Tumor tissue and cell dual targeted mesoporous silicon dioxide nano drug-loading particle and preparation method thereof

A technology of mesoporous silica and nano-drug loading, which is applied in the direction of anti-tumor drugs, pharmaceutical formulations, medical preparations of non-active ingredients, etc., to achieve the effects of large pore volume, excellent biocompatibility, and good biosafety

Active Publication Date: 2019-02-22
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Aiming at the problem of immunotoxicity caused by targeted drugs, the present invention provides a dual-targeted mesoporous silica nanometer drug-loaded particle for tumor tissue and c

Method used

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  • Tumor tissue and cell dual targeted mesoporous silicon dioxide nano drug-loading particle and preparation method thereof
  • Tumor tissue and cell dual targeted mesoporous silicon dioxide nano drug-loading particle and preparation method thereof
  • Tumor tissue and cell dual targeted mesoporous silicon dioxide nano drug-loading particle and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] In this example, the small-molecule targeted drug MEK inhibitor AZD6244 was used as the drug to be loaded to prepare mesoporous silica nanoparticles drug-loaded particles with dual targeting of tumor tissue and cells. The steps are as follows:

[0065] (1) Preparation of mesoporous silica nanoparticles (MSNP)

[0066] Dissolve 100 mg of cetyltrimethylammonium bromide (CTAB) in deionized water to form a CTAB aqueous solution with a concentration of 2.1 mg / mL, adjust the pH value of the CTAB aqueous solution to 11.0 with 2 mol / L NaOH solution, and stir in a water bath Heat to 80°C, and after the temperature stabilizes, add tetraethyl orthosilicate dropwise into the CTAB aqueous solution at a rate of 180 μL / min according to the volume ratio of tetraethyl orthosilicate (TEOS) and CTAB aqueous solution at a ratio of 1:96 , stirred and reacted at 80°C for 3h to obtain a white precipitate, then centrifuged at a speed of 10000rpm for 15min, collected the precipitate, and disperse...

Embodiment 2

[0088] In this example, the drug release rate of MSNP-PAA-PEG prepared in Example 1 in different pH environments was tested.

[0089] The MSNP-PAA-PEG prepared in Example 1 was placed in PBS buffers with different pH conditions (pH=7.4, pH=6.8, pH=5.5, pH=4.5), samples were centrifuged at intervals, and the supernatant was taken. The drug release rate was tested by HPLC. The test conditions of HPLC are: mobile phase, methanol:water=8:2 (v:v), flow rate 1mL / min, detection wavelength 257.8nm, injection volume 20 μ L.

[0090] The release curves of MSNP-PAA-PEG under different pH conditions are as follows: Figure 8 shown by Figure 8 It can be seen that the release rate of drug AZD6244 is 9.9%, 20.1%, 49.82% and 71.02% under the conditions of pH value 7.4, 6.5, 5.5 and 4.5, and the drug release rate increases significantly with the decrease of pH value. Since the pH value of the normal pH environment in the body is about 7.4, it is not enough to protonate the PAA in the PAA f...

Embodiment 3

[0092] In this example, the in vitro cell uptake level and in vivo biodistribution of FITC-loaded mesoporous silica nanoparticles MSNP-PAA-PEG-FITC prepared in Comparative Example 1 were tested.

[0093] Melanoma cells SMM101 and SMM103, as well as lymphocytes EL4T, Jurkat and mouse spleen lymphocytes were treated with MSNP-PAA-PEG-FITC at a final concentration of 50 μg / mL and 25 μg / mL for 24 h, 48 h and 72 h, and then analyzed by flow cytometry The uptake of MSNP-PAA-PEG-FITC in tumor cells and lymphocytes was detected by cytometer and confocal microscope, and the results were as follows: Figures 9 to 11 as shown, Figure 9 is the endocytosis ratio of MSNP-PAA-PEG-FITC detected by flow cytometry in tumor cells. Figure 10 is the endocytosis ratio of MSNP-PAA-PEG-FITC detected by flow cytometry in lymphocytes. Figure 11 It is the result of quantitative analysis of MSNP-PAA-PEG-FITC in vitro tumor and lymphocyte uptake levels. Depend on Figures 9 to 11It can be seen that...

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Abstract

The invention provides a tumor tissue and cell dual targeted mesoporous silicon dioxide nano drug-loading particle. The tumor tissue and cell dual targeted mesoporous silicon dioxide nano drug-loadingparticle is constituted by a mesoporous silicon dioxide nano particle with the modified surface and a drug; the mesoporous silicon dioxide nano particle with the modified surface is constituted by amesoporous silicon dioxide nano particle body with the amine-modified surface, a polyacrylic acid film layer wrapping the mesoporous silicon dioxide nano particle body with the amine-modified surfacethrough the electrostatic effect, and polyethylene glycol connected with polyacrylic acid in the polyacrylic acid film layer through amido bonds; and the polyacrylic acid film layer serves as a blocking valve and can respond to change of the pH value to enable a pore passage of the mesoporous silicon dioxide nano particle with the amine-modified surface to be in a blocked or opened state, and thedrug is located in a pore passage structure of the mesoporous silicon dioxide nano particle body with the amine-modified surface. The nano drug-loading particle can effectively avoid damage of the targeted drug or the chemotherapy drug with lymphocytotoxicity to lymphocyte to and improves the joint treating effect of targeted therapy and immunological therapy on tumourstumors.

Description

technical field [0001] The invention belongs to the field of targeted drug-loaded materials, and relates to mesoporous silicon dioxide nanometer drug-loaded particles for dual targeting of tumor tissue and cells and a preparation method thereof. Background technique [0002] Hyperactivation of the mitogen-activated protein kinase (MAPK) pathway caused by genetic alterations is common in various cancers. Small molecule targeted therapy is considered to be one of the most promising approaches to treat cancer and genetic lesions. BRAF is present in approximately 60% of melanomas V600E Mutations that specifically target BRAF V600E The mutation-targeted drug vemurafenib (PLX4032) has shown unprecedented response rates in the treatment of metastatic melanoma. In a series of clinical trials, the objective overall response rate of patients treated with vemurafenib was 48%-53%, and the average benefit time was 5.3-6.7 months. However, after a period of targeted therapy, tumors de...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/60A61K47/58A61K45/00A61P35/00
CPCA61K45/00A61K47/58A61K47/60A61K47/6923A61P35/00
Inventor 石虎兵刘小伟张海元许杰
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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