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Targeting nano drug delivery system aiming at brain glioma and preparation methods and application thereof

A nano-drug delivery system and brain glioma technology, which is applied in the direction of anti-tumor drugs, drug combinations, non-active ingredients of polymer compounds, etc., can solve the problems of mutual interference of targeted molecules and complex construction methods

Inactive Publication Date: 2014-10-29
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the common nano-targeted drug delivery system still has the following disadvantages. For example, it is difficult to selectively chemotherapy the tumor cells in the tumor-infiltrated area through the blood-brain barrier. The system has the function of penetrating the blood-brain barrier and targeting tumor cells at the same time, the construction method is complicated, and the targeting molecules may interfere with each other

Method used

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  • Targeting nano drug delivery system aiming at brain glioma and preparation methods and application thereof
  • Targeting nano drug delivery system aiming at brain glioma and preparation methods and application thereof
  • Targeting nano drug delivery system aiming at brain glioma and preparation methods and application thereof

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Effect test

Embodiment 1

[0031] Preparation of PEG-PLA nanoparticles (NP): Prepared by single milk method, accurately weigh 28mg MPEG-PLA, 2mgCOOH-PEG-PLA, dissolve in 1ml dichloromethane, add 5ml 0.6% sodium cholate, ice water bath Sonicate for 5 s, stop for 5 s, 20 times in total, remove dichloromethane by rotary steaming at 37°C for 15 min, centrifuge at 13500 rpm at 4°C for 50 min, discard the supernatant, disperse and precipitate with 0.5 mL deionized water to obtain nanoparticles.

[0032] Preparation of Peptide-PEG-PLA nanoparticles (PNP): Add carboxyl activation reagents NHS and EDC to the prepared deionized water-dispersed nanoparticles at 100mmol / L and 200mmol / L respectively, and after standing in the dark for 30min, use 100KD The ultrafiltration tube was ultrafiltered at 6000rpm for 20min three times. Before each ultrafiltration, the volume of the system was fixed to 4ml with deionized water, so as to completely remove the excess NHS and EDC of the activated carboxyl group. Collect nanoparti...

Embodiment 2

[0035] BCEC cells were divided into 5×10 4 The concentration of cells per well was inoculated in the Transwell cell culture pool, and the transmembrane electrical resistance (TEER) of monolayer BCECs was measured by Millcell-ERS, and the TEER value was selected to be greater than 200 Ω cm 2的 cell pool for experiments. Add 1ml paclitaxel carrier solution to each well, totally four groups: Taxol, NP-PTX, PNP-PTX and PNP-PTX+200μg / ml peptide-22 (PTX concentration is 10μg / ml), in 1h, 2h, At 4h, 8h, 12h, and 24h, 300 μl of samples were taken from the receiving pool and supplemented with an equal amount of fresh DMEM. The PTX content in the samples at different time points was analyzed by liquid chromatography. The results showed that the targeted functional molecules helped the nanoparticles cross the BBB, while Pre-incubation of the short peptide occupies the binding site of low-density lipoprotein, which can inhibit the transmembrane transport of PNP-PTX.

Embodiment 3

[0037] Near-infrared dye DiR labeled nanoparticles, normal mice were given 10 μg / kg dose of tail vein for 8 hours, and then the heart was perfused with 4% paraformaldehyde, and the brain was taken out, and the distribution of different nanoparticles in the brain tissue was observed by small animal live imaging. It shows that the distribution of nanoparticles modified by targeting functional molecules in the brain is significantly better than that of ordinary nanoparticles, suggesting that targeting functional molecules help nanoparticles cross the BBB into the brain parenchyma.

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Abstract

The invention belongs to the biological technical field, and relates to a targeting nano drug delivery system aiming at brain glioma modified by short peptides of a low density lipoprotein receptor, and a preparation method and application thereof. The drug delivery system comprises target functional molecules, a drug and nano carriers. The target functional molecules are from the short peptides of the low density lipoprotein receptor, obtained by phage display technology. The drug is enveloped in the nano carriers in an enveloping or covalent connection manner, and the short peptides are connected with the polyethylene glycol on the surfaces of the nanoparticles through covalent connection. The drug delivery system can invade and immerse tumor cells by hemato encephalic barrier, can enter into the tumor cells by EPR (enhanced permeability and retention effect), and can promote uptake of brain glioma cells by mediated effect of the low density lipoprotein receptor on the surfaces of the glioma cells so as to improve the effect of anti-brain glioma chemotherapeutics.

Description

technical field [0001] The invention belongs to the field of biological technology and relates to a tumor-targeted drug delivery system, in particular to a brain tumor-targeted nanometer drug-carrying system modified by short peptides for low-density lipoprotein receptors and its preparation method and application. Background technique [0002] Malignant glioma has become one of the major brain diseases affecting human health, with a high mortality rate. The 5-year survival rate of adult malignant glioma is less than 5%, but there is no effective cure. The main reasons are: (1) Brain tumors are highly infiltrating, with high surgical risk, difficult to completely resect, and easy to relapse; (2) Most anticancer drugs are difficult to penetrate the blood-brain barrier, and cannot treat tumors in the tumor-infiltrated area. (3) Most of the traditional anti-tumor drugs are not tissue-selective. While killing tumor cells, they also have a killing effect on normal cells, causing ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/34A61K47/42A61P35/00
Inventor 庞志清张波蒋新国高会乐沈顺
Owner FUDAN UNIV
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