INGR/R9 dual-modified adriamycin targeted liposome and antitumor activity evaluation

A technology of targeting liposomes and double modification, applied in antitumor drugs, liposome delivery, organic active ingredients, etc., can solve problems such as large toxic side effects, tissue and organ damage, etc. , the effect of reducing poison damage

Pending Publication Date: 2022-03-15
JINLIN MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the present invention, a liposome co-modified with the tissue-penetrating tumor-targeting penetrating peptide iNGR and the cell-penetrating peptide nona-arginine R9 is used as a model to construct a doxorubicin-targeted lipid with iNGR / R9 double modification body drug, to solve the problem of severe side effects and serious damage to normal tissues and organs in the application process of doxorubicin in the prior art

Method used

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  • INGR/R9 dual-modified adriamycin targeted liposome and antitumor activity evaluation
  • INGR/R9 dual-modified adriamycin targeted liposome and antitumor activity evaluation
  • INGR/R9 dual-modified adriamycin targeted liposome and antitumor activity evaluation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: PEG-DSPE coupled to cell penetrating peptide R9 (DSPE-PEG 2000 -R9) Preparation

[0044] DSPE-PEG 2000 -R9 consists of C-R9 and DSPE-PEG 2000 -MAL was synthesized using a one-step synthesis method. DSPE-PEG 2000 -MAL and C-R9 are mixed at a molar ratio of 1:1 (C-R9: DSPE-PEG 2000 -MAL=1:1) was dissolved in the deoxygenated Hepes buffer (pH=7.2, 20mM Hepes) sonicated for 30min. The reaction solution was gently stirred at 4°C under nitrogen protection for 24 hours, and the reaction process should be protected from light. Afterwards, the obtained reaction solution was placed in a dialysis bag (molecular weight cut-off=2000Da) and dialyzed in deionized water for 48 hours, and the water was changed every 2 hours to remove free C-R9. After the reaction was completed, it was dialyzed and freeze-dried, and sealed and stored at -20°C for future use. The product was detected by flight mass spectrometry, and the results were as follows: Figure 7 The molecular w...

Embodiment 2

[0045] Example 2: PEG-DSPE coupled to tumor targeting peptide iNGR (DSPE-PEG 2000 -iNGR) preparation

[0046] DSPE-PEG 2000 -iNGR consists of C-iNGR and DSPE-PEG 2000 -MAL was synthesized using a one-step synthesis method. DSPE-PEG 2000 -MAL and C-iNGR were mixed at a molar ratio of 1:1 and dissolved in ultrasonic for 30min for deoxygenation, N 2 Flow in Hepes buffer (pH=7.2, 20mM Hepes) deoxygenated for 40min. The reaction solution was gently stirred at 4°C under nitrogen protection for 24 hours, and the reaction process should be protected from light. The obtained reaction solution was placed in a dialysis bag (molecular weight cut-off=2000Da) and dialyzed in water for 48 hours, and the water was changed every 2 hours. Afterwards, the reaction solution was pre-frozen in a freeze dryer for 24 hours, and a small hole was pierced on the top, and then drained for 48 hours. The product was detected by flight mass spectrometry, and the results were as follows: Figure 8 Th...

Embodiment 3

[0047] Example 3: Preparation of iNGR / R9 double modified doxorubicin hydrochloride targeted liposomes

[0048] 1. Preparation of iNGR / R9 double modified blank liposomes:

[0049] Precisely weigh phospholipids, cholesterol, DSPE-PEG 2000 -R9 and DSPE-PEG 2000 -iNGR (mass ratio 20:5:1:1) was dissolved in 10ml of chloroform, and was distilled under reduced pressure with a rotary evaporator at 45°C for 40min to form a lipid film, and then 2ml of 300mM (NH 4 ) 2 SO 4 , ultrasonic hydration in a water bath for 30min to form liposomes, and then use a small liposome extruder (Avestin, Canada) to extrude 20 times to control the particle size through a pore size 100nm polycarbonate membrane (WHATMAN, the U.S.). The _iNGR / R9 double modified blank liposome can be prepared.

[0050] 1. Pass the prepared iNGR / R9 co-modified liposomes through Sephadex G-50 column. The (NH 4 ) 2 SO 4 , to generate liposomes in vitro and in vivo (NH 4 ) 2 SO 4 gradient and pH gradient. Accurately ...

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Abstract

The invention relates to an iNGR / R9 dual functional peptide modified doxorubicin targeted liposome, which structurally comprises three parts, namely a doxorubicin hydrochloride liposome, a tumor targeted peptide iNGR and a cell-penetrating peptide R9, and is characterized in that an iNGR or R9 coupled PEG-DSPE functional branched chain is synthesized by adopting a Michael addition reaction; the iNGR / R9 dual-modified doxorubicin hydrochloride targeting liposome is prepared by adopting a film dispersion method and an ammonium sulfate gradient method, so that the liposome has better slow release capability and targeting capability, doxorubicin hydrochloride can efficiently enter tumor tissue cells, and the inhibition capability on tumor cell growth is enhanced. The iNGR / R9 dual-function peptide modified doxorubicin active targeting liposome has better active targeting property, can effectively reduce toxic damage of doxorubicin hydrochloride to normal tissues and cells, and reduces side effects.

Description

technical field [0001] The invention relates to the field of an anti-tumor targeting nano-medicine preparation, in particular to an iNGR / R9 double-modified doxorubicin-targeting liposome and evaluation of its anti-tumor activity. Background technique [0002] Liposomes have cell affinity and tissue compatibility, and can be adsorbed around the target cells for a long time, so that the drug can fully penetrate into the target tissue. Liposomes can also enter cells through fusion, and after being digested by lysosomes The drug is released in the cell; more importantly, the liposome improves the organ targeting of the drug, and can effectively achieve the effect of attenuating toxicity and increasing efficacy. Targeted preparations can maximize the delivery of drugs to and selectively concentrate in target organs, target tissues, and target cells. They can achieve low-toxicity and high-efficiency therapeutic effects, and are considered to be ideal anti-tumor dosage forms. Doxo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/62A61K47/69A61K31/704A61P35/00A61K49/00
CPCA61K47/62A61K47/6911A61K31/704A61P35/00A61K49/0008
Inventor 时念秋张慧锋马莹慧张彦飞于欢郝乘仪林晓影赵小萍
Owner JINLIN MEDICAL COLLEGE
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