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An intelligent drug delivery system regulated by neutrophil extracellular traps in tumor microenvironment and preparation method thereof

A neutrophil and tumor microenvironment technology, applied in the field of tumor and its microenvironment targeting and sustained release drug delivery system, can solve the problems of unsatisfactory curative effect and easy drug resistance, and achieve inhibition of proliferation and distant metastasis , Improve the effect of treatment, improve the effect of degradation effect

Active Publication Date: 2022-07-26
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In view of the unsatisfactory curative effect of the current single preparation only targeting tumor cells and easily causing drug resistance and other defects, a combined treatment method that not only targets tumor cells but also regulates NETs in the tumor microenvironment is provided to improve the therapeutic effect of malignant tumors

Method used

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  • An intelligent drug delivery system regulated by neutrophil extracellular traps in tumor microenvironment and preparation method thereof
  • An intelligent drug delivery system regulated by neutrophil extracellular traps in tumor microenvironment and preparation method thereof
  • An intelligent drug delivery system regulated by neutrophil extracellular traps in tumor microenvironment and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] After adding copper sulfate and sodium ascorbate to the surface polyethylene glycol azide P-NP / PTX solution, add (Pro)GRKKRRQRRRPQPLGLAGGC-DNaseⅠ polypeptide-protein conjugate solution, protect from light, click reaction under nitrogen protection for 6 hours, The reaction solution was refrigerated and centrifuged at 14,000 rpm, and the unreacted (Pro)GRKKRRQRRRPQPLGLAGGC-DNaseI in the supernatant was discarded. After washing twice with water, mP-NP was obtained. S-DNase / PTX. Example 1: Characterization of physicochemical properties of nanoparticles and mP-NPs used in cell migration experiments S - Synthesis of DNase / PTX nanoparticles

[0046] 1.0 g of dithioglycolic acid was mixed with 15 mL of anhydrous acetic anhydride, and under nitrogen protection, the reaction was stirred at 35 °C for 3 h. After the reaction was complete, acetic acid and excess acetic anhydride were removed by rotary evaporation. The rotary-evaporated product was dissolved in dichloromethane, 1....

Embodiment 2

[0052] Example 2: mP-NPs used in qualitative cellular uptake experiments S - Synthesis of DNase / PTX nanoparticles

[0053] PTX-SS-C 18 The synthetic steps are the same as those in Example 1. Weigh out Coumarin-6 and 5mg PTX-SS-C 18 Dissolve in 0.5mL absolute ethanol. At room temperature, the anhydrous ethanol solution was added dropwise to deionized water with constant stirring. After the dropwise addition was completed, the stirring was continued for 5 min, the ethanol was removed by rotary evaporation, and finally filtered through a 0.22 μm microporous membrane to obtain coumarin-6 labeling PTX prodrug nanoparticles.

[0054] Subsequent steps are the same as in Example 1, and the mP-NP of Coumarin-6 must be marked S - DNase / PTX nanoparticles. The nanoparticles can be taken up by tumor cells, and the amount of uptake is time-dependent and concentration-dependent, such as figure 2 shown.

Embodiment 3

[0055] Example 3: mP-NPs for in vivo pharmacodynamics S - Synthesis of DNase / PTX nanoparticles

[0056] 5.0 g of dithioglycolic acid was mixed with 75 mL of anhydrous acetic anhydride, and under nitrogen protection, the reaction was stirred at 35 °C for 3 h. After the reaction was complete, acetic acid and excess acetic anhydride were removed by rotary evaporation. The rotary-evaporated product was dissolved in dichloromethane, 7.45 g of stearyl alcohol and 325 mg of DMAP were added, and the reaction was stirred at room temperature for 15 h, terminated with 1% HAc, and the organic layer was dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography to obtain the intermediate HOOC-CH 2 -SS-CH 2 -COOC 18 . Put the HOOC-CH 2 -SS-CH 2 -COOC 18 HBTU and HBTU were dissolved in dichloromethane in an ice bath, and N,N-diisopropylethylamine was added dropwise. After 30 min of reaction, 1.0 g of PTX was added, and the reaction was con...

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Abstract

The invention discloses an intelligent drug delivery system regulated by extracellular trapping net of neutrophils in tumor microenvironment and a preparation method thereof. The intelligent drug delivery system is composed of intracellular reduced glutathione-responsive PTX prodrug nanoparticles as the core, DNase I grafted polylysine that can be cleaved and released by metal matrix proteases and connected in series with penetrating peptides as the shell. The "core-shell" type DNase I / PTX intelligent co-delivery vector is composed. PTX prodrug nanoparticles are developed using the prodrug molecule PTX‑SS‑C 18 Self-assembly is formed, and the nanoparticles are then coated with polylysine; the DNase I protein is grafted on the surface of the PTX prodrug nanoparticles coated with the MMP-9 substrate peptide tandem penetrating peptide as the connecting molecule. On the amino side chain of polylysine, an intelligent drug delivery system is constructed to achieve the strategy of NETs regulation in the tumor microenvironment and tumor cell targeting, and jointly improve the anti-cancer effect.

Description

technical field [0001] The invention belongs to the technical field of tumor and its microenvironment targeting and sustained-release drug delivery systems, relates to an intelligent drug delivery system regulated by neutrophil extracellular traps (NETs) in tumor microenvironment, and in particular relates to a novel deoxyribose A malignant tumor intelligent targeted nano-delivery system of nuclease combined with paclitaxel nanoparticles and a preparation method thereof. Background technique [0002] With the development of scientific level and medical technology, non-communicable diseases have become the main diseases that plague human health. Among them, malignant tumor has become the second leading cause of death after cardiovascular disease worldwide. According to the prediction of the World Health Organization, the number of deaths of malignant tumor patients worldwide will reach 12 million in 2030, of which two-thirds will occur in low- and middle-income countries. I...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/69A61K47/62A61K47/64A61K47/60A61K47/54A61K38/46A61P35/00A61K31/337
CPCA61K47/6935A61K47/6929A61K47/62A61K47/64A61K47/60A61K47/54A61K38/465A61K31/337A61P35/00C12Y301/21001A61K2300/00
Inventor 辛洪亮尹昊媛曹想叶璐陆红丹
Owner NANJING MEDICAL UNIV
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