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PH-sensitive phospholipid medicinal material as well as preparation method and application thereof

A phospholipid, sensitive technology, applied in the application, pharmaceutical formulation, edible phospholipid composition, etc., can solve the problem that it is difficult to effectively improve the targeting of anticancer drugs, cannot change the accumulation of drug-loaded liposomes, and reduce anticancer drugs. Toxic and side effects, etc., to achieve the effect of good target aggregation ability, good charge reversal ability, and long cycle time

Inactive Publication Date: 2014-12-10
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the above two pH-sensitive liposomes can change the release rate of drugs in normal tissues and tumor tissues, they cannot change the accumulation of drug-loaded liposomes in normal tissues and tumor tissues, and it is difficult to effectively improve the anticancer drugs. Targeting, reducing the toxic and side effects of anticancer drugs on normal tissues

Method used

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  • PH-sensitive phospholipid medicinal material as well as preparation method and application thereof
  • PH-sensitive phospholipid medicinal material as well as preparation method and application thereof
  • PH-sensitive phospholipid medicinal material as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] In this embodiment, the pH-sensitive phospholipid medicinal material is distearoylphosphatidylethanolamine-lysine-2,3-dimethylmaleic acid, and its structural formula is:

[0049]

[0050] Its preparation method is as follows:

[0051] (1) Amidation reaction of phosphatidylethanolamine and lysine with protective group

[0052] According to bis-tert-butoxycarbonyl-L-lysine (BOC-Lys-(BOC)-OH), condensing agent [equal molar 1-hydroxybenzotriazole (HOBT) and benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate (HBTU)], diisopropylethylamine (DIPEA) and distearoylphosphatidylethanolamine (DSPE) in molar ratios of 1.5:1, 3 :1, 6:1 metering of BOC-Lys-(BOC)-OH, HOBT, HBTU, DIPEA and DSPE;

[0053] Add BOC-Lys-(BOC)-OH, HOBT, HBTU, DIPEA and DSPE to chloroform to form a mixed solution. The amount of chloroform should make the concentration of DSPE in the mixed solution 1mmol / L. Stir the reaction at a speed of 52rpm for 24h, then filter the reaction solution an...

Embodiment 2

[0060] In this embodiment, the pH-sensitive phospholipid medicinal material is dioleoylphosphatidylethanolamine-lysine-2,3-diethylmaleic acid, and its structural formula is:

[0061]

[0062] Its preparation method is as follows:

[0063] (1) Amidation reaction of phosphatidylethanolamine and lysine with protective group

[0064] According to bisfluorenylmethoxycarbonyl-L-lysine (Fmoc-Lys-(Fmoc)-OH), cyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP) and dioleoylphosphatidylethanolamine The molar ratio of (DOPE) is 0.1:1, 1:1, 1:1 to measure Fmoc-Lys-(Fmoc)-OH, DCC, DMAP and DOPE respectively;

[0065] Add Fmoc-Lys-(Fmoc)-OH, DCC, DMAP and DOPE into dichloromethane to form a mixed solution. The amount of dichloromethane should make the concentration of DOPE in the mixed solution 10mmol / L. Under the protection of nitrogen, stir the reaction at a speed of 40rpm for 36h, then filter the reaction solution and concentrate the filtrate, add anhydrous ether to the conc...

Embodiment 3

[0072] In this embodiment, the pH-sensitive phospholipid medicinal material is 1-palmitoyl-2-oleoylphosphatidylethanolamine-lysine-2-methyl-3-ethylmaleic acid, and its structural formula is:

[0073]

[0074] Its preparation method is as follows:

[0075] (1) Amidation reaction of phosphatidylethanolamine and lysine with protective group

[0076] According to bisbenzyloxycarbonyl-L-lysine (Z-Lys(Z)-OH), diisopropylcarbodiimide (DIC), 4-dimethylaminopyridine (DMAP) and 1-palmitoyl-2 - Oleoylphosphatidylethanolamine (POPE) in molar ratios of 10:1, 10:1, 10:1 for metering Z-Lys(Z)-OH, DIC, DMAP and POPE;

[0077] Add Z-Lys(Z)-OH, DIC, DMAP and POPE to dichloromethane to form a mixed solution. The amount of dichloromethane should make the concentration of POPE in the mixed solution 50mmol / L. Stir the reaction at a speed of 60 rpm for 48 hours under protection, then filter the reaction solution and concentrate the filtrate, add acetone to the concentrated filtrate and place it...

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Abstract

The invention belongs to the field of medicinal materials and provides a pH-sensitive phospholipid medicinal material. A structural formula of the material is as show in the specification, wherein R1 is -CnH(2n+1) or -CnH2n, n ranges from 11 to 17; R2 is shown in the specification, wherein a is equal to 0, 1, 2, b is equal to 0, 1, 2. A preparation method for the pH-sensitive phospholipid medicinal material comprises the following steps: (1), carrying out amidation reaction on phosphatidyl ethanolamine and lysine with a protective group; (2), modifying phospholipid by virtue of the lysine with the protective group to remove the protective group for reaction; and (3), carrying out amidation reaction on lysine-modified phospholipid and acid anhydride. The medicinal material has good pH sensitivity and charge reversal capacity; and a medicine-carrying lipidosome prepared by use of the medicinal material can be gathered in a targeted manner in a tumor tissue, so that toxic and side effect of medicines on a normal tissue can be reduced.

Description

technical field [0001] The invention belongs to the field of medicinal materials, in particular to a pH-sensitive phospholipid medicinal material and its preparation method and application. Background technique [0002] Malignant tumors (carcinoma for short) are common and frequently-occurring diseases that endanger human life and health. Chemotherapy is one of the main means of cancer treatment. However, traditional anticancer drug preparations have no selectivity, and while killing tumor cells, they also kill normal cells, especially rapidly proliferating bone marrow cells, causing serious and even fatal toxic side effects. Studies have found that tumor tissue has biological characteristics different from normal tissue. Tumor cells grow vigorously and metabolize rapidly, producing a large amount of acidic products. However, the abnormal tumor vasculature cannot remove acidic products in time, resulting in a pH of 5.5-6.8, which is lower than the pH value of normal tissue...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/10A61K9/127A61K45/00A61K47/24A61P35/00
CPCY02P20/55
Inventor 顾忠伟李莉姜雷何斌
Owner SICHUAN UNIV
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