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C(lyp-1) polypeptide and nano-delivery system constructed thereby and application of nano-delivery system

A nano-drug delivery system, lyp-1 technology, is applied in the fields of peptides, anti-tumor drugs, drug combinations, etc., which can solve the problems affecting the application, destruction, and poor stability of disulfide bond structure of LyP-1, and improve the targeted delivery. effect of medicine

Inactive Publication Date: 2015-02-11
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the LyP-1 has shown a certain active targeting function, LyP-1 still has the following defects in the chemical structure; LyP-1 is a cyclic peptide that is cyclized with a disulfide bond, and the disulfide bond structure is stable Poor sex, easy to be destroyed by glutathione reductase in the blood, which affects the application of LyP-1 in the body to a certain extent

Method used

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  • C(lyp-1) polypeptide and nano-delivery system constructed thereby and application of nano-delivery system
  • C(lyp-1) polypeptide and nano-delivery system constructed thereby and application of nano-delivery system
  • C(lyp-1) polypeptide and nano-delivery system constructed thereby and application of nano-delivery system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 Synthesis, purification and characterization of c(LyP-1), LyP-1, FAM-c(LyP-1) and FAM-LyP-1

[0073] 1. Synthesis, purification and characterization of c(LyP-1) and LyP-1

[0074] Synthesize linear peptide LyP-1-2H and c(LyP-1)-Mpr(Trt)-Leu; when synthesizing LyP-1-2H, take by weighing Boc-Cys(Mbzl)-PAM resin 0.4167g (substitution degree 0.6mmol / g) In the peptide bottle, the resin was swelled with DMF for 20 minutes, and then drained; add TFA about twice the volume of the resin to stir the reaction to remove the Boc protecting group, remove the TFA, and then add TFA to perform the same operation once; After washing the resin with DMF, add Boc-Gly activation solution (activated with DMF solution of HBTU and DIEA), shake the reaction; after the reaction, remove the reaction solution, and wash the resin with DMF; then use the above method to follow the sequence of LyP-1 Connect the remaining amino acids; after the reaction, wash the resin and remove the protect...

Embodiment 2c

[0079] Example 2c (LyP-1) stability and affinity evaluation

[0080] 1. c(LyP-1) serum stability evaluation

[0081]c(LyP-1) and LyP-1 were respectively mixed with 25% rat serum, and the peptide concentration was 1 mg / ml. Draw 100 μl of biological sample solution at 0, 0.167, 0.5, 1, 2, 4, 6 and 8 hours respectively, add 20 μl of TCA solution to precipitate serum protein, vortex, centrifuge at 13000 rpm. / min for 10 minutes, and absorb the supernatant solution, HPLC injection to detect the concentration of peptides; the results are as follows figure 2 shown.

[0082] 2.c(LyP-1) affinity evaluation

[0083] 2.1c (LyP-1) and p32 protein affinity evaluation

[0084] 2.1.1 Fluorescence polarization experiment

[0085] FP experiments were performed using a microplate reader with fluorescence bias measurement mode; p32 protein solutions of different concentrations (0.9nM~3.0×10 4 nM) 10μl, then add FAM-c(LyP-1), FAM-LyP-1 PBS (pH7.4) solution 10μl, so that the final concentrat...

Embodiment 3

[0090] Example 3 Construction and Characterization of c(LyP-1)-PEG-Liposome Drug Delivery System

[0091] 1. Synthesis, purification and characterization of c(LyP-1)-PEG-DSPE, LyP-1-PEG-DSPE

[0092] The first is to synthesize LyP-1(2Acm)-Cys linear peptide according to the above solid-phase synthesis method, that is, replace Boc-Cys(Mbzl) in the original sequence with Boc-Cys(Acm), and finally connect Boc-Cys(Mbzl) . After deprotection, cleavage, purification and lyophilization, the pure LyP-1(2Acm)-Cys was obtained.

[0093] Dissolve c(LyP-1) and LyP-1(2Acm)-Cys in PBS solution (pH7.0) respectively, take Mal-PEG-DSPE and dissolve it in DMF, drop the DMF solution into the PBS solution, and magnetically stir the reaction 1h, excess c(LyP-1), LyP-1(2Acm)-Cys and DMF were removed by dialysis (molecular weight cut-off 3.5kDa); freeze-dried to obtain c(LyP-1)-PEG-DSPE and linear LyP -1(2Acm)-PEG-DSPE; Finally, take the straight-chain LyP-1(2Acm)-PEG-DSPE and dissolve it in meth...

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Abstract

The invention belongs to the fields of polypeptides, high-polymer materials and pharmaceutics, and relates to an amido bond cyclized polypeptide c(LyP-1) and an application thereof to a tumor active targeting nano-delivery system. The sequence of the c(LyP-1) is CGNKRTRGA, and a high-polymer carrier material modified by the c(LyP-1) is constructed into a nano-delivery system. As proved by experimental results, the cyclic nonapeptide c(LyP-1) cyclized by an amido bond has higher blood stability, receptor protein binding activity and tumor cell affinity activity than a cyclic nonapeptide (LyP-1) cyclized by using a disulfide bond. A nano-delivery system lipidosome and the like constructed by the high-polymer carrier material modified by the c(LyP-1) have higher tumor tissue targeting properties and better tumor growth resisting effects, and can be used for restraining the regeneration of tumor lymphatic vessels more effectively and preventing the lymphatic metastasis of tumors. As a targeting molecule which can be used for mediating the nano-delivery system in targeting tumor resistance and prevention of tumor lymphatic metastasis, the c(LyP-1) has a good application prospect.

Description

technical field [0001] The invention belongs to the fields of polypeptides, polymer materials and pharmaceutics, and relates to a novel LyP-1 polypeptide and its constructed nano drug delivery system and application, in particular to an amide bond cyclized polypeptide c(LyP-1) and its modification polymer materials, and the constituted active targeting nano-drug delivery system, especially involving the amide bond ring nonapeptide c(LyP-1) and its modification on polymer materials, and the entrapment of c(LyP-1) modification An active targeted nano drug delivery system for anti-tumor drugs, and its application in the preparation of anti-tumor, tumor lymphatic metastasis inhibition and anti-lymphatic metastasis tumor targeted therapy drugs. Background technique [0002] Drug chemotherapy is one of the main means of clinical tumor treatment, because of its lethality to normal cells, it has the disadvantage of high toxicity and side effects. In recent years, nano drug delivery...

Claims

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Application Information

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IPC IPC(8): C07K7/64A61K47/42A61K9/127A61K9/107A61K9/14A61P35/00
Inventor 陆伟跃王飞吴美霖谢操张小雨高洁
Owner FUDAN UNIV
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