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Cell penetrating peptide modified nucleic acid-cation thermosensitive liposome and preparation method thereof

A heat-sensitive liposome and cationic lipid technology, applied in the field of biomedicine, can solve the problems of lack of metabolic pathways, low nucleic acid expression efficiency, high toxicity, etc., and achieve the effects of reducing cytotoxicity, avoiding pre-existing immunity, and inhibiting nucleic acid hydrolysis

Pending Publication Date: 2022-08-02
TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The preparation materials of existing cationic liposomes are mainly cationic lipids with quaternary ammonium salt groups, which lack mature metabolic pathways in vivo and are highly toxic
In addition, the entry pathway through electrostatic adsorption is mostly the "endocytosis-lysosome escape" pathway. Cationic liposomes are wrapped by endosomes formed by invagination of the cell membrane, and endosomes further become "digested" by lysosomes In cationic liposomes, only about 1% of the nucleic acid can escape from the lysosome completely and reach the cytoplasm to perform biological functions, and the expression efficiency of nucleic acid is low

Method used

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  • Cell penetrating peptide modified nucleic acid-cation thermosensitive liposome and preparation method thereof
  • Cell penetrating peptide modified nucleic acid-cation thermosensitive liposome and preparation method thereof
  • Cell penetrating peptide modified nucleic acid-cation thermosensitive liposome and preparation method thereof

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Embodiment 1

[0077]Liposomes were prepared with DOTAP:DOPE:DPPC:chol-CGYKK:MSPC=40%:10%:10%:10%:30% (mass ratio), and weighed DOTAP, DOPE, DPPC, chol-CGYKK, MSPC was dissolved in 3 mL of chloroform, the organic solvent was removed by rotary evaporation under reduced pressure at 50 °C, and a film was formed on the bottle wall; then 2.88 mL of nuclease-free water was added to hydrate for 40 min at 55 °C; then the liposomes were transferred into In the test tube, use the ultrasonic cell crusher probe to ultrasonically treat the liposomes for 2min (100W, work for 2s, interval for 2s), and then filter and granulate through a 0.22 μm sterile filter to obtain cationic thermosensitive liposomes. Its particle size distribution and Zeta see potential Figure 7 .

Embodiment 2

[0079] Liposomes were prepared with DOTAP:DPPC:chol-CGYKK:MSPC=40%:20%:10%:30% (mass ratio), and DOTAP, DPPC, chol-CGYKK and MSPC were weighed in proportion and dissolved in 3 mL of chloroform Then, 3.28 mL of nuclease-free water was added to hydrate for 40 min at 55 °C; then the liposomes were transferred to a test tube, and the cells were crushed using ultrasonic waves. The liposomes were ultrasonically treated with a machine probe for 2min (100W, working for 2s, interval 2s), and then filtered through a 0.22 μm sterile filter to obtain cationic thermosensitive liposomes. The particle size distribution and Zeta potential are shown in Figure 8 .

Embodiment 3

[0081] Liposomes were prepared with DOTAP:DOPE:DPPC:chol-CGYKK:MSPC=35%:10%:10%:15%:30% (mass ratio), and weighed DOTAP, DOPE, DPPC, chol-CGYKK, MSPC was dissolved in 3 mL of chloroform, the organic solvent was removed by rotary evaporation under reduced pressure at 50 °C, and a film was formed on the bottle wall; then, 2.93 mL of nuclease-free water was added to hydrate for 40 min at 55 °C; then the liposomes were transferred to Put it into a test tube, use an ultrasonic cell crusher probe to ultrasonically treat the liposomes for 2min (100W, work 2s, interval 2s), and then filter and granulate through a 0.22 μm sterile filter to obtain cationic thermosensitive liposomes. The particle size distribution and Zeta potential see Figure 9 .

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Abstract

The invention relates to a cell penetrating peptide modified cationic thermosensitive liposome and a preparation method thereof, the prescription comprises three lipid components, namely an ionizable cationic lipid component, an auxiliary lipid component and a sterol conjugate; the invention is mainly used for entrapment and delivery of nucleic acids such as siRNA, mRNA, DNA and the like. According to the characteristics of thermosensitive lipidosome, the storage stability at normal temperature and 4 DEG C is good, the fluidity of a lipidosome membrane at the in-vivo environment temperature (37.5 DEG C) is improved, the lipidosome directly delivers an entrapment substance to cytoplasm mainly in a membrane fusion manner, and an endocytosis-lysosome way is avoided, so that the integrity and space structure of active substances are protected, and the intracellular delivery efficiency is improved; the cell penetrating peptide-sterol conjugate is utilized to play dual roles of cholesterol and cations, the cholesterol is replaced, the dosage of a cationic lipid material is reduced, on one hand, the liposome is modified to carry positive charges, so that entrapment of active ingredients with negative charges is facilitated, and on the other hand, entrapment of the active ingredients with negative charges is facilitated. The cell penetrating peptide-sterol conjugate is metabolized into non-toxic amino acid in vivo, and compared with cationic lipid with a quaternary ammonium head structure, the toxicity is remarkably reduced. The cell penetrating peptide modified nucleic acid-cation thermosensitive liposome disclosed by the invention can be applied to the field of biological medicines.

Description

technical field [0001] The invention relates to a cell-penetrating peptide-modified nucleic acid-cationic thermosensitive liposome and a preparation method thereof, belonging to the technical field of biomedicine. Background technique [0002] Liposomes are closed vesicles formed by phospholipid bilayers, and the inner water phase can encapsulate water-soluble drugs, while lipid-soluble drugs can be encapsulated between the phospholipid bilayers. Liposomes have been widely used for the delivery of labile and poorly soluble drugs. Liposomes have advantages over other nanocarriers, including higher stability and biodegradability in body fluids and tissues, the ability to release drugs over a long period of time, and ease of large-scale production. [0003] Cationic liposomes are positively charged liposomes, mainly composed of positively charged lipid materials and neutral lipids. Cationic lipid, also known as cytotransfectin, is the core part of cationic liposome for cell t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/62A61K47/54A61K47/42A61K9/19A61K39/00A61K31/7105A61K31/713
CPCA61K47/6911A61K47/62A61K47/554A61K47/42A61K9/19A61K39/00A61K31/7105A61K31/713A61K2039/53
Inventor 李明媛李媛王浩猛贾琳严志红邓捷马文林李世勤张倩郁彭朱涛
Owner TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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