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Immune vesicle maytansine conjugate as well as preparation method and application thereof

A technology of maytansinoids and maytansinoids, applied in drug combinations, pharmaceutical formulations, nano-drugs, etc., can solve the problems of limited research, large antibody dosage, and low drug content, and achieve good biocompatibility, high efficiency and stability The effect of the package effect

Active Publication Date: 2021-08-13
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although ADC can improve the circulation time of DM1 and reduce its systemic toxicity, it still faces problems such as low drug content, large antibody dosage, and high cost of use.
In addition, other than ADCs, studies on targeted delivery of DM1 are very limited, mainly due to its strong toxicity, which requires stable encapsulation and tumor-specific drug delivery properties of nanocarriers

Method used

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  • Immune vesicle maytansine conjugate as well as preparation method and application thereof
  • Immune vesicle maytansine conjugate as well as preparation method and application thereof
  • Immune vesicle maytansine conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 Reversible cross-linked and biodegradable vesicular maytansine conjugates (N 3 -Ps-DM1) Preparation

[0044] N 3 -Ps-DM1 is prepared by a solvent replacement method, wherein the dithiolane ring in the hydrophobic segment is chemically bonded to DM1 through sulfhydryl-sulfur-sulfur exchange, and the drug is coupled in the hydrophobic membrane of the vesicle. N 3 -Ps-DM1 by N 3 - PEG-P (TMC-DTC) and PEG-P (TMC-DTC) co-assembled and coupled to DM1, wherein N 3 - The content of PEG-P(TMC-DTC) is 1~10 wt.%. Specifically, to contain 2 wt.% N 3 -N of PEG-P (TMC-DTC) 3 - Take the preparation of Ps-DM1 as an example, weigh 0.72 mgN 3 - PEG-P(TMC-DTC) and 35.28 mg PEG-P(TMC-DTC) were dissolved in DMF (total polymer concentration 40 mg / mL); 0.4 mL of DM1 in DMF (10 mg / mL) was added Mix well with 7.7 mL of PB (pH 7.4, 10 mM), inject 0.9 mL of polymer solution into it under stirring, stir for 3 minutes, then place at 37 ºC for 12 hours. After dialysis (MWCO = 3.5 ...

Embodiment 2

[0046] Example 2 Preparation of mAb-directed immune vesicle maytansine conjugate (Ab-Ps-DM1)

[0047] Ab-Ps-DM1 via DM1 nanomedicine in azide-functionalized polymersomes (N 3 -Ps-DM1) surface post-modified dibenzocyclooctyne functionalized monoclonal antibody (Ab-DBCO). First, in order to bind the mAb efficiently, the N 3 -Ps-DM1 was concentrated from 4 mg / mL to 19.8 mg / mL. Concentrated N 3 -Ps-DM1 has a particle size of 48 nm and a PDI of 0.16. The long-term storage stability of N3-Ps-DM1 was characterized by monitoring its particle size, particle size distribution and drug leakage during storage at 4 ºC for 180 days. -Ps-DM1 exhibited little change in particle size and particle size distribution (within 3 nm), and no DM1 leakage, indicating its best long-term storage stability. After treatment with 10 mMDTT, DM1 was rapidly released in the free form ( figure 1 A). In addition, N 3 -The release of Ps-DM1 at 37 ºC in PBS containing 0.3% Tween 80, no free DM1 was detect...

Embodiment 3

[0056] Example 3 Endocytosis of Dar-Ps-DM1

[0057] Since DM1 itself has no fluorescence, Cy5-labeled polymersomes (Dar-Ps-Cy5) were used to study the effect of Dar-Ps-Cy5 with different Dar densities on 697 acute lymphoid leukemia by flow cytometry and confocal laser microscopy (CLSM). cells, LP-1 multiple myeloma cells and MV4-11 leukemia cells. Ps-Cy5 through 2 wt.% N 3 -Polymer co-assembly of PEG-P(TMC-DTC), 20 wt.% PEG-P(TMC-DTC)-Cy5 and 78 wt.% PEG-P(TMC-DTC) was prepared. The details are as follows: Weigh 0.32 mg N 3 - PEG-P(TMC-DTC), 3.2 mg PEG-P(TMC-DTC)-Cy5, 12.48 mg PEG-P(TMC-DTC) were dissolved in DMF (40 mg / mL), and the three polymers were mixed well Then, inject into 3.6 mL PB (pH 7.4, 10 mM) with stirring. After stirring for 3 min, dialyze (MWCO = 1 kDa) against PB (pH 7.4, 10 mM) to remove the organic solvent and concentrate to a polymer concentration of 17 mg / mL. The preparation method of Dar-Ps-Cy5 is similar to Dar-Ps-DM1, setting Dar-DBCO and N 3 The ...

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Abstract

The invention discloses an immune vesicle maytansine conjugate as well as a preparation method and application thereof. The immune vesicle maytansine conjugate is prepared from an amphiphilic polymer, maytansine and an antibody, specifically, the functionalized amphiphilic block polymer and an amphiphilic block polymer are assembled and spontaneously cross-linked and meanwhile coupled with the maytansine through a sulfydryl-sulfur-sulfur exchange reaction, and then react with the monoclonal antibody to prepare the immune vesicle maytansine conjugate. The maytansine has broad-spectrum anti-tumor activity and is suitable for solid tumors and malignant hematological tumors, but due to the fact that maytansine is extremely high in toxicity, narrow in treatment window and incapable of being used independently, the technical scheme provides possibility for use of potent medicine DM. Experimental results show that under the high dose of the immune vesicle maytansine conjugate, mice is good in tolerance and completely survive, and the therapeutic window of the toxic molecule DM1 is effectively expanded.

Description

technical field [0001] The invention belongs to the technical field of polymer nano-medicines, and in particular relates to a monoclonal antibody-directed reversible cross-linked polymer vesicle maytansinoid conjugate, a preparation method thereof, and an application in tumor targeting therapy. Background technique [0002] Maytansine (DM1) is a plant-derived hydrophobic drug with a macrocyclic lactone structure. It mainly acts on tubulin to prevent its formation in cell mitosis, thereby blocking the cell cycle and inducing apoptosis. Maytansine has been widely studied due to its excellent anti-tumor effect in preclinical experiments, but in early clinical trials, maytansine showed strong gastrointestinal toxicity and neurotoxicity, and the therapeutic window was small, so it cannot be used alone. Due to its strong toxicity, maytansine has been widely studied in recent years for the toxin warhead of antibody-drug conjugates (ADCs). At present, one Ado-transtuzumabemtansine (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K31/537A61K47/60A61K47/68A61P35/00B82Y5/00B82Y30/00B82Y40/00
CPCA61K31/537A61K47/60A61K47/6803A61K47/6849A61K9/1273A61P35/00B82Y5/00B82Y30/00B82Y40/00
Inventor 孙欢利张翼帆袁琴钟志远
Owner SUZHOU UNIV
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