Triphenylphosphine-polyethyleneglycol 1000 vitamin E succinate (TPGS 1000-TPP) conjugated compound, and preparation method and application thereof

The technology of a conjugated compound and polyethylene glycol is applied in the application field of the conjugated compound in the construction of paclitaxel liposomes, and can solve the problems of reduced curative effect of free drugs, low water solubility of paclitaxel and the like

Inactive Publication Date: 2013-03-20
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the low water solubility of paclitaxel, the curative effect of its free drug in tumor treatment is greatly reduced

Method used

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  • Triphenylphosphine-polyethyleneglycol 1000 vitamin E succinate (TPGS 1000-TPP) conjugated compound, and preparation method and application thereof
  • Triphenylphosphine-polyethyleneglycol 1000 vitamin E succinate (TPGS 1000-TPP) conjugated compound, and preparation method and application thereof
  • Triphenylphosphine-polyethyleneglycol 1000 vitamin E succinate (TPGS 1000-TPP) conjugated compound, and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1, triphenylphosphine-polyethylene glycol 1000 vitamin E succinate (TPGS 1000 Synthesis and characterization of -TPP) conjugated compounds

[0066] Synthetic roadmap as figure 1 shown.

[0067] Mix 5 mmol of TPP and 5.25 mmol of 6-bromohexanoic acid in 5 ml of anhydrous acetonitrile, and heat to reflux for 16 hours under the protection of nitrogen. The mixed product was recrystallized to obtain 5-carboxypentyltriphenylphosphine bromide as a white solid powder.

[0068] TPGS1000-TPP consists of the carboxyl group on 5-carboxypentyltriphenylphosphine bromide and TPGS 1000 The hydroxyl groups on it are condensed through esterification, and DCC is used as a reactive condensing agent. 0.33mmol 5-carboxypentyltriphenylphosphine bromide, 0.066mmolTPGS 1000 , 0.40mmol DCC and 0.006mmol DMAP were dissolved in 3ml DMSO solution, and the reaction solution mixture was gently stirred with a magnetic stirrer for 18h at room temperature under nitrogen protection to obt...

Embodiment 2

[0071] Embodiment 2, preparation and characterization of liposome

[0072] 1) Preparation of liposomes:

[0073] Targeted paclitaxel liposomes were prepared by thin film dispersion method and extrusion through the membrane. In addition, unloaded targeted liposomes, common paclitaxel liposomes, common and targeted coumarin liposomes were used as Controls, cytotoxic agents, and fluorescent probes.

[0074] Liposomes are composed of lipid materials (egg yolk lecithin (EPC) and cholesterol) and targeting material TPGS 1000 - TPP composition, the molar ratio of the three is 88:3.5:8.5. The ratio of lipid material and paclitaxel is lipid material: paclitaxel = 35:1 (mass / mass). Put the lipid material, targeting material and paclitaxel in an eggplant-shaped bottle and dissolve them in methanol, then remove the methanol by rotary evaporation, and use PBS to remove the lipid film. The buffer solution was hydrated, the probe was sonicated for 10 minutes (110W), and the polycarbonate ...

Embodiment 3

[0087] Embodiment 3, the pharmacodynamic experiment of mitochondria-targeted paclitaxel liposome

[0088] (1) Cell culture

[0089] Human lung adenocarcinoma A549 cells (purchased from Cancer Institute, Cancer Hospital, Chinese Academy of Medical Sciences) were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% double antibody (100U / ml penicillin, 100μg / ml streptomycin) ; Multidrug-resistant lung cancer A549 / cDDP cells (purchased from Cancer Institute, Cancer Hospital, Chinese Academy of Medical Sciences) were treated with RPMI- 1640 culture medium, in order to maintain the drug resistance of the cells, cisplatin at a final concentration of 4 μM was added to the culture medium, and cultured in the above medium without cisplatin one week before the experiment. Both cells were cultured under 5% CO 2 , 37°C.

[0090] (2) Cytotoxicity

[0091] A549 cells or A549 / cDDP cells in 5.0×10 3 The concentration of cells / well was inoculated in 96-well cell culture pl...

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Abstract

The invention discloses a triphenylphosphine-polyethyleneglycol 1000 vitamin E succinate (TPGS 1000-TPP) conjugated compound, and a preparation method and application thereof. The structural formula of the compound is disclosed as Formula I. The preparation method of the conjugated compound comprises the following steps: (1) reacting triphenylphosphine and 6-bromocaproic acid to obtain 5-carboxyamyltriphenylphosphonium bromide disclosed as Formula IV; and (2) carrying out esterification reaction on the 5-carboxyamyltriphenylphosphonium bromide disclosed as Formula IV and polyethyleneglycol 1000 vitamin E succinate to obtain the conjugated compound disclosed as Formula I. The invention also discloses a mitochondrion targeted taxol liposome comprising the conjugated compound. The drug effect test proves that the mitochondrion targeted taxol liposome has strong cell toxicant action in the in-vitro cell experiment and in-vivo transplantation tumor model of human lung adenocarcinoma A549 cells and drug-resistant A549 / cDDP cells thereof and can enhance the antitumor effect of taxol on drug-resistant A549 / cDDP cells.

Description

technical field [0001] The present invention relates to a kind of triphenylphosphine-polyethylene glycol 1000 vitamin E succinate (TPGS 1000 -TPP) conjugated compound and its preparation method and application, specifically relating to the application of the conjugated compound in the construction of paclitaxel liposomes. Background technique [0002] Drug delivery systems modified with functional materials offer a potential strategy for refractory cancers. Tumor refractory is not only related to the pathophysiological state of the patient, but also related to drug delivery. Chemotherapy drugs are usually administered in the form of injection of free drugs, and this method of administration will lead to less accumulation of drugs in tumor lesions and non-targeted distribution of pharmaceuticals in tissues and organs throughout the body. [0003] In addition, tumor multidrug resistance is the main reason for the failure of chemotherapy, which can lead to drug resistance, re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/48A61K47/34A61K9/127A61K31/337A61P35/00
Inventor 吕万良周佳居瑞军赵炜煜马旭李秀英王小星石继凤孙梦舸
Owner PEKING UNIV
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