Preparation method of nano delivery system of double-pH sensitive supported chemotherapy drug daunorubicin (DNR)

A daunorubicin and sensitive load technology, applied in the field of nano-delivery system preparation, can solve the problems of reducing the activity of anti-cancer drugs, cardiotoxicity, and damage to cardiac cells, so as to enhance the anti-tumor efficacy, improve targeting, The effect of enhancing intake

Active Publication Date: 2020-02-07
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The traditional chemotherapy drugs currently used are mainly small molecule drugs, which have many disadvantages: low selectivity, easy metabolism, easy to produce multidrug resistance, etc.
However, the carbonyl reductase Ⅰ present in the human liver can convert daunorubicin into a new daunorubicin alcohol. This new alcohol metabolite not only reduces the activity of anticancer drugs, but also has cardiotoxicity, causing cardiac Cell damage, due to this shortcoming greatly limits its application

Method used

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  • Preparation method of nano delivery system of double-pH sensitive supported chemotherapy drug daunorubicin (DNR)
  • Preparation method of nano delivery system of double-pH sensitive supported chemotherapy drug daunorubicin (DNR)
  • Preparation method of nano delivery system of double-pH sensitive supported chemotherapy drug daunorubicin (DNR)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] A preparation of a nano-delivery system of dual pH-sensitive loaded chemotherapeutic drug daunorubicin, the specific steps are as follows:

[0044] 1) Synthesis of imine bond daunorubicin:

[0045] Get daunorubicin (195mg, 0.035mmol) to be dissolved in the methanol of 20mL, add triethylamine (285 μ L, 2.075mmol), seal, evacuate, vent nitrogen, place in the collector type constant temperature heating magnetic stirrer, at temperature Stir for 2 hours at 30°C to obtain solution A; dissolve p-alkynylbenzaldehyde (54mg, 0.04mmol) in methanol to obtain solution B; add solution B to solution A through a syringe, and continue to react in the dark for 24 hours , rotary evaporated the solvent, added about 1mL of methanol to redissolve, then added about 3mL of acetonitrile to precipitate, centrifuged, discarded the supernatant, and dried in vacuo to obtain the product imine bond daunorubicin imine-DNR.

[0046] 2) Synthesis of polymer carrier:

[0047] Weigh polyethylene glycol ...

Embodiment 2

[0067] 1) the synthesis of imine bond daunorubicin: with embodiment 1

[0068] 2) Synthesis of polymer carrier: same as Example 1

[0069] 3) Synthesis of daunorubicin polymer prodrug intermediate:

[0070] Get POPAA (100mg, 0.0038mmol) after lyophilization, imine-DNR (20mg, 0.03mmol) get sodium ascorbate (1mg, 0.005mmol) and copper sulfate pentahydrate (1.25mg, 0.005mmol), be dissolved in DMF and water The mixed solution (DMF: water = 1: 1) was placed in a 70°C thermostatically heated magnetic stirrer for 24 hours of reaction, dialyzed, and freeze-dried to obtain the daunorubicin polymer prodrug intermediate POPPA@imine-DNR, Wherein the molar ratio of azide in POPAA to imine-DNR is 1:0.2.

[0071] 4) Synthesis of daunorubicin polymer prodrug:

[0072] Take 60 mg of POPPA@imine-DNR obtained in step 3), 5.04 mg of 2,3-dimethylmaleic anhydride, dissolve in DMSO and continue to react for 2 hours, dialyze, freeze-dry to obtain daunorubicin polymer prodrug DA- POPAA@imine-DNR, wh...

Embodiment 3

[0079] 1) Synthesis of imine bond daunorubicin: same as implementation case 1

[0080] 2) Synthesis of polymer carrier: same as implementation case 1

[0081] 3) Synthesis of daunorubicin polymer prodrug intermediate:

[0082] Get POPAA (100mg, 0.0038mmol) after lyophilization, imine-DNR (100mg, 0.15mmol) take sodium ascorbate (3mg, 0.015mmol) and copper sulfate pentahydrate (3.75mg, 0.015mmol), be dissolved in DMF and water The mixed solution (DMF:water=1:1) was placed in a magnetic stirrer with collector type constant temperature heating at 70°C for 24h. Dialysis and freeze-drying can obtain daunorubicin polymer prodrug intermediate POPPA@imine-DNR, wherein the molar ratio of azide in POPAA to imine-DNR is 1:1.

[0083] 4) Synthesis of daunorubicin polymer prodrug:

[0084] Take 60 mg of POPPA@imine-DNR obtained in step 3), 5.04 mg of 2,3-dimethylmaleic anhydride, dissolve in DMSO and continue to react for 2 hours, dialyze, freeze-dry to obtain daunorubicin polymer prodru...

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Abstract

The invention relates to a preparation method of a nano delivery system of a double-pH sensitive supported chemotherapy drug daunorubicin (DNR). The preparation method comprises specific steps as follows: DNR and p-alkynyl benzaldehyde react to produce imine-DNR; then, a macromolecular carrier POEGMA-poly(p-azido benzyl methacrylate-co-AMA is prepared, and amphipathic blocks, azido and amino are introduced; alkynyl of the imine-DNA and the azido of the macromolecular carrier are subjected to a click chemical reaction to obtain a DNR polymer predrug intermediate; and amino of the macromolecularpredrug intermediate and 2,3-dimethyl maleic anhydride react to obtain a DNR macromolecular predrug, and self-assembly is carried out to obtain polymeric micelle. The polymeric micelle prepared by the method can realize charge reverse in normal systemic circulation and cancer cell environments according to different pH conditions, improve target property, realize precise delivery of drugs, reducetoxic and side effects of drugs and enhance antitumor therapeutic effects.

Description

technical field [0001] The invention belongs to the field of nano-pharmaceutical preparations and macromolecular chemistry, and in particular relates to a preparation method of a nano-delivery system of dual pH-sensitive loaded chemotherapy drug daunorubicin. Background technique [0002] With the rapid increase of tumor morbidity and mortality, it is urgent to seek efficient and safe treatment methods. The traditional chemotherapy drugs currently used are mainly small molecule drugs, which have many disadvantages: low selectivity, easy metabolism, easy to produce multidrug resistance, etc. And because many drugs are hydrophobic drugs, the traditional way of administration will lead to serious toxic and side effects. Modern nano-drug delivery systems that can solve these problems have been developed rapidly. Compared with traditional chemotherapeutic drugs, nanomedicine has the following advantages: (1) it is absorbed through endocytosis, realizes targeted drug use, and im...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K47/69A61K31/704A61P35/00C08F293/00C08F220/34
CPCA61K47/60A61K47/6907A61K31/704A61P35/00C08F293/005C08F220/34C08F2438/03
Inventor 郑化宋亚静李单廖健洪刘灿
Owner WUHAN UNIV OF TECH
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