Preparation And Application Of Smart DNA Micelles Based On Chemically Modified Nucleotide

Nucleic acids play an important role in many important molecular processes.DNA has good biocompatibility and programmability,and shows a good prospect in cancer treatment in recent years.However,the properties of DNA are limited by the structure of four kinds of natural base,which greatly reduces the scope of its application.The natural nucleic acid s containing four bases can already form the colorful world and the nucleic acids will be endowed with more functions with chemical modification.Ferrocene is a kind of metal organic compound with sandwich structure.It is hydrophobic,but can be oxidized to hydrophilic easily in acidic condition.DNA is a hydrophilic molecule,so it can be endowed with amphiphilic structure by the modification of ferrocene group.Amphiphilic DNA molecules can self-assemble into micelles through hydrophobic interaction in s olution.By adjusting the ratio of hydrophilic/hydrophobic segments of amphiphilic DNA micelles,micelles with different initial sizes can be obtained,which improves the designability of size and morphology of micelle materials in the synthesis process.I n addition,ferrocene modified amphiphilic DNA micelles are easily oxidized in acidic environment,resulting in shorter hydrophobic segment and size shrinkage,which makes them become acid responsive smart micelles.Therefore,based on the unique propertie s of ferrocene group,we designed and synthesized the amphiphilic DNA sequence containing ferrocene modification.On this basis,smart micelles with adjustable size and acid response ability were constructed,and their application in chemodynamic therapy w ere explored.The following text describes the specific research contents:(1)The hydrophobic artificial nucleotide containing ferrocene group was synthesized.And Then the artificial nucleotides were attached to the end of hydrophilic DNA aptamer which could target A549 lung cancer cells by DNA solid-phase synthesis to form amphiphilic DNA polymer.(2)The amphiphilic polymer can self-assemble into nucleic acid micelle in solution.The size and morphology of nucleic acid micelle with 3,5,7 and 15artificial nucleotides were characterized.It was found that the size of nucleic acid micelle formed by 7 artificial nucleotide s containing DNA was about 100 nm,which could meet the requirements of enhanced permeability and retention effect mediated tumor targeted accumulation.Next,we found that the nucleic acid micelle could be oxidized by H₂O₂ under the acidic condition of tumor,the artificial nucleotide changed from hydrophobic to hydrophilic,and the micelle size contracted to about10 nm,which had a good potential for tumor deep penetration.(3)The ferrocene group on nucleic acid micelle can catalyze Fenton reaction and realize chemodynamic therapy of tumor.Based on the potential of tumor accumulation and deep penetration of the nucleic acid micelle,we loaded glucose oxidase on it.Taking A549 xenograft tumor bearing mice as the model,we proved that the nucleic acid micelle has excellent ability of chemodynamic therapy.