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CN-121975108-A - Oligomeric amino acid dendritic macromolecular material and preparation method and application thereof

CN121975108ACN 121975108 ACN121975108 ACN 121975108ACN-121975108-A

Abstract

The invention discloses an oligomeric amino acid dendritic macromolecular material and a preparation method and application thereof, and relates to the technical field of nano materials. The general formula of the oligomeric amino acid dendritic macromolecular material is TPE- (PEG) n -(Lys) x -(Arg) y , wherein TPE is a hydrophobic core, has aggregation-induced emission characteristics, can enhance self-assembly capacity and tracing function of a nano carrier, PEG is a connecting arm, can improve water solubility and biocompatibility of the material, lys is a branched skeleton, is a main building unit of dendritic macromolecules, arg is a functional terminal, and guanidine groups of Arg have strong positive charges, can promote electrostatic combination with negatively charged nucleic acid, and can enhance cell uptake through membrane penetration. The oligo-amino acid dendritic macromolecular material has the advantages of stability, modifier and targeting, provides a new scheme for delivering small nucleic acid, and is expected to have profound effects in the fields of tumor accurate treatment, gene therapy and multi-mode diagnosis and treatment.

Inventors

  • ZHANG LU
  • WANG FENGYI

Assignees

  • 南方科技大学

Dates

Publication Date
20260505
Application Date
20251230

Claims (10)

  1. 1. An oligomeric amino acid dendrimer material, which is characterized by having a general formula of TPE- (PEG) n -(Lys) x -(Arg) y ; wherein TPE is a tetraphenyl vinyl group; PEG is polyethylene glycol, the molecular weight is 1000-5000Da, and n represents the polymerization degree of PEG molecules; lys is lysine, x is an integer from 1 to 50; arg is arginine, and y is an integer of 1-50; The TPE and the PEG are connected through an amide bond, one of the PEG and the Lys is connected through an amide bond, the other Lys and the Lys connected with the PEG are connected through an amide bond in a dendritic arrangement, and the Arg is connected to the tail end of the Lys in the dendritic arrangement through an amide bond.
  2. 2. The oligoamino acid dendrimer material according to claim 1, wherein the molecular weight of PEG is 1000-3000da, x is an integer of 1-20, and y is an integer of 1-20.
  3. 3. The oligoamino acid dendrimer material according to claim 1, wherein the oligoamino acid dendrimer material is TPE-PEG 2000 -Lys-Lys 2 -Lys 4 -Arg 8 having the following structural formula: 。
  4. 4. a method for preparing an oligoamino acid dendrimer material according to any one of claims 1 to 3, comprising the steps of: (1) Performing amide condensation reaction on Boc-NH-PEG-NH 2 and (Fmoc) Lys (Fmoc) -OH in a solvent to obtain a first product; (2) After Fmoc groups of the first product are removed, performing an amide condensation reaction with (Fmoc) Lys (Fmoc) -OH in a solvent to obtain a second product; (3) After Fmoc groups of the second product are removed, performing an amide condensation reaction with (Fmoc) Lys (Fmoc) -OH in a solvent to obtain a third product; (4) After Fmoc groups of the third product are removed, carrying out amide condensation reaction with (Fmoc) Arg (pbf) -OH in a solvent to obtain a fourth product; (5) Removing Boc groups from the fourth product, and performing an amide condensation reaction with TPE-COOH in a solvent to obtain a fifth product; (6) Removing Fmoc groups from the fifth product to obtain a sixth product; (7) Removing pbf groups from the fifth product to obtain an oligomeric amino acid dendritic macromolecular material; Wherein, the In the step (1), the molar ratio of Boc-NH-PEG-NH 2 to (Fmoc) Lys (Fmoc) -OH is 1 (0.8-1.2); in the step (2), the molar ratio of the first product to (Fmoc) Lys (Fmoc) -OH is 1 (3-12); In step (3), the molar ratio of the second product to (Fmoc) Lys (Fmoc) -OH is 1 (6-24); in the step (4), the molar ratio of the third product to (Fmoc) Arg (pbf) -OH is 1 (12-48); in the step (5), the molar ratio of the fourth product to TPE-COOH is 1 (1-1.5).
  5. 5. The method for preparing an oligoamino acid dendrimer material according to claim 4, wherein the condensing agent for the amide condensation reaction is N, N' -diisopropylcarbodiimide and ethyl 2-oxime cyanoacetate.
  6. 6. The method for preparing an oligo-amino acid dendrimer according to claim 4, wherein the solvent is one or more selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dichloromethane and tetrahydrofuran.
  7. 7. The method for preparing an oligo-amino acid dendrimer according to claim 4, wherein the Fmoc group removal is performed by 4-methylpiperidine; the removal of the Boc group is performed by trifluoroacetic acid; The removal of the pbf groups is performed by trifluoroacetic acid.
  8. 8. Use of an oligomeric amino acid dendrimer material according to any one of claims 1 to 3 in the preparation of a nucleic acid medicament.
  9. 9. The use according to claim 8, wherein the nucleic acid drug is a drug for targeted release and precise treatment of tumors.
  10. 10. The use of claim 9, wherein the tumor comprises one or more of breast cancer, liver cancer, lung cancer, ovarian cancer, bladder cancer, colon cancer.

