CN-122005449-A - Fluorinated polymorpholine mitochondria targeting micelle and preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a fluorinated polymyosine mitochondrial targeting micelle and a preparation method and application thereof. The invention discloses a self-assembled micelle which is prepared by taking a fluoroalkyl chain as a hydrophobic block and a polyminosine as a hydrophilic block, wherein the general formula of the micelle is shown as formula (1): Formula (1) wherein m and n are positive integers. The optimal structure CF 1 -PSar 24 of the fluorinated polymorpholine mitochondrial targeting micelle is to replace alkyl chain to optimize micelle with fluorocarbon chain, improve the stability of blood environment and internal circulation time, enhance the tumor tissue accumulation effect of the medicine, and adopt fluorocarbon chain-polymorpholine to construct neutral mitochondrial targeting vector, reduce toxicity and off-target effect while maintaining targeting, avoid the application defect of PEG materials and achieve the aim of improving the drug delivery performance.

Inventors

• ZHAO BIN
• LUO ZHENG
• LIU YIN

Assignees

• 国科大杭州高等研究院

Dates

Publication Date

20260512

Application Date

20260129

Claims (9)

1. 1. The fluorinated polyminone mitochondria targeting micelle is characterized in that a fluorinated alkyl chain is used as a hydrophobic block, polyminone is used as a hydrophilic block, and the micelle is self-assembled, and the general formula of the micelle is shown as formula (1): (1) Wherein m and n are positive integers.
2. 2. A fluorinated polymorpholine mitochondria-targeted micelle according to claim 1, characterized in that m=1, n=24.
3. 3. A fluorinated polymorpholine mitochondrial targeting micelle according to claim 1 having a critical micelle concentration of less than 0.1 mg-L -1 .
4. 4. The method for preparing the fluorinated polymorpholine mitochondria-targeted micelle according to claim 1, wherein the fluorinated polymorpholine mitochondria-targeted micelle is obtained by reacting N-ethyl polymorpholine-25 with perfluoro-N-butyric acid under DMAP, DCC, DCM catalysis.
5. 5. The preparation method according to claim 4, comprising the following steps: S.1 dissolving N-ethyl polymorpholine-25 in DCM; s.2, dissolving perfluoro-n-butyric acid in DCM, adding DCC, pre-reacting for 3-5 hours, and adding catalytic amount of DMAP; s.3, slowly adding the N-ethyl polymorpholine-25 solution prepared in the step S.1 into the polymer solution prepared in the step S.2, stirring and pre-balancing in an ice bath at the temperature of 0 ℃, and after a period of time, moving to room temperature and stirring for reaction for 20-30 hours to generate dicyclohexylurea in the process; S.4, filtering to remove dicyclohexylurea and residual micromolecular impurities after the reaction is finished, transferring a crude product CF 1 -PSar 24 of the fluorinated polymorpholine into a dialysis bag, and dialyzing in a pure water environment for 2-4 days; S.5 finally, freeze-drying the purified product to obtain a dried fluorinated polymorpholine product CF 1 -PSar 24 .
6. 6. The method of claim 5, wherein removing in step S.4 comprises filtration, transfer, and dialysis.
7. 7. Use of a fluorinated polymyosine mitochondria-targeted micelle according to any one of claims 1-2 in the preparation of a biological agent.
8. 8. A biologic comprising the fluorinated polymyosine mitochondria-targeted micelle of any one of claims 1-2.
9. 9. Use of a fluorinated polymyosine mitochondrial targeting micelle according to any one of claims 1-2 or a method of preparation according to any one of claims 4-6 for targeted drug delivery.

