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Functional targeting vector material distearoyl phosphatidylethanolamine-polyethylene glycol-polyethylenimine compound and modified liposome thereof

A polymer and targeting technology, applied in liposome delivery, active ingredients of heterocyclic compounds, drug combination, etc., can solve problems such as strong cytotoxicity and application constraints

Active Publication Date: 2017-06-06
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, macromolecular PEI has strong cytotoxicity to normal tissues in the human body, which severely restricts its application in vivo.

Method used

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  • Functional targeting vector material distearoyl phosphatidylethanolamine-polyethylene glycol-polyethylenimine compound and modified liposome thereof
  • Functional targeting vector material distearoyl phosphatidylethanolamine-polyethylene glycol-polyethylenimine compound and modified liposome thereof
  • Functional targeting vector material distearoyl phosphatidylethanolamine-polyethylene glycol-polyethylenimine compound and modified liposome thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Embodiment 1, functional targeting carrier material DSPE-PEG shown in formula I 2000 -PEI 600 Synthesis and characterization of

[0076] 20 μmol PEI 600 (x is 0-15, y is 1-10) and compound DSPE-PEG shown in 20 μ mol formula III 2000 -NHS was dissolved in 4ml of anhydrous DMF, and the reaction solution mixture was gently stirred with a magnetic stirrer for 24 hours at room temperature under the protection of argon to carry out the substitution reaction. After the reaction was completed, the crude product was obtained, and then the crude product was transferred to the regenerated cellulose dialysis bag (MWCO 2500), dialyzed in deionized water for 48h to remove unreacted PEI and DMF solvent. Next, the reaction solution was freeze-dried to obtain the product represented by formula I as a dry white powder, which was stored at -20°C.

[0077] The synthetic route of this product is as follows figure 1 shown.

[0078] The reaction products were verified by matrix-assisted...

Embodiment 2

[0080] Embodiment 2, preparation and characterization of liposome

[0081] 1) Preparation of targeted blank liposomes modified by PEI

[0082] a. Precisely weigh lecithin (EPC), cholesterol (CHOL), DSPE-PEG 2000 -PEI 600 、DSPE-PEG 2000 Add an appropriate amount of chloroform to the eggplant-shaped bottle at a molar ratio of 63:32.5:0.5:4 to dissolve, then remove the organic reagent by rotary evaporation and drying under reduced pressure in a 40°C water bath at a speed of 40 rpm, and form a layer on the bottom and inner wall of the eggplant-shaped bottle Thin uniform lipid film;

[0083] b. Add an appropriate amount of 250mM ammonium sulfate solution to the lipid film obtained in step 1) for hydration: first ultrasonicate in a water bath for 5 minutes at room temperature, and the ultrasonic energy is 100W, until milky white uniform thick liposomes are formed, then transfer to JY92-IID type ultrasonic Further ultrasonication was carried out in the cell pulverizer (setting th...

Embodiment 3

[0110] The drug effect experiment of the daunorubicin liposome of embodiment 3, PEI modification

[0111] (1) Cell uptake

[0112] Figure 5 Shown are the fluorescence intensity results of cell uptake of glioma stem cells (A) and C6 glioma cells (B) after administration of each preparation group. The administration groups were daunorubicin liposome group (b) and PEI-modified daunorubicin liposome group (c). The corresponding values ​​are represented in the histogram.

[0113] After administration and incubation for 4 hours, the uptake ratios of the daunorubicin liposome group and the PEI-modified daunorubicin liposome group obtained in step 2 of Example 1 in glioma stem cells were 1.00±0.03 and 2.18 respectively. ±0.17; the uptake ratios in C6 glioma cells were 1.00±0.01 and 2.28±0.11, respectively.

[0114] The results showed that the uptake ratio of C6 glioma cells and glioma stem cells to the PEI-modified daunorubicin liposome group obtained in step 2) of Example 1 was ...

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Abstract

The invention discloses a functional targeting vector material distearoyl phosphatidylethanolamine-polyethylene glycol-polyethylenimine compound and a modified liposome thereof. According to the invention, a DSPE-PEG2000-PEI600 compound is taken as a targeting molecule to modify a drug-carrying liposome surface, so that the drug can selectively gather in tumor cells through a blood brain barrier effectively so as to generate a targeting effect. For instance, the drug uptake rate of C6 glioma cells and glioma stem cells is increased significantly, so that the drug can have strongest selective concentrated distribution on mitochondria of C6 glioma cells and glioma stem cells, shows stronger growth inhibitory effect on glioma cells, and shows stronger effects of crossing the blood brain barrier and killing glioma stem cells, i.e. dual targeting effect, and the cycle time of the drug in ICR mice and the gathering degree in tumor tissues can be prolonged, thus prolonging the life time of organisms.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a functional targeting carrier material distearoylphosphatidylethanolamine-polyethylene glycol-polyethyleneimine (DSPE-PEG 2000 -PEI 600 ) compounds and modified liposomes thereof. Background technique [0002] Brain tumor is one of the major diseases threatening human health. As a malignant brain tumor, glioma is refractory mainly in the following aspects: the special location of glioma and its invasive growth characteristics make it impossible to completely remove it through surgical treatment; Radiation therapy for glioma has many side effects and is poorly tolerated; traditional chemotherapy drugs cannot penetrate the blood-brain barrier to reach the glioma area; residual glioma stem cells after comprehensive treatment can easily lead to tumor recurrence. How to make chemotherapy drugs cross the blood-brain barrier and clear the remaining glioma and its stem cell tumor is an urgent s...

Claims

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Application Information

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IPC IPC(8): A61K47/34A61K9/127A61K31/704A61K31/37C08G81/00A61P35/00
CPCA61K9/127A61K31/37A61K31/704A61K47/32C08G81/00
Inventor 吕万良赵炜煜张诚翔刘磊居瑞军沐黎敏曾凡谢红军
Owner PEKING UNIV
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