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Phospholipid targeting mitochondria and application

A technology of mitochondria and phospholipids, applied in the field of mitochondria-targeted phospholipids, pH-sensitive and mitochondria-targeted phospholipids, can solve the problems of restricting clinical transformation and application, the synthesis process of poorly permeable polypeptides, and the non-specific toxicity of cationic substances. Effect of cellular uptake, reduction of non-specific toxicity, good therapeutic effect

Active Publication Date: 2019-11-05
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the non-specific toxicity of cationic substances, poor lesion permeability and complex peptide synthesis process seriously restrict the clinical transformation and application of such substances.

Method used

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  • Phospholipid targeting mitochondria and application
  • Phospholipid targeting mitochondria and application
  • Phospholipid targeting mitochondria and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] In this embodiment, the mitochondria-targeted phospholipid is distearoylphosphatidylethanolamine-arginine (G1R), and its structural formula is:

[0052]

[0053] Its preparation method is as follows:

[0054] Take 0.75g (0.75mmol) of DSPE and dissolve it in 15mL of anhydrous chloroform under the protection of nitrogen. Another 1 mL of DIPEA (6.00 mmol) was stirred into the DSPE solution at 0°C. Then 0.79g Boc-Arg(Pbf)-OH (0.79mmol), 0.2g HOBT (0.2mmol) and 0.57g HBTU (1.5mmol) were co-dissolved in 2.5mL of DMF, added to the reaction flask containing DSPE, and then in The reaction was continued for 24 hours at room temperature. After the reaction was finished, the reaction product was repeatedly washed several times with saturated sodium bicarbonate, sodium bisulfate and sodium chloride solution, and then dried with magnesium sulfate for 2 hours. Finally, after the solvent was removed, it was purified by silica gel column chromatography, and the eluent was dichlorome...

Embodiment 2

[0056] In this embodiment, the mitochondria-targeted phospholipid is distearoylphosphatidylethanolamine-second-generation arginine (G2R), and its structural formula is:

[0057]

[0058] Its preparation method is as follows:

[0059] Weigh H-Lys-OMe·2HCl 2.00g (8.6mmol), Boc-Arg(Pbf)-OH 13.56g (13.56mmol), HBTU 9.78g (25.8mmol), HOBT 3.36g (3.36mmol), under nitrogen protection were dissolved together in 50 mL of anhydrous DMF, and then 11.4 mL of DIPEA (68.8 mmol) was added to the above mixture in an ice-water bath, and the reaction was stirred at room temperature for 48 h. Then, the products were washed with saturated NaHCO 3 , NaHSO 4 and NaCl solution several times. The product was then mixed with MgSO 4 Mix for 2h to remove water. After removing the solvent, the product was purified by silica gel column chromatography, the eluent was dichloromethane:methanol (12:1, v / v), and the product was collected. Weigh 8.00 g (6.8 mmol) of the product in 100 mL of methanol so...

Embodiment 3

[0061] In this embodiment, the mitochondria-targeted phospholipid is distearoylphosphatidylethanolamine-second-generation lysine (G2K), and its structural formula is:

[0062]

[0063] Its preparation method is as follows:

[0064] H-Lys-OMe.2HCl (1.00g, 4.3mmol), Boc-L-lys(Boc)-OH (4.46g, 12.9mmol), HBTU (4.89g, 12.9mmol), HOBT (1.68g, 12.9mmol ) was dissolved in anhydrous DMF (25 mL). Add DIPEA (5.7mL, 34.4mmol) in ice-water bath and stir at room temperature for 48 hours, then wash with saturated NaHCO 3 , NaHSO 4 , NaCl solution to wash the mixed solution several times. with MgSO 4 After drying for 2 h and removing the solvent, the product was purified by silica gel column chromatography (DCM / MeOH, 12 / 1, v / v). Take it (4.00g, 3.4mmol) and place it in 50mL NaOH in MeOH (1mol / L) solution for 4h to expose the carboxyl group. After removal of MeOH, the mixture was dissolved in H 2 O, adjust to neutral pH. Extracted with DCM, MgSO 4 Dry for 2h. The product (1.81g, 1...

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Abstract

The invention designs and constructs phospholipid having disease focus part targeting accumulation, reducing non-specifically toxicity, being high in disease focus tissue permeability and targeting mitochondria. The hydrophilic head of the phospholipid is in key connection with (3-carboxypropyl) triphenyl phosphine, arginine, lysine or polypeptide consisting of arginine and / or lysine. The phospholipid can be applied to a medicine delivery carrier, so that medicines can be efficiently enriched in tissue, can be highly permeated and can target cell mitochondria.

Description

technical field [0001] The invention belongs to the field of drug delivery systems, and relates to a mitochondria-targeted phospholipid, in particular to a pH-sensitive mitochondria-targeted phospholipid and an application thereof. Background technique [0002] Mitochondria play an important role in the physiological and pathological development of eukaryotic cells, and their dysfunction is closely related to the occurrence and development of various diseases. The key to mitochondria-targeted therapy is to efficiently deliver bioactive molecules to the interior of mitochondria. [0003] Under physiological conditions, the proteins required for mitochondrial metabolism also need to be synthesized in the cytoplasm and then transported from the cytoplasm to the mitochondria. Currently, mitochondrial targeting signal peptides (MTSs), protein transduction domains (PTDs), and delocalized lipophilic cations (such as triphenylphosphine, TPP) are commonly used as mitochondrial targe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/24A61K47/18A61K47/42A61K41/00A61K9/127A61P35/00
CPCA61K47/24A61K47/183A61K47/42A61K41/0057A61K41/0052A61K9/127A61P35/00A61K2300/00
Inventor 姜雷蒋锡群周森森
Owner NANJING UNIV
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