Description

Fluorinated polymorpholine mitochondria targeting micelle and preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a fluorinated polymyosine mitochondrial targeting micelle and a preparation method and application thereof. Background Poly (Polysarcosine, PSar). PSar is a polypeptide formed by connecting N-methylated glycine through peptide bonds, the repeated unit is- [ -NHCH 2COCH3 - ] -, the main chain is the same as the natural polypeptide, and the side chain has only one methyl group and has a 'protein-like' framework. Well-known characteristics include excellent water solubility (> 500 mg.mL -1, 25 ℃) and extremely weak interaction with plasma proteins and reticuloendothelial phagocytosis system (RES), slow recognition of main chain peptide bonds by intracellular protease, final degradation into sarcosine (natural metabolic product of human body), no accumulated toxicity, large chain segment flexibility, high steric hindrance, and capability of forming a hydrophilic protective layer with the thickness of 3-5 nm, and endowing micelle with stealth performance. Therefore PSar has been widely regarded as a next generation alternative to hydrophilic shells for polyethylene glycol (PEG). Fluorinated amphiphilic polymers self-assembly principle. The known research shows that when the fluorocarbon chain segment DP is more than or equal to 2, compact fluorine nucleus can be formed through fluorine-fluorine acting force, so that micelle CMC can be reduced by 1-2 orders of magnitude, the water permeability in the fluorine-containing kernel is 30-50% lower than hydrocarbon phase, the diffusion leakage of medicine in blood can be obviously inhibited, the kernel formed by the fluorine carbon chain is affinitized with a cell membrane lipid raft area, and the penetration depth of tumor tissue can be improved by 2-3 times. Mitochondrial targeting ligands and their mechanism of action. Mitochondrial membrane potential (Δψm, -180 mV) drives lipophilic cation enrichment. The known ligand comprises triphenylphosphine (TPP +) which is logP-4.5, and the enrichment multiple is improved by 10 times when one carbon chain is added, mitochondrial Penetrating Peptide (MPP) which is KLALKLALKALKAALKLA and has 4-5 positive charges and can enter mitochondria through an electrostatic and membrane potential dual mechanism, and the concentration ratio of the mitochondria/cytoplasm can reach 50-200 after the ligand is coupled with a drug or a carrier. However, TPP + or MPP alone has problems of high positive charge toxicity, strong adsorption of plasma proteins, uncontrolled in vivo distribution, etc. In the prior art, patent CN120484249A discloses a fluorine-containing modified poly (sarcosinate) lipid, and a preparation method and application thereof. The fluorine-containing modified poly (sarcosinate) lipid obtained by chemically modifying poly (sarcosinate) lipid with different fluorine-containing groups can replace PEG lipid to prepare Lipid Nano Particles (LNP), and can be used for loading medicaments such as nucleic acid and the like, thereby achieving the purpose of improving the delivery performance of the medicaments. The patent mainly consists of 3 blocks, N-dialkyl chains are used as hydrophobic cores, polymyosine is used as a hydrophilic block, and CH 2CF3 is used as a liposome surface functional ligand for performance improvement, but the liposome has no good self-assembly performance and mitochondrial targeting effect. Disclosure of Invention Aiming at the problems existing in the prior art, the invention aims to design and provide a technical scheme of fluorinated poly-sarcosine mitochondrial targeting micelle, and a preparation method and application thereof. The scheme can reduce the Critical Micelle Concentration (CMC) of the micelle, solve the problems of advanced dissociation and drug leakage caused by blood dilution after intravenous injection, increase the permeation of the poly-sarcosine micelle at a tumor position, endow the micelle with better mitochondrial targeting capability on the premise of not introducing high positive charges, optimize the subcellular organelle targeting distribution efficiency, and overcome the immunogenicity risk, non-degradability and potential toxicity caused by using polyethylene glycol (PEG) as a hydrophilic block of the nano micelle. The invention is realized by the following technical scheme: The first aspect of the invention provides a fluorinated polyminosine mitochondria targeting micelle, which is self-assembled by taking a fluoroalkyl chain as a hydrophobic block and taking polyminosine as a hydrophilic block, wherein the general formula of the micelle is shown as formula (1): (1) Wherein m and n are positive integers. Further, the fluorinated polymyosine mitochondria-targeted micelle m=1, n=24. Further, the critical micelle concentration of the preferred structure of the t