexaenoic acid are connected by an ester bond, which may make it difficult for paclitaxel to be broken from the prodrug, resulting in poor efficacy

Method used

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  • Construction of paclitaxel-oleic acid small-molecular prodrug self-assembled nanoparticles
  • Construction of paclitaxel-oleic acid small-molecular prodrug self-assembled nanoparticles
  • Construction of paclitaxel-oleic acid small-molecular prodrug self-assembled nanoparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1: the synthesis of paclitaxel-oleic acid prodrug (PTX-OA) linked by ester bond

[0039] Oleic acid (OA) was dissolved in a small amount of dichloromethane, under the catalysis of DCC and DMAP, in N 2 Under protection, ice bath 2-4h, and then with paclitaxel at 25 ℃ N 2 The reaction was carried out for 24-48 hours under protection, and the white powder prodrug was obtained by separation and purification. Determination by NMR 1 H-NMR hydrogen spectrum is determined the structure of prodrug in embodiment 1, and the solvent of selection is CDCl 3 , the result is as figure 1 , the spectral analysis results are as follows:

[0040] 1 H-NMR (400MHz, CDCl 3 )δ:8.13(t,2H),7.74(d,2H),7.61(m,1H),7.59(m,3H),7.42(d,4H),7.40(m,3H),6.87(d,1H , J=9.2Hz, -NH-), 6.29(t, 2H, 10-H, 13-H), 5.95(dd, 1H, J=3.2Hz, J=6.0Hz, 3'-H), 5.69( d,1H,J=7.2Hz,2-H),5.50(d,1H,J=3.2Hz,2'-H),5.34(m,2H,-CH=CH-),4.98(d,1H, J=8.0Hz, 5-H), 4.45(t, 1H, 7-H), 4.31(d, 1H, J=8.4Hz, 20α-H), 4.21(...

Embodiment 2

[0041] Example 2: Synthesis of Paclitaxel-oleic acid prodrug (PTX-S-OA) linked by redox double-sensitive monosulfide bond

[0042] Put ethylene glycol in a 50mL three-necked bottle, add an appropriate amount of p-toluenesulfonic acid to the eggplant-shaped bottle, N 2 Protected, heated to 100-120 ° C, slowly dripping the oleic acid solution dissolved in an appropriate amount of toluene into the reaction bottle, and reacted for 2-4 hours. After the reaction is over, let the layers stand, extract with toluene until the ethylene glycol layer TLC has no product point, combine the toluene layers, and then use saturated NaHCO 3 The solution was washed until neutral, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, separated and purified to obtain (Z)-oleic acid-2-hydroxyethyl ester. Put an appropriate amount of 2,2'-thiodiacetic anhydride and a small amount of triethylamine in a 25mL eggplant-shaped bottle, add 10-15mL CH 2 Cl 2 , joining HOBt and EDCI, N 2 ...

Embodiment 3

[0045] Example 3: Synthesis of Paclitaxel-Oleic Acid Prodrug (PTX-2S-OA) Linked by Redox Double Sensitive Spacer Disulfide Bond

[0046] Put ethylene glycol in a 50mL three-necked bottle, add an appropriate amount of p-toluenesulfonic acid to the eggplant-shaped bottle, N 2 Protected, heated to 100-120 ° C, slowly dripping the oleic acid solution dissolved in an appropriate amount of toluene into the reaction bottle, and reacted for 2-4 hours. After the reaction is over, let the layers stand, extract with toluene until the ethylene glycol layer TLC has no product point, combine the toluene layers, and then use saturated NaHCO 3 The solution was washed until neutral, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, separated and purified to obtain (Z)-oleic acid-2-hydroxyethyl ester. Put an appropriate amount of 1,2-ethylenedithiodiacetic anhydride and a small amount of triethylamine in a 25mL eggplant-shaped bottle, add 10-15mL CH 2 Cl 2 , joining HOBt ...

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Abstract

The invention designs and synthesizes a series of paclitaxel-oleic acid small-molecular prodrugs; with the application of a chemical connecting arm which is sensitive to an oxidation-deoxidation environment, the rapid release of the drugs in tumor cells is promoted. On the basis, small-molecular prodrug self-assembled nano-drug delivery systems are prepared. The small-molecular prodrug self-assembled nano-drug delivery systems have the advantages that by virtue of a one-step nano-precipitation method, nano-drug self-assembled nanoparticles are simple in preparation process and easy for industrialization; the nano-drug self-assembled nanoparticles are small and uniform in grain size (to 100nm), and the nano-drug self-assembled nanoparticles are enriched in a tumor part by virtue of an EPR (enhanced permeability and retention) effect; an ultrahigh drug-loading capacity is guaranteed, which is beneficial for reducing adverse reactions caused by auxiliary materials and biological materials; surface modification is easy to implement, and the intake of a reticuloendothelial system can be effectively avoided and the intake of the tumor cells to the nanoparticles can be improved by virtue of PEG (polyethylene glycol) and active targeting modification; and on the basis of the sensitivity of the chemical connecting arm to the oxidation-deoxidation microenvironment of the tumor cells, the specific drug release of paclitaxel in the tumor part is achieved, a curative effect is improved and toxic and side effects are reduced.

Description

technical field [0001] The invention belongs to the field of new excipients and new dosage forms of pharmaceutical preparations, and includes the synthesis of multiple paclitaxel-oleic acid prodrugs and the construction of a series of paclitaxel-oleic acid small-molecule prodrug self-assembled nanoparticles, as well as their application in drug delivery. Background technique [0002] Paclitaxel (PTX) as a first-line anticancer drug has been widely used in clinical practice. Because the water solubility of paclitaxel is very poor, the commercially available solution (taxol) uses polyoxyethylene castor oil and ethanol as a solubilizer and a cosolvent to dissolve it and apply it clinically. Because of this, Taxol can cause very serious toxic and side effects related to excipients, which greatly limits its clinical application. In recent years, new drug delivery systems based on nanotechnology have attracted much attention, and many nano drug delivery systems have been construc...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K9/14A61K31/337A61K47/34A61P35/00C07D305/14
CPCA61K9/145A61K31/337A61K47/10C07D305/14
Inventor 孙进罗聪何仲贵孙丙军刘丹
Owner SHENYANG PHARMA UNIVERSITY
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