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Construction of photosensitive nano-micelle capable of inducing M1 type polarization of tumor-associated macrophages and anti-tumor application of photosensitive nano-micelle

A macrophage, tumor-related technology, applied in the construction of photosensitive nanomicelles and its anti-tumor application, can solve the problems of immune-related adverse reactions, low tumor selectivity, poor water solubility, etc., and achieve enhanced killing efficacy and better treatment. effect of effect

Active Publication Date: 2022-04-29
GUANGXI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, most of the current macrophage agonists are small molecular compounds or cytokines, which have problems such as poor water solubility, low selectivity for tumors, and sometimes serious immune-related adverse reactions in application.

Method used

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  • Construction of photosensitive nano-micelle capable of inducing M1 type polarization of tumor-associated macrophages and anti-tumor application of photosensitive nano-micelle
  • Construction of photosensitive nano-micelle capable of inducing M1 type polarization of tumor-associated macrophages and anti-tumor application of photosensitive nano-micelle
  • Construction of photosensitive nano-micelle capable of inducing M1 type polarization of tumor-associated macrophages and anti-tumor application of photosensitive nano-micelle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] The preparation of the nano system for photodynamic sensitization and induction of immune response, the specific steps are as follows:

[0070] (1) polyethylene glycol (mPEG-NH 2 , molecular weight 2000) (218 mg, 0.11 mM) was dissolved in 3 mL of anhydrous tetrahydrofuran (THF) as a macroinitiator. Then, Lys(Z)-NCA (N6-benzyloxycarbonyl-L-lysine cyclic anhydride, CASNo.: 1676-86-4) (1 g, 3.27 mM) was dissolved in 5 mL of anhydrous N,N-di Methylformamide (DMF), and the Lys(Z)-NCA solution was added to the mPEG-NH2 solution with a syringe under argon. The reaction mixture was stirred at 35° C. for 3 days under the protection of dry argon, and then the obtained product was precipitated into excess glacial ether, filtered, and vacuum-dried to obtain mPEG-PLL (Z).

[0071] (2) 4-Nitrophenyl chloroformate (70.5 mg, 0.35 mmol) dissolved in 5 mL of dichloromethane was added to pyridine (39 μL, 0.58 mmol) dissolved in 1 mL of dichloromethane at 0°C. Then mPEG-PLL(Z) (0.75 g, ...

Embodiment 2

[0077] The nano system synthesized in embodiment 1 is characterized:

[0078] 1. The product obtained in steps (1), (3), (4) and (5) is passed through nuclear magnetic resonance 1 Confirmed by H-NMR, the results are as follows figure 1 shown.

[0079] 2. Treat the nanomicelle PLAC@R848 synthesized in step (6) with trypsin (typsin, McLean) (final concentration 1mg / mL) in a shaker at 37°C for 24h, and at 98°C for 5min to deactivate the trypsin Live, compared with no trypsin treatment in a shaker at 37°C for 24h, through transmission electron microscopy (TEM), nanoparticle size and Zeta potential analyzer (DLS, Zeta potential), ultraviolet-visible spectrophotometer (UV-Vis) , Fluorescence spectrometer to characterize the nanomicelle PLAC@R848 before and after enzymolysis, using the product PLA obtained in step (4) as a control, the results are as follows figure 2 shown.

[0080] 3. The ability to produce ROS and NO of the nanomicelle PLAC synthesized in step (5) was confirme...

Embodiment 3

[0084] Investigate the generation of polymer micelle PLAC obtained by the method of Example 1 in 4T1 cells ROS and NO, and its influence on tumor cell HSP70 expression, the specific steps are as follows:

[0085] 1. Use DCFH DA as a fluorescent probe to observe the generation of ROS. Using 4T1 cells (Kunming Cell Bank of the Typical Culture Collection Committee of the Chinese Academy of Sciences) as a model, add polymer micellar PLAC (the concentration of ce6 in PLAC is equivalent to 150 μg / mL) Trypsin (final concentration 150 μg / L) was incubated at 37°C for 24h, and then at 98°C for 5min to inactivate trypsin. The 4T1 cells were divided into 6 groups and subcultured in the confocal dish for 48 hours. After the culture medium was removed, each group was added with PBS buffer (Control group), PBS buffer (Laser group), ce6 (ce6+Laser group), PLAC, PLAC ( PLAC+Laser group), enzyme-treated PLAC (incubated with trypsin aqueous solution at a final concentration of 1mg / mL at 37°C for...

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Abstract

The invention discloses construction of a photosensitive nano-micelle capable of inducing M1 type polarization of tumor-associated macrophages and an anti-tumor application of the photosensitive nano-micelle. According to the preparation method, the photosensitizer is connected to the block copolymer containing the polyarginine, then the block copolymer is self-assembled into the nano-micelle PLAC to serve as a carrier, and the PLAC has a good M1 macrophage polarization effect; meanwhile, the nano-micelle PLAC is further loaded with an immune agonist to obtain nano-particles, and after the nano-micelle PLAC is loaded with the immune agonist, the polarization effect is stronger. The constructed nano system has the characteristics of releasing an immune agonist in response to a tumor microenvironment and generating ROS and NO in light response, immune cells can be further activated through transmembrane expression of HSP70, more NO is generated to form a positive feedback cycle, photodynamic therapy and immunotherapy are achieved at the same time, and the nano system has a good application prospect. A new thought is provided for improving the prognosis of the patient with the highly metastatic tumor.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the construction of a light-sensitive nano-micelle capable of inducing the M1 polarization of tumor-associated macrophages and its anti-tumor application. Background technique [0002] Cancer is one of the most serious diseases that threaten human life. The traditional treatment methods are mainly surgery, chemotherapy and radiotherapy, but they only have a good therapeutic effect on early tumors, and have limited effects on advanced tumors, with large side effects and poor prognosis. Therefore, the development of precise, efficient, and long-acting anticancer treatment strategies is still an urgent clinical need. [0003] Photodynamic therapy (PDT), as a therapeutic method that generates cellular reactive oxygen species (ROS) in response to light to kill tumors, has shown promising clinical application prospects for solid tumors. Compared with traditional surgery, ...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K41/00A61K31/198A61K47/64A61K47/60A61K39/39A61K31/437A61P35/00A61P35/04A61P37/04B82Y5/00B82Y40/00
CPCA61K9/1075A61K47/64A61K41/0071A61K31/437A61K39/39A61K31/198A61K47/60A61P35/00A61P37/04A61P35/04B82Y5/00B82Y40/00A61K2039/55555A61K2300/00Y02P20/55
Inventor 陆翠霞张莹文烈伟
Owner GUANGXI UNIV
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