PH-sensitive liposome as well as preparation method and application thereof

A liposome and sensitive technology, applied in the field of biomedicine, can solve the problems of poor anti-tumor efficacy, tumor immune evasion, and low response rate

Pending Publication Date: 2022-03-01
SHANDONG UNIV QILU HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, the response rate among patients who rely solely on ICD-inducing agents is still low, and the clinical effect is unsatisfactory
The main reason is that the immune-stimulating ATP produced after ICD induction will be rapidly degraded into immunosuppressive adenosine by the highly expressed CD39 and CD73 in the tumo

Method used

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  • PH-sensitive liposome as well as preparation method and application thereof
  • PH-sensitive liposome as well as preparation method and application thereof
  • PH-sensitive liposome as well as preparation method and application thereof

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preparation example Construction

[0053] In a second aspect of the present invention, there is provided a method for preparing pH-sensitive liposomes described in the first aspect, the preparation method comprising the steps of:

[0054] (1) Synthetic ICD inducer prodrug;

[0055] (2) Preparation of polypeptide-PEG-N-distearoylphosphatidylacetamide DSPE-PEGn-pep: EDC and NHS were added to PLGLAG (pep, in response to high expression of MMP-2 in the tumor microenvironment) aqueous solution, and the carboxyl group was activated at room temperature , amino-PEG-N-distearoylphosphatidylacetamide DSPE-PEG n -NH 2 Dissolved in DMF, slowly added to it, stirred and reacted, purified by dialysis, and freeze-dried to obtain the final product (DSPE-PEGn-pep);

[0056] (3) Preparation of ICD inducer liposomes: (2,3-dioleoyl-propyl)-trimethylammonium-chloride salt (DOTAP), dioleoylphosphatidylcholine (DOPC), cholesterol succinate Monoester (CHEMS), the ICD inducer prodrug is dissolved in an appropriate amount of chlorofor...

Embodiment 1

[0072] Synthesis of OXA-C: 0.5 g of oxaliplatin (OXA) was dissolved in 8 mL of DMF in 30% H 2 o 2 and kept stirring at room temperature for 24 hours. Then add absolute ethanol to precipitate the crude product, filter it with suction, and dry it to obtain OXA-OH; redissolve the obtained solid in 5-10mL DMF, add 1g hexadecyl isocyanate, and react in the dark for 48h; add saturated saline A white precipitated mixture appeared, and after extraction with ethyl acetate, the mixture was concentrated in vacuo and dried in vacuo; the final white powder OXA-C was obtained by gel column chromatography; the nuclear magnetic resonance spectrum of the final product was as follows: figure 1 shown;

[0073] DSPE-PEG 2000 -Preparation of pep: Add 66mg EDC and 20mg NHS to activate carboxyl groups at room temperature for 2 hours in 40mg PLGLAG (pep, responding to high expression of MMP-2 in tumor microenvironment) dissolved in 10mL ultrapure water, and DSPE-PEG 2000 -NH 2 were dissolved in ...

Embodiment 2

[0078] Synthesis of OXA-C: 0.5 g of oxaliplatin (OXA) was dissolved in 8 mL of DMF in 30% H 2 o 2 and kept stirring at room temperature for 24 hours. Then add absolute ethanol to precipitate the crude product, filter it with suction, and dry it to obtain OXA-OH; redissolve the obtained solid in 5-10mL DMF, add 1g hexadecyl isocyanate, and react in the dark for 48h; add saturated saline A white precipitated mixture appeared, and after extraction with ethyl acetate, the mixture was concentrated in vacuo and dried in vacuo; the final white powder OXA-C was obtained by gel column chromatography; the final product was characterized by nuclear magnetic resonance and mass spectrometry;

[0079] DSPE-PEG 3400 -Preparation of pep: Add 66 mg EDC and 20 mg NHS to activate carboxyl groups at room temperature for 2 hours in 40 mg PLGLAG (pep, responding to high expression of MMP-2 in tumor microenvironment) dissolved in 10 mL ultrapure water, and DSPE-PEG with different PEG lengths 3400...

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Abstract

The invention relates to the technical field of biological medicines, in particular to a pH-sensitive liposome as well as a preparation method and application thereof. The pH-sensitive liposome is prepared from the following medicines and a liposome carrier according to the following amount of substance: (2, 3-dioleoyl-propyl)-trimethyl ammonium-chloride salt, dioleoyl phosphatidylcholine, cholesterol succinic acid monoester and DSPE-PEGn-pep in a molar ratio of (2 to 5): (0.5 to 1.5): (0.5 to 1.5): (0.1 to 0.3), the total mass ratio of the ICD inducer to the (2, 3-dioleoyl-propyl)-trimethyl ammonium-chloride salt, the dioleoyl phosphatidylcholine and the cholesterol succinic acid monoester is (5-12): 100; the mass ratio of the adenosine pathway blocking agent to the ICD inducer is (0.5-2): (0.5-3). The ICD inducer and the adenosine pathway inhibitor are combined for use, so that the problems that the anti-tumor curative effect is poor and tumor immunity escapes when only the ICD inducer is used for treatment are solved, and in-vivo co-delivery of the ICD inducer and the adenosine pathway inhibitor is realized by utilizing the liposome carrier; the pH sensitive characteristic of the POL effectively ensures that the POL is kept stable in the blood circulation process.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a pH-sensitive liposome and its preparation method and application. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Chemotherapy is one of the most classic cancer treatment methods, for example, the use of cytotoxic drugs such as anthracyclines, such as oxaliplatin, mitoxantrone, doxorubicin, cyclophosphamide, etc., can induce tumor cell immunity Induced cell death (ICD) to enhance anti-tumor immunity. Adenosine triphosphate (ATP) generated during this process can recruit DCs, thereby activating the maturation and infiltration of T cells and memory T cells into tumors, tr...

Claims

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Application Information

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IPC IPC(8): A61K47/60A61K47/69A61K45/06A61K31/555A61K33/24A61P35/00A61P35/02C07F15/00
CPCA61K47/60A61K47/6911A61K45/06A61K31/555A61K33/24A61P35/00A61P35/02C07F15/0093A61K2300/00
Inventor 王庆杰傅相蕾林贵梅
Owner SHANDONG UNIV QILU HOSPITAL
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