Polymer vesicle nano STING agonist as well as preparation method and application thereof

A polymer and agonist technology, applied in drug combination, drug delivery, pharmaceutical formulation, etc., can solve the problems of high molecular weight PEI transfection ability, hindering in vivo application, low transfection efficiency, etc., and achieve a strong anti-tumor immune response , improve cell uptake, improve the effect of immune activity

Pending Publication Date: 2021-08-03
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the strong transfection ability and high toxicity of high-molecular-weight PEI hinder its practical in vivo application.
Low molecular weight PEI has low toxicity but low transfection efficiency

Method used

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  • Polymer vesicle nano STING agonist as well as preparation method and application thereof
  • Polymer vesicle nano STING agonist as well as preparation method and application thereof
  • Polymer vesicle nano STING agonist as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The synthesis of PEG-P(TMC-DTC)-PEI and PEG-P(TMC-DTC)-SP can be found in the applicant’s published patents or articles. The specific preparation method is the prior art, such as:

[0040] In the first step, polymer PEG-P(TMC-DTC) was prepared by ring-opening polymerization. Weigh MeO-PEG-OH (0.50 g, M n =5.0 kg / mol, 100 μmol), DTC (0.23 g, 1.18 mmol), TMC (1.52 g, 14.55 mmol), they were dissolved in 7.0 mL of dichloromethane (DCM), stirred on a magnetic stirring table While adding diphenyl phosphate (DPP, DPP / OH molar ratio of 10 / 1) as a catalyst. Put the sealed airtight reactor in an oil bath at 40 °C, stir (600 rpm) for 48 h, and use triethylamine as the reaction terminator. According to the volume ratio of polymer solution / glacial ether of 1:15, precipitate twice in glacial ether, centrifuge, and vacuum dry to obtain the polymer PEG-P (TMC-DTC).

[0041] In the second step, N', N'-carboxydiimidazole (CDI) is used to activate the hydroxyl group at the end of PEG-P ...

Embodiment 2

[0049] Example 2 Characterization of empty vesicles and CDN-loaded polymersomes (CPs / PEI-CDN or CPs / SP-CDN)

[0050] The size, size distribution, and surface Zeta potential of the vesicles were determined by dynamic light scattering (DLS) and electrophoresis techniques. Through particle size tracking, the stability of CPs / PEI-CDN and CPs / SP-CDN in 10% FBS solution, high dilution and long-term storage at 4 ℃ and the reduction response behavior under 10 mM GSH were analyzed. The drug loading (DLC) and encapsulation efficiency (DLE) of ADU-S100 were measured by NanoDrop, with the empty carrier of equal concentration and particle size as the background, the absorbance at 260 nm was recorded, according to the known concentration of ADU-S100 Calculate the standard curve drawn from the absorbance values. Representation diagram see image 3 , (A) CPs / PEI and (B) CPs / SP particle size distribution, TME electron micrograph (scale is 50 nm), and (C) CPs / PEI and (D) CPs / SP SLS test; (E) ...

Embodiment 3

[0057] Example 3 Cytotoxicity experiment of blank vesicles

[0058]In order to study the in vitro toxicity of blank vesicles (CPs / PEI, CPs / SP), B16F10, DC 2.4 and RAW 264.7 cells were plated in 96-well plates at a density of 2000 / well, 5000 / well and 10000 / well, respectively After incubation for 24 h, blank vesicles of different concentrations were added, and after 24 h of co-cultivation, 10 μL of sterile MTT solution (5 mg / mL) was added to each well and placed in an incubator for further incubation for 4 h. Slowly aspirate the medium with a pipette gun, add 150 μL DMSO to each well to dissolve the blue-purple formazan crystals, and measure the absorbance at 570 nm of each well with a microplate reader. Cell viability was calculated by the ratio of the absorbance of each well to that of the control group.

[0059] Although PEI has shown great advantages in the efficient delivery of nucleic acid drugs and gene transfection, its application in vivo is often limited due to its sy...

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Abstract

The invention discloses a polymer vesicle nano STING agonist as well as a preparation method and application thereof. The method includes: adding the STING agonist solution into the buffer solution, adding the polymer solution, performing stirring, and performing dialyzing to obtain the polymer vesicle nano STING agonist. The polymer vesicle nano STING agonist disclosed by the invention is formed by loading an STING agonist on polymer vesicles; the polymer vesicles are small in particle size, can efficiently load the STING agonist and have high biological safety, drug loading stability and reduction responsiveness, the vesicles are used for loading the STING agonist for the first time and combined with radiation to be used for treating malignant melanoma, uptake of antigen presenting cells (APC) to the STING agonist is improved through the nano-scale characteristic of the polymer vesicles, the retention of the STING agonist in a tumor part is prolonged, the immunocompetence of the STING agonist is greatly improved, and the activation of an STING pathway is enhanced.

Description

technical field [0001] The invention belongs to nano-medicine technology, and in particular relates to a polymer vesicle nano-STING agonist and a preparation method and application thereof. Background technique [0002] The activation of the STING pathway can enhance the body's anti-tumor immunity, which is a promising method for tumor immunotherapy. Studies have shown that STING agonists are beneficial to promote the infiltration of T cells in the TME and anti-tumor immunotherapy. In addition to natural cGAMP, viruses, liposomes and cyclic dinucleotides (CDN) are also agonists of the STING pathway. At present, the main research is on CDN, such as synthetic cGAMP and cdiAMP. However, as a small molecule with negative charge and strong hydrophilicity, CDN is not easy to pass through the cell membrane to enter APC, and is also easy to be enzymatically hydrolyzed. In addition, CDN is easy to diffuse and clear randomly in the body, and its pharmacokinetics is poor. May cause a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/34A61K47/60A61K47/69A61K31/7084A61P35/00A61N5/10
CPCA61K9/1273A61K47/34A61K47/60A61K47/6915A61K31/7084A61P35/00A61N5/10
Inventor 孟凤华郑欢曲艳钟志远
Owner SUZHOU UNIV
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