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PH/cathepsin B step-by-step response polymer-drug conjugate and micelle, as well as preparation method and application of pH/cathepsin B step-by-step response polymer-drug conjugate and micelle

A technology of cathepsin and polymer, which is applied in the field of biomedicine, can solve the problems of poor response to disease signals and weak penetration promotion ability, and achieve the effects of avoiding drug release, reducing toxic and side effects, and rapid response

Pending Publication Date: 2021-11-26
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the currently reported smart-responsive polymer-drug conjugate systems have poor responsiveness to disease signals in vivo and weak permeation-promoting ability, and it is necessary to develop new smart-responsive polymers with faster signal response speed and stronger permeation-promoting ability. -drug conjugate system

Method used

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  • PH/cathepsin B step-by-step response polymer-drug conjugate and micelle, as well as preparation method and application of pH/cathepsin B step-by-step response polymer-drug conjugate and micelle
  • PH/cathepsin B step-by-step response polymer-drug conjugate and micelle, as well as preparation method and application of pH/cathepsin B step-by-step response polymer-drug conjugate and micelle
  • PH/cathepsin B step-by-step response polymer-drug conjugate and micelle, as well as preparation method and application of pH/cathepsin B step-by-step response polymer-drug conjugate and micelle

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preparation example Construction

[0116] The preparation method of the polymer-drug conjugate micelles of the present invention can adopt solvent removal method, thin film ultrasonic method, ethanol injection method, etc., preferably solvent removal method.

[0117] For example, the polymer-drug conjugate micelles of the present invention can be prepared by the following steps:

[0118] Step 1: Weigh one or more polymer-drug conjugates according to a certain proportion, add an appropriate amount of organic solvent to ultrasonically dissolve, and set aside;

[0119] Step 2: Take ultrapure water with a volume ratio of 10-100, and quickly add the solution obtained in "Step 1" into the ultrapure water under the ultrasonic condition of the probe, and continue ultrasonication for 1-3 minutes;

[0120] Step 3: Transfer the micellar solution containing the organic solvent after the ultrasonication to an ultrafiltration tube, and perform ultrafiltration with ultrapure water for 3 to 5 times to remove the organic solven...

Embodiment 1

[0143] Embodiment 1: the synthesis of macromolecular chain transfer agent PEG-CTA

[0144] Accurately weigh PEG-OH (5g, 1mmol) and equimolar equivalent of CTA in a round bottom flask, add 50mL of dichloromethane, ultrasonically dissolve, then add 0.1 times the molar equivalent of 4-dimethylaminopyridine and 1.5 times the molar equivalent of dicyclohexylcarbodiimide. After reacting at room temperature in the dark for 36 hours, the precipitate was removed by ultrafiltration, and the organic filtrate was concentrated to 10 mL with a rotary evaporator. The product was purified three times in glacial ether to obtain 4.2 g of macromolecular chain transfer agent PEG-CTA with a yield of 84%.

Embodiment 2

[0145] Example 2: RAFT Polymerization and Structural Characterization of Polymer-Drug Conjugates

[0146] 1. Synthesis of polymer-drug conjugate PEG-PC7A-DTX

[0147] Weigh the PEG-CTA (50mg, 0.01mmol) in "Example 1" in the reaction bottle, add 100 times molar equivalent of C7A monomer and 5 times molar equivalent of MA-GFLG-DTX prodrug monomer, and use 1mL N,N-dimethylformamide was dissolved, and then 0.333 times the molar equivalent of initiator azobisisobutyronitrile was added, and it was fully dissolved and mixed evenly by ultrasonication. Freezing-nitrogen-filling-thawing cycles were performed 3 times to remove oxygen, and the reaction was placed at 60°C for 36 hours. After the reaction is terminated, transfer the reaction solution to a 10kD dialysis bag and dialyze with N,N-dimethylformamide for 48 hours to remove unreacted monomers and other small molecules, then dialyze against distilled water for 12 hours to remove organic solvents, and dialyze the product The polym...

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Abstract

The invention provides a series of polymer-drug conjugates and micelles with pH / cathepsin B step-by-step response characteristics, as well as a preparation method and application of the polymer-drug conjugates and micelles. The polymer-drug conjugate is composed of a hydrophilic chain segment and a hydrophobic chain segment, the hydrophilic chain segment is mainly composed of a highly hydrophilic polymer such as polyethylene glycol, and the hydrophobic chain segment is composed of a polyalkyl amino acrylate unit with a tertiary amino structure as shown in a structural formula 1 described in the specifications and a drug precursor unit with a Gly-Phe-Leu-Gly polypeptide connecting arm, wherein each symbol is defined in the specifications. In addition, the invention also provides application of the polymer-drug conjugate and the micelle in chemotherapy of tumor and inflammatory diseases and combined application of immunotherapy and photodynamic therapy.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a polymer-drug conjugate, a micelle and a micelle composition with pH / cathepsin B stepwise response drug release characteristics, a preparation method and a medical application thereof. Background technique [0002] Nanomedicine is a new drug delivery technology developed based on nanotechnology, material chemistry, pharmacy and clinical medicine, and has been widely used in the prevention, diagnosis and treatment of various diseases. Through the nano-design of drugs, the in vivo pharmacokinetic characteristics and tissue distribution of drugs can be significantly improved, and the delivery efficiency and therapeutic efficacy of drugs can be improved, which has shown great potential in clinical research. Polymer-drug conjugates are a kind of drug delivery system formed by linking drug molecules with polymer macromolecules through chemical covalent bonds. Compared with the ph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08F293/00C08F2/38C08F8/30C08G65/334A61K9/107A61K31/337A61K45/00A61K47/58A61K47/60A61K47/65A61K47/69A61K49/00A61P29/00A61P35/00
CPCC08F293/005C08F2/38C08F8/30C08G65/3348A61K47/58A61K47/60A61K47/65A61K47/6907A61K9/1075A61K45/00A61K31/337A61P35/00A61P29/00A61K49/0054A61K49/0056C08F2438/03
Inventor 汪贻广杜洪亮赵绥王增辉王瑶琪张强
Owner PEKING UNIV
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