Drug delivery system of combining blood vessel blocking agent and double-drug-loading bionic liposome

A vascular blocking agent and double drug-loading technology, applied in the field of medicine, can solve the problems of unsatisfactory treatment effect of prodrugs, aggravating the degree of tumor hypoxia, etc., so as to reduce adverse reactions, reduce tumor microvessel density, and reduce the particle size of tumor cells. Effect

Active Publication Date: 2021-06-15
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the hypoxia-selective cytotoxicity of this prodrug and the heterogeneity of tumor hypoxia, the therapeutic effect of a single hypoxia-activated prodrug is often not ideal
Studies have shown that the combination of photodynamic therapy and hypoxia-activated prodrugs, although photodynamic therapy can rapidly consume tumor oxygen and cause acute hypoxia while generating reactive oxygen species after laser irradiation, tumor hypoxia will continue to develop over time. The condition is gradually relieved, so how to prolong the time of tumor hypoxia and aggravate the degree of tumor hypoxia to promote the activation of hypoxia-activated prodrugs remains to be studied

Method used

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  • Drug delivery system of combining blood vessel blocking agent and double-drug-loading bionic liposome
  • Drug delivery system of combining blood vessel blocking agent and double-drug-loading bionic liposome
  • Drug delivery system of combining blood vessel blocking agent and double-drug-loading bionic liposome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Synthesis of the dinitrobenzamide mustard derivative DMG-PR104A (DP) whose base part is dimethylamino

[0051] Dissolve N,N-dimethylglycine (DMG, 69mg, 0.67mmol) in anhydrous acetonitrile and incubate in an ice bath at low temperature, and 2-(7-azabenzotriazole)-N,N,N', N'-Tetramethyluronium hexafluorophosphate (320mg, 0.84mmol) and N-methylmorpholine (180μL, 1.78mmol) were dissolved in a small amount of anhydrous acetonitrile and added dropwise to the above solution, and reacted under ice cooling for 1~ 2 hours. PR104A (500mg, 1mmol) was dissolved in a small amount of anhydrous acetonitrile and added dropwise to the reaction flask, reacted under nitrogen protection at room temperature for 24 hours, and separated and purified to obtain DP.

[0052] The structure of DP is as figure 1 As shown in (A), structure confirmed mass spectrum and 1 H NMR spectrum as figure 1 (B) As shown in (C), the solvent used for nuclear magnetic resonance is CDCl 3 , the analy...

Embodiment 2

[0054] Example 2: In vitro cytotoxicity test to screen the optimal ratio of photosensitizer PPa and hypoxia-activated prodrug DP for synergistic effect.

[0055] Cytotoxicity was assessed by MTT viability assay. 4T1 cells were seeded into 96-well plates at a density of 2500 cells per well and incubated overnight. After the cells adhered to the wall, the old culture medium was discarded, and serial dilutions containing PPa and DP were added to each well to treat the cells, and after incubation for 4 hours, irradiated with a 660nm laser (100mW / cm 2 , 2 minutes), and then continue to culture for 20 hours to examine the cytotoxicity. Using the Chou-Talalay method (also known as the median pharmacodynamic method), the combination index value (Combination Index, CI) of PPa and DP is used to quantitatively describe the synergistic effect of the combined application of the two drugs. , additive or antagonistic effects. The calculation formula of CI is as follows. When CI1, there is...

Embodiment 3

[0061] Example 3: Preparation of photosensitizer / hypoxia-activated prodrug double-loaded liposomes

[0062] DSPC, cholesterol, DSPE-mPEG 2k Put it into an eggplant-shaped bottle according to the ratio of 3:1:0.05 (w / w), and add photosensitizer PPa, the ratio of PPa to total lipid is 1:200, dissolve it with a small amount of chloroform, and evaporate it under reduced pressure at 37°C Chloroform forms a lipid film. Add 300mM ammonium sulfate solution, hydrate at 65°C for 20 minutes, and sonicate for 10 minutes to prepare photosensitizer single-loaded liposomes. By means of agarose gel column chromatography, the external aqueous phase of the liposome was replaced with a mixed solution of 300mM sucrose and HEPES at pH 6, and the hypoxia-activated prodrug DP solution dissolved in ethanol was added dropwise, and the amount of DP and total lipid Drug-to-lipid ratio 1:10, incubate at 60°C for 20 minutes, stop drug loading in ice bath, and obtain photosensitizer / hypoxia-activated pro...

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Abstract

The invention belongs to the technical field of medicines, and relates to a drug delivery system of combining a blood vessel blocking agent and a double-drug-loading bionic liposome, in particular to preparation of a platelet membrane fused bionic liposome co-carrying a photosensitizer and a hypoxia activation prodrug, and application of combination of the bionic liposome with the blood vessel blocking agent in regulation of tumor microenvironment and inhibition of tumor growth and metastasis. The platelet membrane fused bionic liposome co-carrying the photosensitizer and the hypoxia activated prodrug is a liposome containing a platelet membrane, the photosensitizer and the hypoxia activated prodrug, wherein the molar ratio of the photosensitizer to the hypoxia activated prodrug is 1:1 to 1:20, the drug-lipid ratio of the photosensitizer to the total lipid is 1:(50-500), and the drug-lipid ratio of the hypoxia activated prodrug to the total lipid is 1:(2-50). The double-drug-loading liposome disclosed by the invention is preferably a double-drug-loading liposome of a dinitroenzamide mustard derivative and pyropheophorbide a. The drug delivery system provided by the invention can promote the activation of the hypoxia activation prodrug, and realizes photodynamic therapy and hypoxia selective chemotherapy synergetic anti-tumor therapy.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and relates to a drug delivery system combining a blood vessel blocking agent and a double-loaded biomimetic liposome, in particular to a biomimetic liposome co-loaded with photosensitizer and hypoxia-activated prodrug for platelet membrane fusion The preparation of plastids, and the combined administration of the plastids and blood vessel blocking agents are used in regulating tumor microenvironment and inhibiting tumor growth and metastasis. Background technique: [0002] Due to defective tumor vasculature and impaired lymphatic drainage, nanomedicines can accumulate in solid tumors through the enhanced permeability and retention effect (EPR effect). Although nano-preparations have been successful in preclinical animal tumor models, studies have shown that after systemic administration, only <0.7% of nano-preparations can be successfully delivered to tumor tissues to exert curative effects...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C309/66C07D295/205C07D211/62C07D211/58A61K31/27A61K31/4545A61K31/4465A61K31/40A61K31/495A61K31/5375A61K9/127A61K41/00A61K45/06A61K47/24A61K47/28A61P35/00A61P35/04
CPCC07C309/66C07D295/205C07D211/62C07D211/58A61K31/27A61K31/4545A61K31/4465A61K31/40A61K31/495A61K31/5375A61K45/06A61K41/0057A61K41/0061A61K41/0071A61K9/127A61K47/24A61K47/28A61P35/00A61P35/04
Inventor 孙进何仲贵陶文慧赵东阳
Owner SHENYANG PHARMA UNIVERSITY
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