Preparation Of Functionalized Nano-drug Delivery Carriers In Collaborative Treatment Research

Nano-drug delivery systems（DDSs）have the ability to solve the limitations of small-molecule anticancer drugs in the chemotherapy process,including the low concentration of drugs delivered to tumor sites and their toxicity to healthy tissues.Currently,researches on drug delivery mainly aims at precise targeting,precise dose delivery,and low toxicity to achieve the best therapeutic effect.In this paper,functional polymer drug delivery vectors with different tumor microenvironment responses were synthesized based on reversible addition-fragmentation chain transfer（RAFT）polymerization,and chemotherapy was combined with other treatment methods,so as to synergistically enhance the inhibitory effects on tumor.The main research contents of the thesis are as follows:1.Prepared the functionalized block copolymer poly（p-hydroxybenzaldehyde）-poly（methyl methacrylate）-poly（phenylboronic acid）-poly（imidazole）)（P（ALD）-g-DOX-b-PEG-b-PBA-VI.）for p H-responsive linked nanomedicine combined with photodynamic therapy.Through the substitution reaction between hydroxybenzaldehyde and p-nitrophenol,the aldehyde group can be effectively protected from being oxidized in a strong oxidizing environment during polymerization.The terminal aldehyde group reacted with the amino group of doxorubicin hydrochloride（DOX·HCl）to form a p H-sensitive imine bond,thereby carrying the anticancer drug DOX·HCl in a bonding manner.Polyethylene glycol（PEG）,due to its high biocompatibility and hydrophilicity,can effectively inhibit non-specific protein adsorption,thus improving the blood compatibility of the nanocomposite and prolonging their blood circulation time.Ligand4-toluene boronic acid as an active alternative ligand to increase bulkiness,imidazole group coordination CdTe quantum dots（QDs）as photosensitizers for photodynamic therapy,successfully Combination of chemotherapy and photodynamic therapy.The successful synthesis of the polymer was proved by transforming the polymer structure and morphology.The polymer has good p H responsiveness under different p H conditions,and the loaded DOX can be released in a weakly acidic environment.Therefore,the polymer is expected to become a good drug delivery carrier.2.Synthesis of a metal-polyphenol nano-drug delivery carrier for synergistic chemotherapy and chemokinetic therapy,polyphenol-modified block polymer poly（ethylene glycol methyl methacrylate）-poly（N-（3-aminopropyl））Methacrylamide)-poly（imidazole）（PEG-b-PPOH-b-VI）,which forms a stable core cross-linked structure with Fe³⁺through strong coordination.ZnO QDs were used to coordinate glucose oxidase（GOx）and doxorubicin hydrochloride（DOX·HCl）.After the cells are internalized,the slightly acidic environment at the tumor site dissociates the ZnO quantum dots and releases DOX and GOx.GOx acts on intracellular glucose to produce exogenous H₂O₂,and at the same time consumes the supply of glucose at the tumor site to achieve the effect of starvation treatment.After the imine bond is responsively broken,the metal reacts with H₂O₂ to produce toxic hydroxyl radicals（·OH）.By comparison,the combination of the two drug loading methods can effectively increase the drug loading of the carrier by about9.4%.In vitro cell experiments show that the increase in drug loading and chemokinetic treatment after entering the cells significantly inhibit cell growth.Compared with free DOX,the combination of chemotherapy and chemokinetics reduces the IC₅₀ value of cells by about 0.76±0.06.Therefore,it is expected to be an effective drug delivery vehicle.3.Designed GSH-responsive dual drug therapy imaging agent poly（ethyl methacrylate-SS-chlorambucil）-poly（ethylene glycol methyl methacrylate）-poly（diethylenetriaminepentaacetic acid）-Poly（phenylboronic acid）（PCBLMA-PEG-DTPA-PBA）.The hydrophobic drug chlorambucil（CBL）was loaded onto micelles in a bonding manner through glutathione（GSH）-responsive disulfide bonds,and Doxorubicin（DOX）and Rose Bengal（RB）were encapsulated into the micelles to enhance the antitumor effect.Then,the breakdown of the tumor microenvironment-responsive bond led to release of the drugs into the tumor tissue,in which DOX and CBL achieved dual-drug therapeutic effect together,while the released RB generated cytotoxic reactive oxygen species（~1O₂）for photodynamic therapy under visible light irradiation.Phenylboronic acid ligands targeting sialic acid could help micelles to be better endocytosed,and single photon emission computed tomography（SPECT）imaging was used to characterize the drug delivery and cumulative effect of the micelles in tumor sites.The imbalance of GSH and~1O₂produced by PDT treatment increased the oxidative stress in the cell.The synthesis of the polymer is determined by characterizing the polymer’s NMR and morphological characteristics（DLS,TEM）,analyzing the drug loading capacity（DLC）and drug loading efficiency（DLE）by ultraviolet visible spectroscopy.In vitro experiments confirmed the responsiveness of GSH and cytotoxicity.The results showed that the cell IC₅₀（0.56±0.08）of the drug carrier was significantly reduced compared with free DOX.Therefore,it shows that functional polymer micelles have good anti-tumor effect and broad application prospect.