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PH-sensitive conjugate, micelle, and preparation method and application thereof

A conjugate and sensitive technology, applied in drug combination, sensory disease, drug delivery, etc., can solve the problems of poor response to disease signals and low activation effect

Pending Publication Date: 2020-03-03
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, currently reported photodynamic delivery systems have poor response to disease signals in vivo and low activation effects, and it is necessary to develop new intelligent responsive photodynamic delivery systems that are more sensitive and have high signal activation effects.

Method used

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  • PH-sensitive conjugate, micelle, and preparation method and application thereof
  • PH-sensitive conjugate, micelle, and preparation method and application thereof
  • PH-sensitive conjugate, micelle, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0122] As the preparation method of the pH-sensitive conjugated micelles of the present invention, common formulation preparation methods in the field can be used, such as thin-film ultrasonic method, reverse evaporation method, ethanol injection method, desolventization method, etc., preferably desolventization method.

[0123] For example, the preparation method of the pH-sensitive conjugate micelles of the present invention comprises the following steps: 1) adding the pH-sensitive conjugates respectively linked with various marker molecules to an organic solvent to dissolve completely; 2) under the condition of ultrasonic probe, Quickly add the solution obtained in step 1 into ultrapure water and perform ultrasonication; 3) Ultrafiltration or dialysis with ultrapure water to remove the organic solvent; 4) Concentrate the micelles and discard the precipitated insoluble part to obtain the micelles.

[0124] In particular, the present invention provides micelles comprising conj...

Embodiment

[0147] The present invention is illustrated and explained through the following specific synthesis examples and examples, but the present invention is not limited by these specific examples.

[0148] In this document, unless otherwise stated, each symbol stands for the following meanings:

[0149] PEG 5k -OH:

[0150] PEG 5k -Br:

[0151] EPA: The monomer structure is

[0152] DPA: The monomer structure is

[0153] iDPA: The monomer structure is

[0154] DBA: The monomer structure is

[0155] AMA: The monomer structure is for ligation of marker molecules

[0156] QSY21-NHS: A succinimide-functionalized fluorescence quencher

[0157]

[0158] BHQ3-NHS: a succinimide-functionalized fluorescence quencher

[0159]

[0160] ICG-NHS: a succinimide-functionalized photothermal probe

[0161]

[0162] MTT: Cell Viability Assay Reagent 3-(4,5-Dimethylthiazole-2)-2,5-Diphenyltetrazolium

Synthetic example 1

[0163] Synthesis Example 1: Synthesis of Polyethylene Glycol Macroinitiator

[0164] Precisely weigh PEG 5k -OH (20g, 4mmol) was dissolved in a round-bottomed flask with 250mL of dichloromethane, and then 5 equivalents of triethylamine and 4-dimethylaminopyridine were added to the reaction solution. Stir and sonicate to dissolve. Add 5 times equivalent of 2-bromoisobutyryl bromide at low temperature, and react at room temperature for 24 hours. After the reaction was completed, the reaction solution was concentrated to about 50 mL with a rotary evaporator. The reaction solution was transferred to a separatory funnel, washed 3 times with 10% sodium bicarbonate solution, and then washed 3 times with saturated sodium chloride solution. The organic phase was added dropwise to glacial ether, and a precipitate was precipitated. The solid was collected by suction filtration and dried in vacuo. Repeat the ether precipitation operation 3 times to obtain 16.3g of macromolecular init...

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Abstract

The invention provides a pH-sensitive conjugate with a high signal activation effect, micelle, and a preparation method and application thereof. The pH-sensitive conjugate comprises a hydrophilic chain segment and a hydrophobic chain segment, wherein the hydrophilic chain segment is mainly a strongly hydrophilic polymer such as polyethylene glycol, and the hydrophobic chain segment is a polyalkylaminoacrylate having a tertiary amino structure as shown in the formula 1, wherein each symbol is as defined in the specification. The hydrophobic chain segment contains marker molecules. By modifyingthe hydrophobic chain segment of the polymer with the marker molecules, the pH response activation of photodynamic effect can be realized and the phototoxicity to normal tissues can be reduced. In addition, the invention also provides the application of the pH-sensitive conjugate and micelle in photodynamic therapy of tumors, skin diseases and ophthalmic diseases and in combination with photothermal therapy, chemotherapy and immunotherapy.

Description

technical field [0001] The invention relates to the field of photodynamic medicine, in particular to a pH-sensitive conjugate, micelle and micelle composition with a high signal activation effect, its preparation and its medical application. Background technique [0002] Photodynamic therapy (PDT) refers to irradiating local tissues with excitation light of a specific wavelength to excite the photosensitizer molecules distributed in the tissues and generate active oxygen such as singlet oxygen, which can interact with intracellular lipids and amino acids. Bioactive macromolecules such as residues and nucleic acids react directly to induce cell necrosis and apoptosis. As an emerging treatment technology, photodynamic therapy has the advantages of less invasiveness, low systemic toxicity, and fast healing ability, and can quickly cure diseases with minimally invasive photosensitization reactions. Due to the strong hydrophobicity of most photosensitizers, the target tissue del...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/34A61K41/00A61K49/00A61P35/00A61P29/00A61P27/02A61P17/00
CPCA61K47/6907A61K47/34A61K41/0071A61K49/0082A61P35/00A61P29/00A61P27/02A61P17/00
Inventor 汪贻广张强陈斌龙王增辉鄢月殷晴晴陈卫
Owner PEKING UNIV
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