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Multi-purpose targeting molecule and applications thereof

A molecularly targeted, multifunctional technology, applied in the field of pharmacy, can solve problems such as damage and low permeability

Active Publication Date: 2017-08-11
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Clinical practice shows that the drug treatment of brain tumors is very important in the comprehensive treatment strategy of brain tumors, but there are still many difficulties, mainly in the following aspects: ① There is a blood-brain barrier (BBB) ​​in the early stage of brain tumor growth, which makes about 98 % small molecule chemotherapeutic drugs and almost 100% proteins and other macromolecular drugs cannot enter the brain through the BBB; ②As the brain tumor grows, the BBB is partially destroyed, and the blood-brain tumor barrier (BBTB) is formed, which exists in the brain between the tumor tissue and capillaries in the brain, but the permeability is significantly lower than that of tumor neovascularization outside the brain, and only positively charged substances smaller than 12nm can pass through; The current focus, especially the multiple targeted delivery targeting the development characteristics of brain tumors, will have more obvious advantages

Method used

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  • Multi-purpose targeting molecule and applications thereof
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  • Multi-purpose targeting molecule and applications thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0044] Preparation of RGD-pHA, RGD-pHA-FAM, RGD-pHA-drug, RGD-pHA-PEG-DSPE

[0045] 1) Synthesis and characterization of RGD cyclic peptide-pHA (c(RGDyK)-pHA)

[0046] Using the Fmoc solid-phase synthesis method, c(RGDyK) polypeptide and Cys(Trt)-Acp-4-tert-Butoxybenzoic acid were prepared respectively, and the two were condensed to obtain c(RGDyK)-pHA;

[0047] The synthesis process of c(RGDyK) polypeptide is as follows: Fmoc-Gly-CTC resin was deprotected with 20% piperidine in N,N-dimethylformamide (DMF) solution for 15 minutes twice, and the Fmoc-protected amino acid was dissolved in 0.5 In HBTU and HOBt (solvent is DMF) of M, add DIEA and add to the resin, react at room temperature for 45 minutes; after the reaction, the resin is washed with DMF, 20% piperidine removes Fmoc protection, and the same reaction is carried out in sequence according to the amino acid sequence; sequence reaction After completion, 1% trifluoroacetic acid (TFA) cuts the polypeptide from the resin ...

Embodiment 2c

[0061] In vitro cell targeting verification of embodiment 2c (RGDyK)-pHA

[0062] 1) In vitro targeting of c(RGDyK)-pHA-FAM

[0063] In vitro targeting of glioma cell U87: take the monolayer cultured brain glioma cells (U87 cells) in the logarithmic growth phase, digest the monolayer culture cells with 0.25% trypsin, and use 10% fetal bovine The DMEM culture solution of serum was prepared into a single cell suspension, and 1×10 5 Cells were inoculated in a 12-well culture plate with a volume of 1 mL per well, and the culture plate was moved into a carbon dioxide incubator at 37°C and 5% CO 2 and saturated humidity conditions, after 24 hours, prepare c(RGDyK)-pHA-FAM at a concentration of 5 μM with DMEM culture solution containing 10% fetal bovine serum, and use FAM, c(RGDyK)-FAM and pHA-FAM The solution is used as a control, added to the cell culture plate, incubated at 37°C for 4 hours, discarded the supernatant, washed three times with PBS solution, fixed the cells with fo...

Embodiment 3c

[0065] In vitro targeting verification of embodiment 3c (RGDyK)-pHA-LS

[0066] 1) Preparation of c(RGDyK)-pHA-LS / FAM

[0067] Liposome membrane material prescription is HSPC / Chol / mPEG 2000 -DSPE / c(RGDyK)-pHA-PEG 3400 -DSPE (52:43:4:1, molar ratio), weigh the above membrane material and dissolve it in chloroform, remove the organic solvent by rotary evaporation under reduced pressure, and obtain a uniform lipid film, dry it in vacuum for 24 hours; add 5-FAM aqueous solution to hydrate , shaken in a water bath at 60°C for 2 hours to obtain a liposome suspension; in a water bath at 60°C, use a high-pressure homogenizer (if the liposome volume is less than 10mL, use a micro-extruder instead) to squeeze the liposomes sequentially Press through 400, 200, 100 and 50nm nuclear pore membranes to reduce the particle size; then use normal saline as the eluent to separate and remove unencapsulated drugs through a Sephadex G-50 column to obtain FAM-loaded Liposomes;

[0068] 2) In vit...

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Abstract

The invention belongs to the field of pharmacy, and relates to a multi-purpose targeting molecule, and applications of a compound and a drug delivery system modified by the multi-purpose targeting molecule in brain tumor diagnosis and treatment. According to the invention, the multi-purpose targeting molecule RGD-pHA being compatible to brain capillary endothelial cells and crossing the blood-brain barrier, being highly compatible to integrin and crossing the blood-brain tumor barrier, and targeting to the brain tumor cells is prepared by adopting a molecule splicing method; the invention further relates to preparation of fluorescein and a medicine modified by RGD-pHA, and a macromolecular carrier material, and applications of RGD-pHA in construction of the drug delivery system. The experimental result shows that the RGD-pHA can be specifically taken by brain capillary endothelial cells expressing the dopamine receptor for mediating the model drug or the nanometer drug delivery system to enter the brain, so that the model drug or the nanometer drug delivery system is specifically taken by the positive cells and the tumor sphere tissue expressing the integrin, the good brain tumor targeting effect is shown in vitro and vivo, and the efficiency in resisting brain tumor is obviously improved.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a multifunctional targeting molecule and its application, especially a multifunctional targeting molecule capable of targeting tumor cells across the blood-brain barrier and blood-brain tumor barrier, and its modified compound Drugs, drug delivery systems and their use in the preparation of preparations for the targeted diagnosis and treatment of brain tumors. Background technique [0002] Data show that brain tumors include primary brain tumors and brain metastases. Brain primary tumors and brain metastases account for a considerable number of cancer patients in my country, and are extremely harmful; at present, the incidence and mortality of brain primary tumors are in the top 10 of my country's tumor rankings, of which Glioma accounts for about 45% of primary brain tumors, and the incidence rate is even higher in children, whose median survival time is less than 16 months; the total inci...

Claims

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Application Information

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IPC IPC(8): A61K47/18A61K49/00A61P35/00
CPCA61K47/42A61K49/0019A61K49/0056
Inventor 陆伟跃扎琪亚谢操胡雪峰
Owner FUDAN UNIV
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