Grafted retinol polymer and camptothecin compound adopting grafted retinol polymer as carrier

A retinol and polymer technology, applied in the field of preparation of camptothecin compounds, can solve the problems of large toxic and side effects, limited application, insoluble in water, etc., and achieve the goal of reducing toxic and side effects, reducing toxic and side effects, and improving enrichment Effect

Inactive Publication Date: 2017-05-31
SOUTHWEST JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] The activation and massive expansion of hepatic stellate cells (HSCs) play a very important role in the occurrence of liver fibrosis; Inhibition of HSC proliferation, activation, and induction of apoptosis through signal transduction and other pathways has become an important method for the treatment of liver fibrosis; at present, some people have tried to use drugs such as paclitaxel, curcumin, and NO to inhibit the proliferation of activated HSC and the deposition of ECM. The activation of HSC and the maintenance of the activated phenotype require vigorous glycolytic metabolic activity, and the inhibition of glycolytic metabolic activity can promote the reversal of the activated HSC from the myofibroblast (Myofibroblastic, MF) phenotype to the quiescent phenotype Therefore, the present invention uses my country's unique drug camptothecin to inhibit the protein level and activity of the key regulatory protein hypoxia factor (hypoxia-inducible-factor 1-alpha, HIF-1-alpha) in the glycolytic pathway, thereby inhibiting its downstream The expression of genes related to the glycolysis pathway and the expression of proteins related to MF phenotype; however, camptothecin is insoluble in water and has high toxic and side effects; if it is made into salt, its activity will be reduced, and it will be easily cleared by the body's circulatory system when it enters the body; therefore, it is in Clinical application is very limited

Method used

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  • Grafted retinol polymer and camptothecin compound adopting grafted retinol polymer as carrier
  • Grafted retinol polymer and camptothecin compound adopting grafted retinol polymer as carrier
  • Grafted retinol polymer and camptothecin compound adopting grafted retinol polymer as carrier

Examples

Experimental program
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Effect test

preparation example Construction

[0040] A preparation method of a camptothecin compound using a grafted retinol polymer as a carrier, comprising the following steps:

[0041] (1) dissolving camptothecin and grafted retinol polymer in dimethyl sulfoxide at a mass ratio of 1:5, 1:10 or 1:20;

[0042] (2) Put the solution obtained in step (1) into a dialysis bag, and after dialysis for 48 hours, freeze-dry the collected micellar solution to obtain the desired compound; wherein the molecular weight cut-off of the dialysis bag is 3500.

[0043] An application of a camptothecin compound grafted with a retinol polymer as a carrier, and the micelles can reduce the expression of protein hypoxia factor HIF-1-α in fibrotic liver tissue.

[0044] The application of a camptothecin compound grafted with a retinol polymer as a carrier, and the micelles can reduce the expression of the rate-limiting enzyme gene of the glycolysis pathway in fibrotic liver tissue.

[0045] Application of a camptothecin compound grafted with a...

Embodiment 1

[0067] Example 1 In vitro targeting experiment of grafted retinol polymer micelles

[0068] The rat liver was digested by in situ perfusion, and the primary rat hepatic stellate cells (HSC) and hepatocytes (HC) obtained by digestion were inoculated on 24-well plates, and high-glucose DMEM medium (containing 15%- 20% FBS, 1% double antibody P / S) at 37°C, 5% CO 2 Culture in the cell incubator; after 2 days of HC growth and 7 days of HSC growth, add Nile Red polymer nanomicelles and continue to culture for 2 hours, wash twice with phosphate buffered saline (PBS), add 2.5% glutaraldehyde Fix for 0.5h, wash twice with PBS, add 4',6-diamidino-2-phenylindole DAPI (1:600, V / V) for about 5min, then discard DAPI, wash twice, add appropriate amount of PBS Protected from light, use a fluorescence microscope to observe the uptake of retinol-targeted nanomicelles coated with Nile red (VA-PEG-PCL) and non-targeted nanomicelles coated with Nile red (PEG-PCL) by HSC cells and HC cells -PCL) ...

Embodiment 2

[0070] Example 2 Targeting experiment of grafted retinol polymer micelles in mice

[0071] Get 16 mice, 8 in each group are randomly divided into 2 groups; inject olive oil (control group) or 20% CCl into the mice through the abdominal cavity respectively 4 - olive oil (dose 2ml / kg) for acute liver injury; after two days of administration, the animals in each group were randomly divided into two groups, and the mice were injected with Nile Red VA-PEG-PCL and PEG through the tail vein respectively. -PCL micellar solution; the mice were killed three hours later, and the heart, liver, spleen, lung, and kidney tissues of each mouse were collected, and after homogenization, the fluorescence intensity of Nile Red in the tissue samples was detected to analyze the micellar drug in vivo Biological distribution, the results are as follows Figure 6 shown.

[0072] The mice used are male ICR mice of SPF level, weighing 20-25g, provided by Chengdu Dashuo Animal Co., Ltd.; CCl 4 It is a...

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Abstract

The invention discloses a grafted retinol polymer and a camptothecin compound adopting the grafted retinol polymer as a carrier. The camptothecin compound can be used for specifically lowering the expression of hypoxia-inducible-factor 1-alpha (HIF-1-alpha) for activating a hepatic stellate cell (HSC), a glycolytic pathway rate-limiting enzyme gene and a myofibroblastic labeled gene in fiberized hepatic tissue, inhibiting the occurrence and development of hepatic fibrosis and lowering toxic or side effects on hepar cells caused by camptothecin; an active targeting action on the HSC is achieved by using specific recognition and combination between a ligand and a receptor by adopting a retinol modified carrier.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a grafted retinol polymer and a camptothecin compound using it as a carrier, a preparation method and an application thereof. Background technique [0002] The activation and massive expansion of hepatic stellate cells (HSCs) play a very important role in the occurrence of liver fibrosis; Inhibition of HSC proliferation, activation, and induction of apoptosis through signal transduction and other pathways has become an important method for the treatment of liver fibrosis; at present, some people have tried to use drugs such as paclitaxel, curcumin, and NO to inhibit the proliferation of activated HSC and the deposition of ECM. The activation of HSC and the maintenance of the activated phenotype require vigorous glycolytic metabolic activity, and the inhibition of glycolytic metabolic activity can promote the reversal of the activated HSC from the myofibroblast (Myofibroblastic, MF) phenoty...

Claims

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Application Information

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IPC IPC(8): C08G81/00A61K9/107A61K47/34A61K31/4745A61P1/16
Inventor 陈渝萍汪辛程江张艳军
Owner SOUTHWEST JIAOTONG UNIV
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