PH-sensitive targeted LPNs (lipid poly-L-histidine hybrid nanoparticles) for encapsulating anti-tumor drugs

A polyhistidine-targeted phospholipid technology, which is applied in antineoplastic drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of low cell entry efficiency and ineffective release of drugs in cells

Inactive Publication Date: 2018-01-09
TIANJIN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its pH sensitivity causes LPNs to undergo potential reversal in the tumor microenvironment, from negative to near neutral, which promotes the uptake of the carrier into the cell, mediates lysosome escape in the lysosome after entering the cell, releases the drug quickly, and effectively kills the tumor. Tumor cells, so as to solve the problems of low cell entry efficiency of PEGylated nanocarriers and inability to effectively release drugs in cells after entry, and improve the therapeutic effect of drugs

Method used

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  • PH-sensitive targeted LPNs (lipid poly-L-histidine hybrid nanoparticles) for encapsulating anti-tumor drugs
  • PH-sensitive targeted LPNs (lipid poly-L-histidine hybrid nanoparticles) for encapsulating anti-tumor drugs
  • PH-sensitive targeted LPNs (lipid poly-L-histidine hybrid nanoparticles) for encapsulating anti-tumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] The preparation of the blank LPNs of embodiment 1

[0053]LPNs were prepared by a one-step precipitation method. A certain amount of polyhistidine (synthesized by Qiangyao Biotechnology Co., Ltd., molecular weight 3000, 4.1 mg) was precisely weighed and dissolved in anhydrous dimethyl sulfoxide solution, stirred for 2 hours, and used as the organic phase. Weigh a certain proportion of egg yolk lecithin (EPC, pharmaceutical grade, Shanghai Everett Pharmaceutical Technology Co., Ltd.) and phospholipid-PEG (DSPE-PEG, ≥98%, Shanghai Everett Pharmaceutical Technology Co., Ltd.) (the molar ratio is 1:3, 2.2g and 3.3g respectively, PEG molecular weight is 2000) in 2mM borax solution in 4% ethanol, stirred in a water bath at 65°C, as the water phase. Subsequently, the organic phase was dropped into the water phase under high-speed stirring (800-1200 rpm, preferably 1000 rpm), the water bath was removed, and the mixture was slowly lowered to room temperature and continued to st...

Embodiment 2

[0056] Example 2 Preparation of LPNs loaded with doxorubicin (DOX)

[0057] LPNs were prepared by a one-step precipitation method. Accurately weigh DOX (1 mg) and polyhistidine (molecular weight 3000, 4.1 mg) and dissolve them in anhydrous dimethyl sulfoxide solution respectively, add triethylamine in a molar ratio of 1:3 to DOX for 2 h to alkalinize. Then the two were mixed and stirred for 2h as the organic phase. Weigh a certain proportion of EPC and DSPE-PEG (the molar ratio is 1:3, respectively 2.2g and 3.3g, and the molecular weight of PEG is 2000) in 2mM borax solution of 4% ethanol, stir in a water bath at 65°C, as water Mutually. Subsequently, the organic phase was dropped into the water phase under high-speed stirring (800-1200 rpm, preferably 1000 rpm), the water bath was removed, and the mixture was slowly lowered to room temperature and continued to stir for 2 h. Finally, put it into a dialysis bag (3500kDa) and place it in 2mM borax dialysate, and replace the d...

Embodiment 3

[0058] Example 3 Preparation of LPNs loaded with docetaxel (PTX)

[0059] Accurately weighed PTX (1 mg) and polyhistidine (molecular weight 3000, 4.1 mg) were dissolved in DMSO solution and stirred for 2 h as the organic phase. Weigh a certain proportion of EPC and DSPE-PEG (the molar ratio is 1:3, respectively 2.2g and 3.3g, and the molecular weight of PEG is 2000) in 2mM borax solution of 4% ethanol, stir in a water bath at 65°C, as water Mutually. Subsequently, the organic phase was dropped into the water phase under high-speed stirring (800-1200 rpm, preferably 1000 rpm), the water bath was removed, and the mixture was slowly lowered to room temperature and continued to stir for 2 h. Finally, put it into a dialysis bag (3500kDa) and place it in 2mM borax dialysate, and replace the dialyzed fluid at room temperature for 1h, 2h, 4h, 8h, and 12h. The solution obtained in the dialysis bag is the prepared LPNs solution. Store in a refrigerator at 4°C for use: measure the par...

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Abstract

The invention relates to PH-sensitive targeted LPNs (lipid poly-L-histidine hybrid nanoparticles) for encapsulating anti-tumor drugs. The LPNs comprise raw materials in percentage by mass as follows:50%-80% of PHIS (poly-histidine) and 20%-50% of lipid (including lipid-PEG), wherein the lipid PEG accounts for 1%-100% of the total mass of lipid. A hydrophobic core consists of PHIS, and the surfaceis modified with polyethylene glycol and tumor targeted peptide. The PEGylated lipid surface has the characteristics of good biocompatibility, high stability and long in-vivo circulation. A histidinecore can encapsulate the hydrophobic anti-cancer drugs under the neutral condition, histidine is protonized in the tumor microenvironment to mediate the carrier potential to change from negative to near neutral, intake and endocytosis of a carrier arepromoted, the carrier mediates the lysosome to escape after endocytosis, the drugs are released rapidly, tumor cells are effectively killed, and accordingly, the problems that the PEGylated nano-carrier endocytosis efficiency is low and cannot release the drugs in cells effectively after endocytosis are solved. The surface of the carrier can bemodified with a tumor-specific antibody or ligand, the tumor targeting property is further improved, and the therapeutic effect is improved.

Description

technical field [0001] The invention relates to a pH-sensitive targeting phospholipid polyhistidine nanoparticle for loading anticancer drugs, which aims at increasing anticancer efficacy and reducing toxic and side effects, and is used for the treatment of tumors. Background technique [0002] Malignant tumors are one of the main causes of human death. Chemotherapy is a commonly used method for the treatment of malignant tumors in humans. However, most chemotherapeutic drugs are non-selective. While killing tumor cells, they also have a killing effect on normal cells, resulting in serious toxic side effects, such as the cardiotoxic effect of doxorubicin. In recent years, nano-formulations (liposomes, micelles, nanoparticles, etc.) have been widely used in tumor therapy. Studies have shown that nanoparticles with a particle size below 200nm can deliver drugs to tumor sites through the high permeability and retention effect (EPR) of solid tumors, reduce systemic side effect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K9/51A61K47/60A61K47/68A61K31/704A61K31/337A61K47/62A61P35/00
Inventor 高薇叶桂花
Owner TIANJIN MEDICAL UNIV
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