Dual-targeted liposome, and preparation method and application thereof

A liposome, dual-targeting technology, applied in the directions of liposome delivery, pharmaceutical formulations, medical preparations with non-active ingredients, etc., can solve the problems of less than 5%, short survival period, and difficulty in complete surgery, etc. High safety and good biocompatibility

Inactive Publication Date: 2013-08-14
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Glioma is the most common intracranial tumor, accounting for about half of brain tumors. At present, surgical resection is the main treatment for clinical treatment. Because glioma grows infiltratingly and has no clear boundary, it is difficult to completely remove it through surgery. Therefore, combined surgery is required. However, the sensitivity of glioma to treatment is low, so its recurrence is still unavoidable, which also leads to poor clinical efficacy, short survival period and high mortality rate. The average survival period of patients with high-grade glioma is less than one year, while the 5-year survival rate of malignant glioma is less than 5%, and its mortality rate ranks third after pancreatic cancer and lung cancer
However, applying it to brain diseases requires overcoming the blood-brain barrier. At the same time, the main adverse reactions of DOX currently used in clinical practice are common hair loss, bone marrow suppression, and myocardial toxicity, among which myocardial toxicity is one of the serious adverse reactions of DOX.

Method used

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  • Dual-targeted liposome, and preparation method and application thereof
  • Dual-targeted liposome, and preparation method and application thereof
  • Dual-targeted liposome, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] The preparation of embodiment 1 liposome

[0071] 1. Preparation of folic acid-modified liposomes

[0072] (1) Modification of folic acid

[0073] 1) Dissolve 6.25mg of folic acid in 0.5ml of anhydrous DMSO, add 125μl of pyridine, 8.15mg of dicyclohexylcarbodiimide (DCC) (both pyridine and DMSO are dehydrated with 4A molecular sieve), N 2 Protection, reaction at room temperature (25°C) in the dark for 4 hours to activate the carboxyl group;

[0074] 2) 25mg DSPE-PEG2000-NH 2 Add the above reaction system, avoid light and stir for 24 hours;

[0075] 3) Rotary evaporator evaporates under reduced pressure to remove pyridine in the mixture;

[0076] 4) After adding 3.5ml of water, pass through a 220nm oil film to remove the insoluble by-product dicyclohexyl, the supernatant is dialyzed with a dialysis bag of MWCO8000-14000, dialyzed twice with 2L of 50mM normal saline, and dialyzed three times with water, each time for 12h, DSPE-PEG2000-F was obtained.

[0077] (2) Pr...

Embodiment 2

[0091] Example 2 Ligand Synthesis and Characterization of Preparations

[0092] (1) NMR detection of DSPE-PEG2000-F

[0093]Folic acid, DSPE-PEG2000-NH 2 and the synthesized product were dissolved in DMSO for NMR detection.

[0094] In Figure 1, a represents the synthesized product, b represents folic acid, and c represents DSPE-PEG2000-NH2.6.0-9.0ppm is the hydrogen peak on the benzene ring structure of folic acid, 3.56-3.75ppm is the hydrogen peak of polyoxyethylene, 2.48ppm Because it is the γ of Glu in the folic acid molecule, the hydrogen peak on β-CH2, the existence of the three indicates the existence of folic acid and polyoxyethylene in the product structure, indicating that DSPE-PEG2000-F was successfully prepared, because the lipid modified by folic acid Both DSPE-PEG2000-F is used as one of the raw materials for liposomes and dual-targeted liposomes, so folic acid has been successfully modified in liposomes modified with folic acid and dual-targeted liposomes.

...

Embodiment 3

[0105] Example 3 Release of dual-targeted doxorubicin liposomes

[0106] The in vitro release of doxorubicin liposomes co-modified with folic acid and transferrin (ie, dual-targeted doxorubicin liposomes or doxorubicin dual-targeted liposomes) was determined by dialysis.

[0107] In the dialysis bag of MWCO8000-14000Da, place 5ml total amount and be 1mg doxorubicin solution and doxorubicin preparation respectively, the external phase of dialysis is 30ml release fluid, and release fluid is the phosphate buffer saline (PH7.4, concentration 10mM) that contains 0.5% Tween80 ), 37°C, 75 times / min shaking, sample 1ml at regular intervals, and add 1ml of fresh release solution at the same time, after the sample is centrifuged at high speed, take the supernatant and enter the HPLC to determine the DOX content.

[0108] Figure 4 In vitro release curves of doxorubicin solution and double-ligand modified doxorubicin liposomes (that is, doxorubicin liposomes co-modified with folic acid ...

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Abstract

The invention discloses a dual-targeted liposome, and a preparation method and application thereof. The dual-targeted liposome comprises liposome and ligands for surface modification, wherein the ligands are folic acid and transferrin. The invention also provides a preparation method of the dual-targeted liposome, and application of the dual-targeted liposome in preparation of a drug for treating brain glioma. The dual-targeted liposome disclosed by the invention is modified by two ligands, plays the dual-targeted role, and can help doxorubicin hydrochloride span a blood brain barrier; and transferrin and folic acid of the dual-targeted liposome disclosed by the invention are safe and nontoxic, are inherent ingredients in the body, and are high in security and good in biocompatibility.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a dual-target liposome and its preparation method and application. Background technique [0002] Glioma is the most common intracranial tumor, accounting for about half of brain tumors. At present, surgical resection is the main treatment for clinical treatment. Because glioma grows infiltratingly and has no clear boundary, it is difficult to completely remove it through surgery. Therefore, combined surgery is required. However, the sensitivity of glioma to treatment is low, so its recurrence is still unavoidable, which also leads to poor clinical efficacy, short survival period and high mortality rate. The average survival period of patients with high-grade glioma is less than one year, while the 5-year survival rate of malignant glioma is less than 5%, and its mortality rate ranks third after pancreatic cancer and lung cancer. [0003] Chemotherapy for glioma is usua...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00A61K47/22A61P25/00A61K31/704A61K47/42A61K9/127
Inventor 韩旻吕清李黎明陈芝兰傅应华高建青
Owner ZHEJIANG UNIV
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