Description

Oligomeric amino acid dendritic macromolecular material and preparation method and application thereof Technical Field The invention relates to the technical field of nano materials, in particular to an oligomeric amino acid dendritic macromolecular material and a preparation method and application thereof. Background Ribonucleic acid (RNA) has remarkable potential in the fields of tumor treatment, genetic disease intervention and the like as a gene regulatory molecule. However, its clinical application is limited by two major bottlenecks, (1) nuclease sensitivity: RNA is easily degraded by nucleases in blood and tissues, half-life is short (e.g., siRNA has half-life in plasma for only several minutes), and (2) cell membrane permeability is poor, RNA is negatively charged and has a large molecular weight (e.g., mRNA about 2000-5000 Da), and passive penetration of cell membrane is difficult. Therefore, how to deliver it efficiently to intracellular targets has been a key research hotspot for RNA therapy. Existing delivery systems such as Lipid Nanoparticles (LNP) and polymer nanoparticles (e.g., PLGA) can partially improve nucleic acid delivery efficiency, but still face a number of challenges. Firstly, some delivery vehicles rely on passive enrichment of EPR effect, tumor targeting efficiency is low (< 5%), secondly, the phospholipid component of LNP may trigger immune response, there is significant cytotoxicity of cationic polymers (such as PEI) and there is a risk of biocompatibility, furthermore, unmodified nanoparticles are easily cleared by mononuclear phagocytes, resulting in short circulation time in vivo. Unlike traditional polymer, the oligomeric amino acid dendritic polymer material has the advantages of algebraic controllability, precise molecular structure, good biocompatibility, easy functionalization and the like, and becomes an ideal carrier for solving the problems. By reasonably designing algebra and surface amino density, high-efficiency load and accurate delivery of the medicine can be realized. However, most of the current oligomeric amino acid materials still have the problems of insufficient stability, short in vivo circulation time and the like, and development of novel oligomeric amino acid vectors is needed to meet the requirements of efficient nucleic acid precise delivery and targeted therapy. Disclosure of Invention In view of the defects of the prior art, the invention aims to provide an oligomeric amino acid dendritic macromolecular material, a preparation method and application thereof, and aims to solve the problems of insufficient stability and short in-vivo circulation time of the existing oligomeric amino acid material. The technical scheme of the invention is as follows: In a first aspect, an oligomeric amino acid dendrimer material is provided, wherein the oligomeric amino acid dendrimer material has a general formula of TPE- (PEG) n-(Lys)x-(Arg)y; wherein TPE is a tetraphenyl vinyl group; PEG is polyethylene glycol, the molecular weight is 1000-5000Da, and n represents the polymerization degree of PEG molecules; lys is lysine, x is an integer from 1 to 50; arg is arginine, and y is an integer of 1-50; The TPE and the PEG are connected through an amide bond, one of the PEG and the Lys is connected through an amide bond, the other Lys and the Lys connected with the PEG are connected through an amide bond in a dendritic arrangement, and the Arg is connected to the tail end of the Lys in the dendritic arrangement through an amide bond. In a preferred embodiment, the molecular weight of the PEG is 1000-3000Da, x is an integer of 1-20, and y is an integer of 1-20. According to a preferred technical scheme, the oligomeric amino acid dendritic macromolecular material is TPE-PEG 2000-Lys-Lys2-Lys4-Arg8, and the structural formula is as follows: 。 In a second aspect, there is provided a method for preparing an oligomeric amino acid dendrimer material according to the first aspect, comprising the steps of: (1) Performing amide condensation reaction on Boc-NH-PEG-NH 2 and (Fmoc) Lys (Fmoc) -OH in a solvent to obtain a first product; (2) After Fmoc groups of the first product are removed, performing an amide condensation reaction with (Fmoc) Lys (Fmoc) -OH in a solvent to obtain a second product; (3) After Fmoc groups of the second product are removed, performing an amide condensation reaction with (Fmoc) Lys (Fmoc) -OH in a solvent to obtain a third product; (4) After Fmoc groups of the third product are removed, carrying out amide condensation reaction with (Fmoc) Arg (pbf) -OH in a solvent to obtain a fourth product; (5) Removing Boc groups from the fourth product, and performing an amide condensation reaction with TPE-COOH in a solvent to obtain a fifth product; (6) Removing Fmoc groups from the fifth product to obtain a sixth product; (7) Removing pbf groups from the fifth product to obtain an oligomeric amino acid dendritic macromolecular material; Wherein, the In the step (1)