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NRP-1 ligand polypeptide-polyethylene glycol-phosphatide compound, active targeting liposome drug delivery system mediated thereby and preparation method thereof

A technology of NRP-1 and phospholipid complexes, which can be used in liposome delivery, pharmaceutical formulations, preparations for in vivo tests, etc., and can solve problems such as no expression

Inactive Publication Date: 2012-06-27
SHANGHAI NAT ENG RES CENT FORNANOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

NRP-1 is significantly expressed in clinicopathological specimens of human glioma, and its expression level increases with the degree of malignancy of glioma, but it is not expressed in the corresponding normal tissue epithelial cells
There is no report on the use of NRP-1 receptor polypeptide-mediated nano-drug delivery system for tumor-targeted therapy

Method used

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  • NRP-1 ligand polypeptide-polyethylene glycol-phosphatide compound, active targeting liposome drug delivery system mediated thereby and preparation method thereof
  • NRP-1 ligand polypeptide-polyethylene glycol-phosphatide compound, active targeting liposome drug delivery system mediated thereby and preparation method thereof
  • NRP-1 ligand polypeptide-polyethylene glycol-phosphatide compound, active targeting liposome drug delivery system mediated thereby and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0044] Example 1: RPARPAR-PEG 3350 -Synthesis, purification and characterization of DSPE

[0045] a) Synthesis, purification and characterization of CRPARPAR

[0046] CRPARPAR polypeptides were synthesized using Boc solid-phase peptide synthesis technology. Weigh 0.4167g of arginine-modified resin (degree of substitution: 0.6mmol / g) into a peptide bottle, swell the resin with DMF for 20min, and drain it. Add about twice the resin volume of TFA and stir for 1 min, remove the TFA, then add TFA and operate in the same way once to remove the Boc protecting group. Use HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate) in DMF (N'N-dimethylformamide) solution and DIEA (N,N-di Isopropylethylamine) to activate Boc-Ala, add the resin and shake for 20min. After the reaction was completed, the reaction solution was removed, and the resin was washed with DMF. Subsequently, the remaining amino acids were sequentially connected according to the sequence of CRP...

Embodiment 2

[0049] Example 2: RPARPAR-PEG 2000 -DSPE ( 1,2- Synthesis, Purification and Characterization of Stearoyl Phosphatidylethanolamine)

[0050] Dissolve CRPARPAR polypeptide in PBS solution (pH7.0), take Mal-PEG 2000 - DSPE (maleimide-polyethylene glycol (molecular weight 2000)-1,2-stearyl phosphatidylethanolamine complex) was dissolved in DMF, the two were mixed and reacted with magnetic stirring, HPLC (high performance liquid chromatography ) to monitor the reaction, to be Mal-PEG 2000 - After the DSPE reaction is complete, the reaction is stopped, and excess CRPARPAR and DMF are removed by dialysis (molecular weight cut-off 3.5kDa). Freeze-dried to obtain RPARPAR-PEG 2000 - DSPE, HPLC and FTIR to characterize its structure. The HPLC spectrum shows that the retention time of the main peak moves from about 24 min in Figure A to about 14 min in Figure B; the FTIR spectrum shows that, compared with Figure A, the characteristic peaks of N-H and C=O in Figure B (located a...

Embodiment 3

[0051] Example 3: RPARPAR-PEG 3350 -DOPE( 1,2- Synthesis, Purification and Characterization of Oleoyl Phosphatidylethanolamine

[0052] Dissolve CRPARPAR polypeptide in PBS solution (pH7.0), take Mal-PEG 3350 -DOPE (maleimide-polyethylene glycol (molecular weight 3350)-1,2-oleoylphosphatidylethanolamine complex) was dissolved in DMF, the two were mixed and reacted with magnetic stirring, HPLC (high performance liquid chromatography) Monitor the reaction until Mal-PEG 3350 - Stop the reaction after the DOPE reaction is complete, and remove excess CRPARPAR and DMF by dialysis (molecular weight cut-off 3.5kDa). Freeze-dried to obtain RPARPAR-PEG 3350 -DOPE, HPLC and FTIR characterize its structure. The HPLC spectrum shows that the retention time of the main peak moves from about 24 min in Figure A to about 14 min in Figure B; the FTIR spectrum shows that, compared with Figure A, the characteristic peaks of N-H and C=O in Figure B (located at about 3420 and 1666cm -1...

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Abstract

The invention relates to an NRP-1 ligand polypeptide-polyethylene glycol-phosphatide compound, an active targeting liposome drug delivery system mediated thereby and a preparation method thereof. A carrier system comprises; a. phosphatide; b. cholesterol; c. methoxy polyethylene glycol-phosphatide compound; and d. polypeptide-polyethylene glycol-phosphatide compound containing an RPARPAR sequence. The above components are in a molar ratio of: a:b=5:1-1:5, a:c=1000:0.1-1000:100, and a:d=1000:0.1-1000:100. The system can carry out intravenous route drug administration and target the drug to a tumour position according to tumour EPR effect and RPARPAR mediation effect. The liposome drug delivery system can be applied to tumour diagnosis or targeting delivery of a treatment medicament.

Description

Technical field [0001] The present invention involves a NRP-1 ligand polypeptide-polyethylene-phospholipid complex, its mediated active targeting lipid drug delivery system and its preparation method. Background technique [0002] Tumor is the main disease that threatens human health and life. In recent years, its incidence has shown a significant upward trend.At present, the conventional treatment of tumors in clinical clinical is to remove the primary stove of the tumor and perform lymphatic cleaning, and perform systemic chemotherapy or radiotherapy.However, surgery cannot completely remove tumor cells and tumor metastatic lymph nodes, leading to recurrence of tumor; chemotherapy drugs have no selectivity to tumor tissue and have serious systemic toxic side effects; radiotherapy often causes patients with serious local partsSkin reactions, blood image changes, local mucosal reactions, etc.Because the tumor tissue has an EPR (Qualcommid transparency and retention) effect on nan...

Claims

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Application Information

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IPC IPC(8): C07K7/06A61K47/34A61K9/127A61K49/00A61P35/00A61K47/18
Inventor 闫志强杨一祎魏岱旭钟建周涓朱君金彩虹何丹农
Owner SHANGHAI NAT ENG RES CENT FORNANOTECH
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