Active targeting amphiphilic polypeptide composite nanomicelle prodrug and its preparation and application

A nanomicelle and active targeting technology, applied in the field of biomedicine, can solve the problems of poor deep delivery of chemotherapy drugs, inability to track drug distribution in real time, poor targeting of tumor cells, etc. The effect of promoting disassembly and broad application prospects

Active Publication Date: 2022-05-17
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The present invention solves the problems of poor targeting of tumor cells by nanocarriers in the prior art and the inability to track the distribution of drugs in tumors in real time, and at the same time solves the problems of poor deep delivery of chemotherapy drugs and low cell uptake efficiency The disadvantages brought by the mode of action can realize the synergistic effect of anti-tumor drugs, photothermal and photodynamic

Method used

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  • Active targeting amphiphilic polypeptide composite nanomicelle prodrug and its preparation and application
  • Active targeting amphiphilic polypeptide composite nanomicelle prodrug and its preparation and application
  • Active targeting amphiphilic polypeptide composite nanomicelle prodrug and its preparation and application

Examples

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Embodiment 1

[0045] Example 1: Preparation method of active targeting amphiphilic composite polypeptide nano-therapeutic agent based on electrostatic interaction

[0046] (i) Preparation of Active Targeting Negatively Charged Amphiphilic Peptides

[0047] (1) Take 0.305 grams of Rink Amide-AM resin to the peptide synthesis device, add dry N,N-dimethylformamide to soak the resin for 2 hours to make it fully swell, and finally discharge the solvent N,N-dimethylformamide . Then, a piperidine:N,N-dimethylformyl solution (10 ml) with a volume ratio of 1:4 was used to remove the protective group of the resin, and the reaction was performed twice, each lasting 20 minutes. Then wash the resin N,N-dimethylformyl repeatedly with 10ml N,N-dimethylformyl for 3 times, each time for 5 minutes, take a little resin and add it to the ethanol solution of ninhydrin and phenol, heat After boiling, observe the color change of the resin. If the resin turns blue or even black, it means that the protective grou...

Embodiment 2

[0064] Embodiment 2: synthetic polypeptide chemotherapeutic prodrug

[0065] Dissolve 1.5g (6.8mmol) of dithiodipyridine in 12ml of ethanol, add 0.16ml of acetic acid into a 50ml two-necked round-bottomed flask, dissolve 235.2μL (312.8mg 3.4mmol) of thioglycolic acid in 8mL of ethanol, and add constant pressure drops In the funnel, under the protection of argon, thioglycolic acid ethanol solution was added dropwise, and stirred at room temperature for 3 h. After the reaction, the solvent was spin-dried to obtain a yellow oily liquid. Purification by high-pressure preparative column yielded pure pyridine acetic acid.

[0066] Take 20.1mg (0.1mmol) of pyridineacetic acid and dissolve it in 400μl DMF, add Pybop 104.1mg (0.2mmol activated carboxyl group) and stir at room temperature for 30min under the protection of argon, take DOX 48.3mg (0.083mmol) and dissolve it in 1.5ml DMF, Add dropwise under air protection, then add DIPEA 69.8μl (0.4mmol 51.7mg), and stir at room temperatu...

Embodiment 3

[0068] Example 3: Preparation of Polypeptide Composite Nanomicelles

[0069] At room temperature, dissolve in 10 μl DMSO according to the amount ratio of negatively charged polypeptide 1 with active targeting function and positively charged prodrug polypeptide 2: (0.1-5), and then dissolve the peptide containing polypeptide 1 and polypeptide 2 DMSO solution was added to 1ml of PBS while sonicating, then sonicated for 20 minutes, and then dialyzed for 12 hours to obtain polypeptide composite nanomicelles, named PP. figure 1 It is a schematic diagram of the composite nanomicelle. The chain segment outside the sphere is the hydrophilic part of polypeptide 1 and polypeptide 2, the shell is the hydrophobic alkyl chain, the four-pointed star in the hydrophobic cavity is the near-infrared dye, and the sphere is the chemotherapeutic drug DOX.

[0070] Morphological observation: Observing the polypeptide composite nano-therapeutic agent with a transmission electron microscope, it was f...

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Abstract

The invention discloses an active-targeting amphiphilic polypeptide composite nano-micelle prodrug, its preparation and application, and belongs to the technical field of biomedicine. The composite nanomicelle prodrug of the present invention is obtained by co-assembling a negatively charged first polypeptide and a positively charged second polypeptide through electrostatic interaction and hydrophilic-hydrophobic interaction; the first polypeptide is Lys-AA m ‑Gly‑Arg‑Gly‑Asp‑Ser, wherein AA is aspartic acid or glutamic acid, m is 1, 2, 3 or 4; the second polypeptide is Cys‑BB n , wherein BB is lysine, arginine or histidine, and the value of n is 1, 2, 3 or 4; the amino group at the N-terminal of the first polypeptide is connected to a hydrophobic alkyl chain, and the lysine side of the first polypeptide is The amino group of the chain is connected with the fluorescent molecule; the cysteine ​​in the second polypeptide is covalently connected with the anti-tumor drug through the sulfhydryl group. The nanocomposite micelles can actively target tumor cells and disassemble in response to the slightly acidic environment of the tumor to form small-sized micelles with a size of 20-30nm, which is conducive to the deep delivery of polypeptide anti-tumor prodrugs in tumor sites.

Description

technical field [0001] The invention belongs to the technical field of biomedicine. More specifically, the invention provides an active-targeting amphiphilic polypeptide composite nanomicelle prodrug based on electrostatic interaction, its preparation and application. Background technique [0002] The research and development of anti-tumor drugs based on peptide carriers is one of the current hot spots. In recent years, the rapid development of the field of molecular self-assembly has provided new opportunities for the research and development of smart peptide nano-medicines. This technology assembles molecules with different functions into highly ordered nano-systems through non-covalent bonds. An effective strategy for nanomedicine. Amino acid residues in biomolecular polypeptide sequences have different chemical structures, which can effectively realize molecular self-assembly by utilizing the hydrogen bond interaction between peptide chains and various non-covalent bond...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/107A61K47/64A61K41/00A61K49/00A61K45/00A61P35/00
CPCA61K9/1075A61K47/64A61K41/0052A61K41/0057A61K49/0056A61K49/0021A61K45/00A61P35/00A61K2300/00
Inventor 朱锦涛马腾蒋皓
Owner HUAZHONG UNIV OF SCI & TECH
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