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A step-by-step response nanometer self-assembled dendritic prodrug and its preparation method and application

A nanometer self-assembly, dendritic technology, applied in pharmaceutical formulations, drug combinations, anti-tumor drugs, etc., can solve problems such as difficulty in breaking through physiological barriers, achieve strong tumor penetration and tumor inhibition effects, increase uptake, and overcome physiological barriers. Effect

Inactive Publication Date: 2019-10-18
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The purpose of the present invention is to overcome the defect that existing nano-carriers are difficult to break through the physiological barrier, and provide a step-by-step response in the system delivery process, a step-by-step response nanometer self-assembled dendritic prodrug (i.e. nano-prodrug) that overcomes the physiological barrier. drug assembly)

Method used

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  • A step-by-step response nanometer self-assembled dendritic prodrug and its preparation method and application
  • A step-by-step response nanometer self-assembled dendritic prodrug and its preparation method and application
  • A step-by-step response nanometer self-assembled dendritic prodrug and its preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0076] Embodiment 1: the preparation of amphiphilic peptide dendritic prodrug molecule (synthetic route such as figure 1 shown)

[0077] a) Synthesis of metallomatrix protease-sensitive capsids in the tumor microenvironment (NH 2 -GPLGLAG-mPEG)

[0078] Accurately weigh 2.00g Boc-Gly-Pro-Leu-Gly-Leu-Ala-Gly-COOH (Boc-GPLGLAG), 3.52g polyethylene glycol monomethyl ether (average molecular weight: 750), 0.90g 1-ethyl -(3-Dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) and 0.63g 1-hydroxybenzotriazole (HOBT) were added in a single-necked bottle with a branch tube under nitrogen protection Dichloromethane (DCM) was dissolved, and 2.1 mL of N,N-diisopropylethylamine (DIPEA) was added under ice-cooling. After reacting at room temperature for 24 hours, the resulting solution was washed, dried, concentrated under reduced pressure, and separated by column chromatography to obtain Boc-GPLGLAG-mPEG.

[0079] De-tert-butoxycarbonyl (Boc) protection

[0080] Accurately weigh...

Embodiment 2

[0098] Example 2: Molecular Sensitization of Amphiphilic Dendritic Prodrug Molecules

[0099] The DPs solution was incubated for 3 hours under different conditions containing 2 μg / mL MMP-2, 10 mM DTT and pH 5.0. Molecular fragments under different conditions were observed by high performance liquid chromatography and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Figure 7 and Figure 8 As shown, the shifts of the chromatographic peaks and the mass spectra of the corresponding molecular fragments were observed after the above conditions were applied.

Embodiment 3

[0100] Example 3: Preparation of Multi-level Responsive Prodrug Assembly

[0101] Weigh 10.00 mg amphiphilic prodrug molecule and dissolve it in 1 mL of good solvent dimethyl sulfoxide to prepare a 10.00 mg / mL solution. The above solution was dropped into deionized water for assembly under ultrasonic conditions, dialyzed (MWCO 2000Da) to remove the organic solvent, and then freeze-dried to obtain multi-level responsive prodrug assemblies (DNs).

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Abstract

The invention relates to a progressive-response nano-self-assembled dendritic prodrug and a preparation method and application thereof. In-vivo multiple biological signals can be responded progressively, so that the change of biological functions of the prodrug and the release of antitumor drugs are caused. The dendritic prodrug is of an amphiphilic dendritic macromolecule with polypeptide as a skeleton, a hydrophilic end, a hydrophobic end and the dendritic molecular skeleton are connected through environment-responsive chemical bonds, and the hydrophobic end is a hydrophobic drug and is connected with the dendritic molecular skeleton through a sensitive bond. According to the progressive-response nano-self-assembled dendritic prodrug and the preparation method and application thereof, multiple physiological barriers in an antitumor drug delivery process are overcome by using the self-assembled nano prodrug, so that the efficient delivery of drugs is achieved, meanwhile, the recognition of efflux proteins can be avoided, and the reversion of tumor multidrug drug resistance is achieved.

Description

technical field [0001] The present invention relates to an antitumor drug and a preparation method thereof, in particular to a preparation method and application of a step-by-step response nano-prodrug assembly constructed by self-assembly. Background technique [0002] At present, anti-tumor drugs face multiple physiological barriers during the in vivo delivery process, for example, they face the possibility of being cleared by the endothelial reticular system during blood circulation; The penetration of drugs into the deep tumor; when entering cells, the cell membrane will hinder the uptake of drugs; for multi-drug resistant cells, after the drugs enter the cells, the efflux proteins on the cell surface will expel the drugs, reducing the drug efficacy, etc. Therefore, overcoming these physiological barriers step by step has become an urgent problem to be solved in the systemic delivery of chemotherapy drugs. Currently, dendritic supramolecular assemblies have attracted ex...

Claims

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Application Information

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IPC IPC(8): A61K47/59A61K47/64A61K31/704A61P35/00
Inventor 徐翔晖顾忠伟李亚超李芸焜张晓张壮壮
Owner SICHUAN UNIV